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Regorafenib in Glioblastoma Recurrence: How to Deal With MR Imaging Treatments Changes

Regorafenib in Glioblastoma Recurrence: How to Deal With MR Imaging Treatments Changes MINI REVIEW published: 25 February 2022 doi: 10.3389/fradi.2021.790456 Regorafenib in Glioblastoma Recurrence: How to Deal With MR Imaging Treatments Changes 1,2 1 1 1 Simona Gaudino *, Giammaria Marziali , Carolina Giordano , Riccardo Gigli , 1 1 3 2,3 Giuseppe Varcasia , Francesca Magnani , Silvia Chiesa , Mario Balducci , 1 4 2,4 Alessandro Maria Costantini , Giuseppe Maria Della Pepa , Alessandro Olivi , 1 1,2 Rosellina Russo and Cesare Colosimo Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico 2 3 Universitario Agostino Gemelli IRCCS, Rome, Italy, Università Cattolica Sacro Cuore of Rome, Rome, Italy, Department of Diagnostic Imaging, Oncological Radiotherapy, and Hematology, UOC di Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, Institute of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, Rome, Italy The treatment of recurrent high-grade gliomas remains a major challenge of daily neuro-oncology practice, and imaging findings of new therapies may be challenging. Regorafenib is a multi-kinase inhibitor that has recently been introduced into clinical practice to treat recurrent glioblastoma, bringing with it a novel panel of MRI imaging findings. On the basis of the few data in the literature and on our personal experience, we have identified the main MRI changes during regorafenib therapy, and then, we defined Edited by: two different patterns, trying to create a simple summary line of the main changes of Nicoletta Anzalone, pathological tissue during therapy. We named these patterns, respectively, pattern A San Raffaele Hospital (IRCCS), Italy (less frequent, similar to classical progression disease) and pattern B (more frequent, Reviewed by: Federico Bruno, with decreased diffusivity and decrease contrast-enhancement). We have also reported University of L’Aquila, Italy MR changes concerning signal intensity on T1-weighted and T2-weighted images, SWI, *Correspondence: and perfusion imaging, derived from the literature (small series or case reports) and from Simona Gaudino our clinical experience. The clinical implication of these imaging modifications remains [email protected] to be defined, taking into account that we are still at the dawn in the evaluation of such Specialty section: imaging modifications. This article was submitted to Neuroradiology, Keywords: regorafenib, glioblastoma, MRI, treatment changes, imaging a section of the journal Frontiers in Radiology Received: 06 October 2021 INTRODUCTION AND BACKGROUND Accepted: 29 December 2021 Published: 25 February 2022 Glioblastoma (GB), previously called glioblastoma multiforme, is the most common malignant primary brain tumor in adults. Despite multimodality treatment comprising maximal safe Citation: Gaudino S, Marziali G, Giordano C, resection, radiotherapy, and concomitant and adjuvant chemotherapy, the best median survival is Gigli R, Varcasia G, Magnani F, in the range of 14 and 18 months and relapse occurs between 6 and 9 months in over 75% of patients Chiesa S, Balducci M, Costantini AM, (1). Indeed, conventional therapy has been supported by novel strategies as immunomodulators, Della Pepa GM, Olivi A, Russo R and immunotherapy, peptide, and mRNA vaccines (2, 3). Colosimo C (2022) Regorafenib in From the histological standpoint, GBs are infiltrating glial tumors, displaying abnormal glial Glioblastoma Recurrence: How to cells with variable morphology, high mitotic activity, microvascular proliferation, and necrosis Deal With MR Imaging Treatments with pseudopalisading patterns. Microvascular proliferation and necrosis are two critical histologic Changes. Front. Radiol. 1:790456. doi: 10.3389/fradi.2021.790456 features used for the differentiation between an anaplastic astrocytoma, WHO grade III, and a GB, Frontiers in Radiology | www.frontiersin.org 1 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes WHO grade IV. Early clinicopathological studies demonstrated are very active in angiogenesis (VEGFR1, VEGFR2, VEGFR3, that the degree of microvascular proliferation, as a surrogate and TIE2), cancer development and growth (KIT, RAF-1, BRAF, of tumor-driven neo-angiogenesis, correlated with survival in and BRAFV600E), and sustaining the tumor microenvironment patients with high-grade glial tumors (4). (PDGFR-alpha, PDGFR-beta, FGFR1, and FGFR2) (13). In Antiangiogenic approaches have been investigated in both in vivo models, REG demonstrated anti-angiogenic activity, primary and recurrent GB (2, 3, 5, 6) for recurrent GB inhibition of tumor growth, and metastasis (12, 14). In the phase bevacizumab (BEV) first and, more recently, regorafenib (REG) 2 REGOMA trial for first recurrence of a GB, REG increased the has been the most studied agents. REG is an oral multi- median OS from 5.6–7.4 months compared to lomustine (15), kinase inhibitor targeting VEGFR-1,−2,−3, tyrosine kinase with acceptable toxicity and treatment-related adverse events (56 with Ig and EGF (TIE2), platelet-derived growth factor and 40%). The 12-month Overall survival (OS) in the REG group receptors (PDGFR), Fibroblast growth factor receptors (FGFR), was twice that reported in the lomustine group with a substantial proto-oncogene receptor tyrosine kinase (KIT), Raf-1 Proto- and clinically meaningful reduction in the risk of death. Oncogene, Serine/Threonine Kinase (RAF-1), rearranged during transfection (RET), and BRAF, investigated in the randomized THE RANO CRITERIA AND THE CONCEPT phase II trial Regorafenib in Relapsed Glioblastoma (REGOMA) OF PSEUDO-RESPONSE and approved for the management of recurrent GB by the European Medicines Agency. Since then, the number of patients The response assessment in neuro-oncology (RANO) criteria receiving this agent is increasing, even outside trials, and few standardizes the radiologic assessment of treatment response in single-center experiences and case reports of REG treatment patients with GB, but they focus primarily on measurements in recurrent GB have been published (7). Moreover, MRI of contrast enhancement (CE), whereas the importance of non- modifications during REG are not yet well codified, and enhancing components of tumors is frequently overlooked (16). evaluation of GB response could not be straightforward, even for Weaknesses in these criteria have emerged with the introduction experienced neuroradiologists. Therefore, we provide insights of in the clinical practice of anti-angiogenic drugs. Their main MRI REG-related changes in recurrent GB. effects of stabilizing the immature and friable vasculature of the tumor and decreasing of rate of microvascular proliferation and the blood-brain barrier permeability translate into a dramatic ANTIANGIOGENIC THERAPY, CURRENT reduction in the tumor CE as well as reduction of edema on MRI GUIDELINE (17, 18). The initial interpretation of tumor response was not confirmed in two different clinical trials (19, 20), and the term The optimal treatment of recurrent GB remains controversial, pseudoresponse was designated to describe the decrease of the and options include surgery, re-irradiation, and systemic CE on MRI as the effect of the antiangiogenic treatment without therapy, alone or in combination (1, 8). Surgery for local a true antitumor effect (21). Regarding BEV, several articles have recurrence is reasonable followed by a second-line treatment. reported the changes induced by the drug on morphological Re-irradiation may be considered in selected cases, and there is sequences, as well as on diffusion-weighted imaging (DWI) and no recommended dose or type of radiation used in this setting. perfusion-weighted imaging (PWI), also assessing the association Temozolamide (TMZ) is the preferred chemotherapy option if between MRI pattern and patient survival. Less well-known is there has been a long interval between the end of adjuvant TMZ the effect of REG on morphological and non-morphological MRI and development of recurrent disease, particularly in patient sequences. Knowing the different ways of action of the two drugs, whose tumor is 06-methylguanine-DNA methyltransferase it is inductive to hypnotize that drug-induced MRI changes may (MGMT)-methylated. Nitrosourea-based treatments, such as be similar but not the same. carmustina and lomustine, have been widely used in tumor progression and as control in several studies. In 2009, the US MRI CHANGES IN REGORAFENIB Food and Drug Administration approved the use of BEV for the treatment of recurrent GB (8). BEV is a humanized monoclonal TREATMENT antibody directed to the isoform A of the vascular endothelial growth factor (VEGF) (9). Its therapeutic effect is blocking We propose two patterns of MRI changes in GB recurrence the process of angiogenesis, one of the main features of GB under BEV treatment (patterns A and B), comparing the MRI pathogenesis. Most recently, another anti-angiogenic, namely, immediately prior to REG onset and the next MRI. REG, that has shown efficacy in several cancers (10, 11), as To summarize these pattern, we relied on the literature well as preclinical glioma models (12), has been introduced in review (reported below in the text), and on our personal clinical practice. REG is a multikinase inhibitor that inhibits, experience based on 28 patients with recurrent GB. They among others, the VEGF receptors 1–3 (5). Tyrosine kinases were all isocitrate dehydrogenase (IDH) wild type, and 11/28 (TKs) are multiple membrane-bound and intracellular kinases methylation of MGMT promoter was present. All patients that are involved in normal cellular functions. Deregulated action received postoperative RT in combination with TMZ, according of TKs plays a relevant role in pathologic conditions as cancer. In to the STUPP regimen, and received REG as a last line treatment. in vitro biochemical or cellular assays, REG or its major human MRI exams had been acquired almost exclusively on 1.5T active metabolites has shown efficacy in inhibition of kinases that scanners, with highly variable protocols (having been acquired in Frontiers in Radiology | www.frontiersin.org 2 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes different canters), and were evaluated by neuroradiologists with DISCUSSION experience in neuro-oncology. The treatment of recurrent gliomas remains a major challenge To sum up the two patterns, we assessed morphological of daily neuro-oncology practice, and imaging findings of sequences as T2, FLAIR, T1, and T1 after gadolinium, as new therapies may be challenging. Novel therapies have led well as DWI and apparent diffusion coefficient (ADC) map, to the occurrence of interesting but sometimes confusing susceptibility-weighted imaging (SWI), and PWI, the latter post-treatment imaging appearances, as happened with BEV nowadays are part of many clinical standard glioma protocols. treatment and the coining of the term pseudoresponse. At first, Pattern A is similar to the classic progression disease MRI changes during BEV had puzzled neuroradiologists, as model, reported by increasing CE and increasing T2/FLAIR they presented differently from those observed during other signal abnormality. treatments in several MRI sequences. The first step was to catalog Pattern B holds MRI changes frequently reported as T2- the new MRI changes and then attempt to describe radiographic dominant growth, characterized by decreasing CE and increasing patterns of MRI changes and to correlate with outcome. Previous (relative or absolute) T2/FLAIR hyperintensity. Pattern B also studies have shown that most significant modifications during includes some MRI findings reported by case reports that, based BEV concerned proton diffusivity, CE, and T1 signal intensity on our experience, are more associated with this pattern (23, 24). evaluated with qualitative or quantitative methods. Therefore, specific MRI patterns including ADC hypointensity (in terms Pattern A of visual signal intensity and ADC histograms), presence of T2/FLAIR: there are no evident modifications of the signal T1 hyperintensity, and changes in T1 enhancing volume were intensity in the solid components of the tumor, the T2 signal proposed as radiographic prognostic models (25). intensity, already heterogeneous, can increase focally or diffusely, Recently, few studies reported MRI changes during REG mixed with a component of mild hypointensity, and already therapy, somewhat similar to what was observed for BEV, and a evident in previous MRI (Figure 1). “T2-dominant growth pattern,” a term coined for BEV, was also DWI/ADC: stable or new sporadic hyperintensity dots. associated with REG (26). However, REG studies were based on a T1: usually iso-hypointense, without evidence of small cohort and a few MRI sequences. From the literature review hyperintensities in the tumor area. (including case reports) and based on our clinical experience, SWI: black dots within the solid component. we reported two MRI progression patterns, containing more T1 after contrast: Pattern of CE similar to previous MRI exam, sequences as DWI, SWI, and PWI, and named patterns A and usually increase in size/extension. B. Figure 3 summarizes A and B patterns. PWI: high rCBV, somewhat stable or increase compared to Pattern A is similar to classic progression disease. previous MRI. There is a trend toward an increase in T2/FLAIR signal Edema: increase. intensity, presumed to represent edema and tumor infiltration growth (27). Pattern B DWI changes appear less pronounced than in pattern B, T2/FLAIR: increase in the T2 component, relative to the with new or increased small areas of hyperintensity, not reduction of the enhancing component, and often absolute for a always corresponding to less diffusivity on ADC maps. As significant increase of T2 abnormality compared to pre-Reg MRI. previously mentioned, focal restricted diffusion may correlate However, we noticed that, under a careful evaluation of the T2-w with increased tumor cellularity, as well as with ischemia, or other images, tumor components that decrease contrast enhancement treatment changes (cell death, necrosis, and hemorrhage), which also decrease T2 signal intensity, with better differentiation from affect the Brownian movement of water (28). the hyperintense perifocal edema (Figure 2). On SWI, there are an increasing number of the so-called DWI/ADC: marked hyperintensity on DWI (with equally intratumoral black dots, intratumoral susceptibility signals, or marked hypointensity on ADC map) of tumor components SWI-positive tumor pixels (29), which have been proposed as showing decreased signal intensity on T2. an early biomarker of tumor progression for GB treated with T1: no visually noticeable changes. postoperative chemo-radiotherapy (TMZ) (30). SWI: hypointense rim surrounding the hyperintense tissue On T1-w after gadolinium administration, CE areas usually on DWI, smooth, and both complete and incomplete, often increase in size/extension. It has been well established that CE corresponding to marginal enhancement on T1 after gadolinium. most often corresponds to the highest density of tumor tissue and T1 after contrast: overall decrease of contrast enhancement the most aggressive histological features in gliomas (31). of the target lesions, with marginal or dot-like enhancing Perfusion MRI can be used to image neovascularization, component, residual or of new-onset. as a hallmark of tumor progression. The abnormal vascular PWI: reduced relative cerebral blood volume (rCBV) proliferation increases the amount of blood per brain tissue in the DWI hyperintensity component. Outside the DWI volume unit, and, consequently, relative CBV was significantly hyperintensity usually decrease or just mild increase of rCBV. higher in patients with recurrent GB (32, 33). There are, however, reported cases of increased rCBV (22, 23). Pattern B includes most features of the “T2-dominant growth An overall decrease of the peritumoral edema, without an pattern.” In particular, the main finding in pattern B was the increase of steroid dosage, was observed in some patients. marked hyperintensity of signal on DWI, corresponding to low Frontiers in Radiology | www.frontiersin.org 3 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes FIGURE 1 | Pattern A. MRI changes in recurrent high grade glioma under regorafenib, pattern A. MRI scans performed at baseline (top image) and 3 months after first administration of REG therapy (bottom image). T2-weighted images (a,a’), T1-weighted images with gadolinium (b,b’), DWI images (c,c’), apparent diffusion coefficient (d,d’), and SWI images (e,e’) are shown from left to right. The 3-month follow-up showed increase in size, more than 25%, of enhancing tumor in the left temporo-mesial area, and progressive extension into the ipsilateral parahippocampal gyrus. T2 signal intensity was similar to the previous MR exam, but contained focal hyperintensities on DWI (corresponding to low ADC values), and multiple black dots on SWI. FIGURE 2 | Pattern B. MRI changes in recurrent high grade glioma under regorafenib, pattern B. MRI scans performed at baseline (top image) and after six months (bottom image) from the first administration of REG therapy. T2w images (a,a’), contrast enhanced T1w images (b,b’), diffusion-weighted b1000 (c,c’), apparent diffusion coefficients (ADC) map (d,d’), SWI images (e,e’), and color-coded perfusion map (f,f’) are shown from left to right. On 6-month follow-up MRI, the previously enhanced tumor component showed a dramatically absence of CE, diffusion restriction on DWI and ADC map, and decrease signal on corresponding T2 image, surrounding by a thin hypointense rim on SWI, and peripheral contrast enhancement on T1-wi after gadolinium. There was also a decrease of peritumoral edema. Frontiers in Radiology | www.frontiersin.org 4 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes FIGURE 3 | Summary table of MRI changes during REG. The patterns defined as A and B are divided into two columns, and the MRI sign changes most frequently reported in the literature have been graphically identified with a thicker cell margin. signal intensity on T2-wi, and marked decrease of CE. This development of a rich vascular system with regression of pattern was similar to what was described for BEV treatment and hypervascularization in the tumor (38). referred to as “stroke-like” DWI restriction. However, although Although recent studies indicate poor performance of DWI hyperintensity in BEV was (pathologically) reported as regorafenib in recurrent high-grade glioma (39), it may be coagulative necrosis surrounded by the viable hypercellular potential for clinical utility to understand whether the two tumor (34), a precise histological correlation and interpretation MRI patterns may correlate with different survival. Taking into of modification under REG is still uncertain. Mansour et al. (23) account the current relative lack of REG cases reported in the hypothesized that the diffusion restriction could be explained by literature, it will probably take several studies to identify and constant hemorrhagic diapedesis. In addition, the reduction of categorize radiographic patterns to respond to REG, as happened CE has already been associated with antiangiogenic agents (35). with BEV (40). Certainly, more extensive researches on a larger Regarding the hypointense rim on SWI, it was thinner patient cohort are necessary, as well as the combination of a and less marked, as reported by Mansour et al. on the first large number of MRI data coming from morphological and MRI after REG, more similar to what was demonstrated in non-morphological sequences (DWI, PWI, and MRS) (41), also the subsequent follow-up MRI (23). The black rim on SWI considering the opportunity of processing multi-parametric data has been described in many brain diseases, as in cerebral through deep learning to arrive at more definite conclusions (42). abscesses, GB, and progressive multifocal leukoencephalopathy, respectively, representing granulation tissue, blood product, or CONCLUSION neuroinflammatory process (36, 37). We do not currently know the significance of this hypointensity, but we may postulate that MRI assessment in recurrent GB treated with REG remains a it may be due to one or a combination of the mentioned above challenge, and radiologists have to be aware of these new post causes, as well as to free radicals or other causes of susceptibility. treatment imaging. A more extensive and rigorous collection In pattern B, predominantly observed PWI modification was and assessment of multiparametric MR data and identification hypoperfusion. As reported for BEV, decreased perfusion was of MRI patterns correlated with clinical outcome are needed to probably due to the antiangiogenetic action that prevents the overcome this challenge. Frontiers in Radiology | www.frontiersin.org 5 February 2022 | Volume 1 | Article 790456 Gaudino et al. 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Radiologic progression of glioblastoma under therapy-an exploratory publication in this journal is cited, in accordance with accepted academic practice. analysis of AVAglio. Neuro Oncol. (2018) 20:557–66. doi: 10.1093/neuonc/no No use, distribution or reproduction is permitted which does not comply with these x162 terms. Frontiers in Radiology | www.frontiersin.org 7 February 2022 | Volume 1 | Article 790456 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Radiology Unpaywall

Regorafenib in Glioblastoma Recurrence: How to Deal With MR Imaging Treatments Changes

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MINI REVIEW published: 25 February 2022 doi: 10.3389/fradi.2021.790456 Regorafenib in Glioblastoma Recurrence: How to Deal With MR Imaging Treatments Changes 1,2 1 1 1 Simona Gaudino *, Giammaria Marziali , Carolina Giordano , Riccardo Gigli , 1 1 3 2,3 Giuseppe Varcasia , Francesca Magnani , Silvia Chiesa , Mario Balducci , 1 4 2,4 Alessandro Maria Costantini , Giuseppe Maria Della Pepa , Alessandro Olivi , 1 1,2 Rosellina Russo and Cesare Colosimo Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Institute of Radiology, Fondazione Policlinico 2 3 Universitario Agostino Gemelli IRCCS, Rome, Italy, Università Cattolica Sacro Cuore of Rome, Rome, Italy, Department of Diagnostic Imaging, Oncological Radiotherapy, and Hematology, UOC di Radioterapia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, Institute of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, Rome, Italy The treatment of recurrent high-grade gliomas remains a major challenge of daily neuro-oncology practice, and imaging findings of new therapies may be challenging. Regorafenib is a multi-kinase inhibitor that has recently been introduced into clinical practice to treat recurrent glioblastoma, bringing with it a novel panel of MRI imaging findings. On the basis of the few data in the literature and on our personal experience, we have identified the main MRI changes during regorafenib therapy, and then, we defined Edited by: two different patterns, trying to create a simple summary line of the main changes of Nicoletta Anzalone, pathological tissue during therapy. We named these patterns, respectively, pattern A San Raffaele Hospital (IRCCS), Italy (less frequent, similar to classical progression disease) and pattern B (more frequent, Reviewed by: Federico Bruno, with decreased diffusivity and decrease contrast-enhancement). We have also reported University of L’Aquila, Italy MR changes concerning signal intensity on T1-weighted and T2-weighted images, SWI, *Correspondence: and perfusion imaging, derived from the literature (small series or case reports) and from Simona Gaudino our clinical experience. The clinical implication of these imaging modifications remains [email protected] to be defined, taking into account that we are still at the dawn in the evaluation of such Specialty section: imaging modifications. This article was submitted to Neuroradiology, Keywords: regorafenib, glioblastoma, MRI, treatment changes, imaging a section of the journal Frontiers in Radiology Received: 06 October 2021 INTRODUCTION AND BACKGROUND Accepted: 29 December 2021 Published: 25 February 2022 Glioblastoma (GB), previously called glioblastoma multiforme, is the most common malignant primary brain tumor in adults. Despite multimodality treatment comprising maximal safe Citation: Gaudino S, Marziali G, Giordano C, resection, radiotherapy, and concomitant and adjuvant chemotherapy, the best median survival is Gigli R, Varcasia G, Magnani F, in the range of 14 and 18 months and relapse occurs between 6 and 9 months in over 75% of patients Chiesa S, Balducci M, Costantini AM, (1). Indeed, conventional therapy has been supported by novel strategies as immunomodulators, Della Pepa GM, Olivi A, Russo R and immunotherapy, peptide, and mRNA vaccines (2, 3). Colosimo C (2022) Regorafenib in From the histological standpoint, GBs are infiltrating glial tumors, displaying abnormal glial Glioblastoma Recurrence: How to cells with variable morphology, high mitotic activity, microvascular proliferation, and necrosis Deal With MR Imaging Treatments with pseudopalisading patterns. Microvascular proliferation and necrosis are two critical histologic Changes. Front. Radiol. 1:790456. doi: 10.3389/fradi.2021.790456 features used for the differentiation between an anaplastic astrocytoma, WHO grade III, and a GB, Frontiers in Radiology | www.frontiersin.org 1 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes WHO grade IV. Early clinicopathological studies demonstrated are very active in angiogenesis (VEGFR1, VEGFR2, VEGFR3, that the degree of microvascular proliferation, as a surrogate and TIE2), cancer development and growth (KIT, RAF-1, BRAF, of tumor-driven neo-angiogenesis, correlated with survival in and BRAFV600E), and sustaining the tumor microenvironment patients with high-grade glial tumors (4). (PDGFR-alpha, PDGFR-beta, FGFR1, and FGFR2) (13). In Antiangiogenic approaches have been investigated in both in vivo models, REG demonstrated anti-angiogenic activity, primary and recurrent GB (2, 3, 5, 6) for recurrent GB inhibition of tumor growth, and metastasis (12, 14). In the phase bevacizumab (BEV) first and, more recently, regorafenib (REG) 2 REGOMA trial for first recurrence of a GB, REG increased the has been the most studied agents. REG is an oral multi- median OS from 5.6–7.4 months compared to lomustine (15), kinase inhibitor targeting VEGFR-1,−2,−3, tyrosine kinase with acceptable toxicity and treatment-related adverse events (56 with Ig and EGF (TIE2), platelet-derived growth factor and 40%). The 12-month Overall survival (OS) in the REG group receptors (PDGFR), Fibroblast growth factor receptors (FGFR), was twice that reported in the lomustine group with a substantial proto-oncogene receptor tyrosine kinase (KIT), Raf-1 Proto- and clinically meaningful reduction in the risk of death. Oncogene, Serine/Threonine Kinase (RAF-1), rearranged during transfection (RET), and BRAF, investigated in the randomized THE RANO CRITERIA AND THE CONCEPT phase II trial Regorafenib in Relapsed Glioblastoma (REGOMA) OF PSEUDO-RESPONSE and approved for the management of recurrent GB by the European Medicines Agency. Since then, the number of patients The response assessment in neuro-oncology (RANO) criteria receiving this agent is increasing, even outside trials, and few standardizes the radiologic assessment of treatment response in single-center experiences and case reports of REG treatment patients with GB, but they focus primarily on measurements in recurrent GB have been published (7). Moreover, MRI of contrast enhancement (CE), whereas the importance of non- modifications during REG are not yet well codified, and enhancing components of tumors is frequently overlooked (16). evaluation of GB response could not be straightforward, even for Weaknesses in these criteria have emerged with the introduction experienced neuroradiologists. Therefore, we provide insights of in the clinical practice of anti-angiogenic drugs. Their main MRI REG-related changes in recurrent GB. effects of stabilizing the immature and friable vasculature of the tumor and decreasing of rate of microvascular proliferation and the blood-brain barrier permeability translate into a dramatic ANTIANGIOGENIC THERAPY, CURRENT reduction in the tumor CE as well as reduction of edema on MRI GUIDELINE (17, 18). The initial interpretation of tumor response was not confirmed in two different clinical trials (19, 20), and the term The optimal treatment of recurrent GB remains controversial, pseudoresponse was designated to describe the decrease of the and options include surgery, re-irradiation, and systemic CE on MRI as the effect of the antiangiogenic treatment without therapy, alone or in combination (1, 8). Surgery for local a true antitumor effect (21). Regarding BEV, several articles have recurrence is reasonable followed by a second-line treatment. reported the changes induced by the drug on morphological Re-irradiation may be considered in selected cases, and there is sequences, as well as on diffusion-weighted imaging (DWI) and no recommended dose or type of radiation used in this setting. perfusion-weighted imaging (PWI), also assessing the association Temozolamide (TMZ) is the preferred chemotherapy option if between MRI pattern and patient survival. Less well-known is there has been a long interval between the end of adjuvant TMZ the effect of REG on morphological and non-morphological MRI and development of recurrent disease, particularly in patient sequences. Knowing the different ways of action of the two drugs, whose tumor is 06-methylguanine-DNA methyltransferase it is inductive to hypnotize that drug-induced MRI changes may (MGMT)-methylated. Nitrosourea-based treatments, such as be similar but not the same. carmustina and lomustine, have been widely used in tumor progression and as control in several studies. In 2009, the US MRI CHANGES IN REGORAFENIB Food and Drug Administration approved the use of BEV for the treatment of recurrent GB (8). BEV is a humanized monoclonal TREATMENT antibody directed to the isoform A of the vascular endothelial growth factor (VEGF) (9). Its therapeutic effect is blocking We propose two patterns of MRI changes in GB recurrence the process of angiogenesis, one of the main features of GB under BEV treatment (patterns A and B), comparing the MRI pathogenesis. Most recently, another anti-angiogenic, namely, immediately prior to REG onset and the next MRI. REG, that has shown efficacy in several cancers (10, 11), as To summarize these pattern, we relied on the literature well as preclinical glioma models (12), has been introduced in review (reported below in the text), and on our personal clinical practice. REG is a multikinase inhibitor that inhibits, experience based on 28 patients with recurrent GB. They among others, the VEGF receptors 1–3 (5). Tyrosine kinases were all isocitrate dehydrogenase (IDH) wild type, and 11/28 (TKs) are multiple membrane-bound and intracellular kinases methylation of MGMT promoter was present. All patients that are involved in normal cellular functions. Deregulated action received postoperative RT in combination with TMZ, according of TKs plays a relevant role in pathologic conditions as cancer. In to the STUPP regimen, and received REG as a last line treatment. in vitro biochemical or cellular assays, REG or its major human MRI exams had been acquired almost exclusively on 1.5T active metabolites has shown efficacy in inhibition of kinases that scanners, with highly variable protocols (having been acquired in Frontiers in Radiology | www.frontiersin.org 2 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes different canters), and were evaluated by neuroradiologists with DISCUSSION experience in neuro-oncology. The treatment of recurrent gliomas remains a major challenge To sum up the two patterns, we assessed morphological of daily neuro-oncology practice, and imaging findings of sequences as T2, FLAIR, T1, and T1 after gadolinium, as new therapies may be challenging. Novel therapies have led well as DWI and apparent diffusion coefficient (ADC) map, to the occurrence of interesting but sometimes confusing susceptibility-weighted imaging (SWI), and PWI, the latter post-treatment imaging appearances, as happened with BEV nowadays are part of many clinical standard glioma protocols. treatment and the coining of the term pseudoresponse. At first, Pattern A is similar to the classic progression disease MRI changes during BEV had puzzled neuroradiologists, as model, reported by increasing CE and increasing T2/FLAIR they presented differently from those observed during other signal abnormality. treatments in several MRI sequences. The first step was to catalog Pattern B holds MRI changes frequently reported as T2- the new MRI changes and then attempt to describe radiographic dominant growth, characterized by decreasing CE and increasing patterns of MRI changes and to correlate with outcome. Previous (relative or absolute) T2/FLAIR hyperintensity. Pattern B also studies have shown that most significant modifications during includes some MRI findings reported by case reports that, based BEV concerned proton diffusivity, CE, and T1 signal intensity on our experience, are more associated with this pattern (23, 24). evaluated with qualitative or quantitative methods. Therefore, specific MRI patterns including ADC hypointensity (in terms Pattern A of visual signal intensity and ADC histograms), presence of T2/FLAIR: there are no evident modifications of the signal T1 hyperintensity, and changes in T1 enhancing volume were intensity in the solid components of the tumor, the T2 signal proposed as radiographic prognostic models (25). intensity, already heterogeneous, can increase focally or diffusely, Recently, few studies reported MRI changes during REG mixed with a component of mild hypointensity, and already therapy, somewhat similar to what was observed for BEV, and a evident in previous MRI (Figure 1). “T2-dominant growth pattern,” a term coined for BEV, was also DWI/ADC: stable or new sporadic hyperintensity dots. associated with REG (26). However, REG studies were based on a T1: usually iso-hypointense, without evidence of small cohort and a few MRI sequences. From the literature review hyperintensities in the tumor area. (including case reports) and based on our clinical experience, SWI: black dots within the solid component. we reported two MRI progression patterns, containing more T1 after contrast: Pattern of CE similar to previous MRI exam, sequences as DWI, SWI, and PWI, and named patterns A and usually increase in size/extension. B. Figure 3 summarizes A and B patterns. PWI: high rCBV, somewhat stable or increase compared to Pattern A is similar to classic progression disease. previous MRI. There is a trend toward an increase in T2/FLAIR signal Edema: increase. intensity, presumed to represent edema and tumor infiltration growth (27). Pattern B DWI changes appear less pronounced than in pattern B, T2/FLAIR: increase in the T2 component, relative to the with new or increased small areas of hyperintensity, not reduction of the enhancing component, and often absolute for a always corresponding to less diffusivity on ADC maps. As significant increase of T2 abnormality compared to pre-Reg MRI. previously mentioned, focal restricted diffusion may correlate However, we noticed that, under a careful evaluation of the T2-w with increased tumor cellularity, as well as with ischemia, or other images, tumor components that decrease contrast enhancement treatment changes (cell death, necrosis, and hemorrhage), which also decrease T2 signal intensity, with better differentiation from affect the Brownian movement of water (28). the hyperintense perifocal edema (Figure 2). On SWI, there are an increasing number of the so-called DWI/ADC: marked hyperintensity on DWI (with equally intratumoral black dots, intratumoral susceptibility signals, or marked hypointensity on ADC map) of tumor components SWI-positive tumor pixels (29), which have been proposed as showing decreased signal intensity on T2. an early biomarker of tumor progression for GB treated with T1: no visually noticeable changes. postoperative chemo-radiotherapy (TMZ) (30). SWI: hypointense rim surrounding the hyperintense tissue On T1-w after gadolinium administration, CE areas usually on DWI, smooth, and both complete and incomplete, often increase in size/extension. It has been well established that CE corresponding to marginal enhancement on T1 after gadolinium. most often corresponds to the highest density of tumor tissue and T1 after contrast: overall decrease of contrast enhancement the most aggressive histological features in gliomas (31). of the target lesions, with marginal or dot-like enhancing Perfusion MRI can be used to image neovascularization, component, residual or of new-onset. as a hallmark of tumor progression. The abnormal vascular PWI: reduced relative cerebral blood volume (rCBV) proliferation increases the amount of blood per brain tissue in the DWI hyperintensity component. Outside the DWI volume unit, and, consequently, relative CBV was significantly hyperintensity usually decrease or just mild increase of rCBV. higher in patients with recurrent GB (32, 33). There are, however, reported cases of increased rCBV (22, 23). Pattern B includes most features of the “T2-dominant growth An overall decrease of the peritumoral edema, without an pattern.” In particular, the main finding in pattern B was the increase of steroid dosage, was observed in some patients. marked hyperintensity of signal on DWI, corresponding to low Frontiers in Radiology | www.frontiersin.org 3 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes FIGURE 1 | Pattern A. MRI changes in recurrent high grade glioma under regorafenib, pattern A. MRI scans performed at baseline (top image) and 3 months after first administration of REG therapy (bottom image). T2-weighted images (a,a’), T1-weighted images with gadolinium (b,b’), DWI images (c,c’), apparent diffusion coefficient (d,d’), and SWI images (e,e’) are shown from left to right. The 3-month follow-up showed increase in size, more than 25%, of enhancing tumor in the left temporo-mesial area, and progressive extension into the ipsilateral parahippocampal gyrus. T2 signal intensity was similar to the previous MR exam, but contained focal hyperintensities on DWI (corresponding to low ADC values), and multiple black dots on SWI. FIGURE 2 | Pattern B. MRI changes in recurrent high grade glioma under regorafenib, pattern B. MRI scans performed at baseline (top image) and after six months (bottom image) from the first administration of REG therapy. T2w images (a,a’), contrast enhanced T1w images (b,b’), diffusion-weighted b1000 (c,c’), apparent diffusion coefficients (ADC) map (d,d’), SWI images (e,e’), and color-coded perfusion map (f,f’) are shown from left to right. On 6-month follow-up MRI, the previously enhanced tumor component showed a dramatically absence of CE, diffusion restriction on DWI and ADC map, and decrease signal on corresponding T2 image, surrounding by a thin hypointense rim on SWI, and peripheral contrast enhancement on T1-wi after gadolinium. There was also a decrease of peritumoral edema. Frontiers in Radiology | www.frontiersin.org 4 February 2022 | Volume 1 | Article 790456 Gaudino et al. Regorafenib in Glioblastoma: Treatment Changes FIGURE 3 | Summary table of MRI changes during REG. The patterns defined as A and B are divided into two columns, and the MRI sign changes most frequently reported in the literature have been graphically identified with a thicker cell margin. signal intensity on T2-wi, and marked decrease of CE. This development of a rich vascular system with regression of pattern was similar to what was described for BEV treatment and hypervascularization in the tumor (38). referred to as “stroke-like” DWI restriction. However, although Although recent studies indicate poor performance of DWI hyperintensity in BEV was (pathologically) reported as regorafenib in recurrent high-grade glioma (39), it may be coagulative necrosis surrounded by the viable hypercellular potential for clinical utility to understand whether the two tumor (34), a precise histological correlation and interpretation MRI patterns may correlate with different survival. Taking into of modification under REG is still uncertain. Mansour et al. (23) account the current relative lack of REG cases reported in the hypothesized that the diffusion restriction could be explained by literature, it will probably take several studies to identify and constant hemorrhagic diapedesis. In addition, the reduction of categorize radiographic patterns to respond to REG, as happened CE has already been associated with antiangiogenic agents (35). with BEV (40). Certainly, more extensive researches on a larger Regarding the hypointense rim on SWI, it was thinner patient cohort are necessary, as well as the combination of a and less marked, as reported by Mansour et al. on the first large number of MRI data coming from morphological and MRI after REG, more similar to what was demonstrated in non-morphological sequences (DWI, PWI, and MRS) (41), also the subsequent follow-up MRI (23). The black rim on SWI considering the opportunity of processing multi-parametric data has been described in many brain diseases, as in cerebral through deep learning to arrive at more definite conclusions (42). abscesses, GB, and progressive multifocal leukoencephalopathy, respectively, representing granulation tissue, blood product, or CONCLUSION neuroinflammatory process (36, 37). We do not currently know the significance of this hypointensity, but we may postulate that MRI assessment in recurrent GB treated with REG remains a it may be due to one or a combination of the mentioned above challenge, and radiologists have to be aware of these new post causes, as well as to free radicals or other causes of susceptibility. treatment imaging. A more extensive and rigorous collection In pattern B, predominantly observed PWI modification was and assessment of multiparametric MR data and identification hypoperfusion. As reported for BEV, decreased perfusion was of MRI patterns correlated with clinical outcome are needed to probably due to the antiangiogenetic action that prevents the overcome this challenge. Frontiers in Radiology | www.frontiersin.org 5 February 2022 | Volume 1 | Article 790456 Gaudino et al. 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Radiologic progression of glioblastoma under therapy-an exploratory publication in this journal is cited, in accordance with accepted academic practice. analysis of AVAglio. Neuro Oncol. (2018) 20:557–66. doi: 10.1093/neuonc/no No use, distribution or reproduction is permitted which does not comply with these x162 terms. Frontiers in Radiology | www.frontiersin.org 7 February 2022 | Volume 1 | Article 790456

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