Review of Cerebral Radiotherapy‐Induced Vasculopathy in Pediatric and Adult Patients

Radiation therapy (RT) causes radiation‐induced vasculopathy, which requires clinicians to identify and manage this side effect in pediatric and adult patients. This article reviews previous findings about the pathophysiology of RT‐induced vascular injury, including endothelial cell injury, oxidative stress, inflammatory cytokines, angiogenic pathways, and remodeling. The vasculopathy is categorized into ischemic vasculopathy, hemorrhagic vasculopathy, carotid artery injury, and other malformations (cavernous malformations and aneurysms) in populations of pediatric and adult patients separately. The prevention and management of this RT‐induced side effect are also discussed. The article summarizes the distribution and risk factors of different types of RT‐induced vasculopathy. This will help clinicians identify high‐risk patients with corresponding vasculopathy subtypes to deduce prevention and treatment strategies accordingly.


Introduction
Radiation therapy (RT), a significant development in the nonsurgical treatment of brain tumors and facial neoplasms in past decades, now plays a vital role in treating local central nervous system (CNS) disease and improving overall survival in cancers.It is also being used in treating functional disorders (e.g., trigeminal neuralgia) and arteriovenous malformations.Selectively delivering radiation to the target tissue with minimally involving DOI: 10.1002/adbi.202300179 the surrounding nontarget tissue is the objective of RT With the advancement of radiation technology, RT is administered more precisely nowadays.But the adverse effects of RT caused by injury to surrounding tissues are still common.One of the most common adverse effects after RT is angiopathy, which is the consequence of vascular injury from radiation.Specifically, vascular steno-occlusive changes, [1] cerebral hemorrhage, aneurysm formation, and other vascular malformations have been observed in adults and pediatric cases. [2]Here, we review radiation-induced vasculopathy and discuss the pathophysiology, clinical incidence, risk factors, prevention, and management of each type of vasculopathy in pediatric and adult patients.

Radiation Effects on Endothelial Cells
Radiation impacts not just cancer cells, but also healthy cells that are actively dividing, including the vascular endothelial, gastrointestinal tract, and hematopoietic stem cells, etc., located in the irradiated area.Endothelial cells react to radiation in several ways depending on the time after radiation and the radiation dose. [3]cute vascular injury presents in days to weeks following RT, whereas chronic effects can take months to years to be found.In the rat model, more than 15% of endothelia were lost after 200 Gy radiation during the first day and the continuous endothelial loss lasts for months. [4]During the initial phase following radiation exposure, the blood-brain barrier is compromised, leading to the development of vasogenic edema and a hypoxic environment within the brain tissue. [2]Acute thrombus formation and hemorrhage may also present in the setting of endothelial injury. [5]Chronic physiological changes are mainly the process of vascular remodeling, which involves alterations in the size, shape, composition, and reactivity of vascular cells and extracellular matrix components. [6]When reflected on imaging findings, steno-occlusive changes, cerebral hemorrhage, aneurysm formation, and lacunar lesions have been observed as chronic vasculopathy in the brain after RT Chronic vasculopathy reflects endothelial cell senescence in the cerebral vessel, which is more common in the CNS.
The degree of endothelial cell differentiations also defines the behaviors of vessels after RT. [7,8] Given the higher proportion of undifferentiated endothelial cells in children, different vasculopathy patterns in adult, and pediatric patients have been reported.

Radiation-Induced Effects on Reactive Oxygen Species (ROS) and Cytokines
Increased intracellular levels of oxidative stress are implicated in endothelial vascular injury. [9,10]Oxidative stress is mediated by reactive oxygen species, including hydroxide, superoxide, and hydroxyl radicals which are products of water molecules' radiolysis.RT-induced ROS production interferes with the vasomotor vessel response and the endothelium's structure. [9,10]T also induces inflammatory cytokines secretion.The radiation-induced activation of the nuclear factor-kappa B (NF-B) pathway is the main mechanism of endothelial activation. [11]t the same time, RT potentiates the secretion of interleukin (IL)−1, IL-6, TNF-, and TGF-.Among all the RT-induced cytokines, TGF- is one of the most important factors promoting the vasculature's remodeling.Even low-dose radiation induces TGF- activation.TGF- mediates multiple vascular remodeling changes, including epithelial cell growth, mesenchymal cell proliferation, and extracellular matrix synthesis. [12]It may lead to vessel stenosis, increase the risk of ischemic events in the long term, and contribute to Moyamoya disease.Regarding the thromboembolic process, RT also potentiates the production of von Willebrand factor and thromboxane, which mediates thrombosis in the arteries by activating platelets. [13]

The Effect of Radiation on Angiogenic Pathways and Remodeling
Ionizing radiation affects angiogenesis, the process of new blood vessel formation.This process involves endothelial cells' migration, growth, and differentiation. [18]An animal study showed arterial aneurysmal formation, endothelial denudation, thrombus formation, and reduced blood flow in the vessels exposed to highdose single-fraction radiation. [14]In a rat model, increased VEGF expression is observed after RT, which critically affects vascular and extravascular remodeling. [15]In a bovine model, radiation induces the transcription of genes encoding the basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF)-B, and both are essential angiogenesis genes to mediate the remodeling of the vasculature. [16]It is also reported that ionizing radiation promotes the polarization of dermal microvascular endothelial cells into a profibrogenic phenotype through TGF-1/TGF--RII/Smad3 pathway. [17]In an in vitro study using human umbilical vein endothelial cells, radiation induces the expression of pro-angiogenic microRNAs. [18]The pro-angiogenic and pro-fibrogenic effects from RT will disrupt the normal vessel structure and affect laminar blood flow within vessels.

Radiation Dose and Vasculopathy
Different doses of radiation will induce endothelial cell injury with disparate pathogenesis.It has been reported that radiation therapy elicits vascular inflammatory processes in a manner that is dependent on both the dose and duration of exposure. [19,20] higher dose of RT causes edema, thrombosis, hemorrhage in vessels, and necrosis of vessels, [21] which increases the risk of vessel rupture in the acute phase.In the chronic setting, hyaline necrosis of arteries and vasa vasorum pathology will cause other ischemic or hemorrhagic vasculopathy processes.On the contrary, a low dose and duration of RT are less likely to induce evident changes in the acute phase.Less commonly, telangiectasia formation and hemorrhagic infarcts may be observed years after RT. [21] Around 90% of endothelial cells will go through mitotic cell death without apoptosis after exposure to conventionally fractionated RT.A larger fractional dose of radiation will trigger cell death through apoptosis. [22]A systematic review of 81 children, revealed that the rates of both overall and severe vasculopathy were 9.9% and 6.2%, respectively.These effects typically occurred ≈2 years after radiation treatment.Risk factors for the development of vasculopathy included a radiation dose greater than 45 Gy to the optic chiasm and a tumor location in the suprasellar region. [23]In a series of 16 craniopharyngiomas patients treated with proton therapy, a major association between average/maximum values of linear energy transfer and vascular structures change are observed.Conversely, radiation locations were not found to be correlated to the presence of vasculopathy. [24]mong the pediatric cancer patients who had stroke present in a delayed phase after RT, the Childhood Cancer Survivor Study identified the radiation dose as the major risk factor. [25]Regarding adult patients, a comparative study examining a cohort of 462 pituitary adenoma patients who received cranial RT showed that high-dose RT is significantly associated with higher rates of stroke. [26]n summary, cranial RT causes vasculopathy through direct endothelial injury, inducing ROS production, proinflammatory/fibrogenic cytokines secretion, and interfering with angiogenic pathways and vascular remodeling in a dosedependent manner (Figure 1).Different pathologies can be observed in acute and chronic phase (Figure 2).Researchers should focus on minimizing the radiation dose to surrounding tissues, to mitigate the occurrence and intensity of vasculopathy in pediatric patients in the future.

Radiation-Induced Vasculopathy in Pediatric Patients
The development of radiation therapy has significantly improved the prognosis and survival of children with brain tumors.However, significant radiation-related late effects, especially vasculopathy, are present in long-term survivors of childhood brain cancer. [27,28]The vasculopathy subtype distribution and correlation to the dose of radiation therapy differ in adults and pediatric patients.

Radiation-Induced Ischemic Vasculopathy
Ischemic vasculopathy is a well-observed post-RT complication, with cerebral vessel steno-occlusive changes and ischemic stroke.RT causes vessel steno-occlusive changes, which begin with vascular endothelial thickening and fibrosis.The endothelial injury from RT also induces chronic inflammation, thrombosis, plaque formation, and accelerated atherosclerosis. [29]Children with radiation-induced vasculopathy carry a higher risk of having an ischemic stroke, with a 5 year recurrence rate of 66%. [30] study assessed RT-induced ischemic vasculopathy and stroke in 644 pediatric patients with CNS tumors treated with proton therapy between 2006 and 2015.After three years of surveillance, 13.1% of pediatric patients receiving ≥54 Cobalt Gray Equivalent (CGE) developed vasculopathy, compared with 2.2% at <54 CGE (P < 0.001).Vasculopathy distributes more in younger patients (8.4% in patients aged <5) compared to older patients (5.4% in patients ≥5). [31]This study demonstrates that higher radiation doses and younger age are strong risk factors in pediatric patients.Another study analyzed the ischemic vasculopathy in 431 primary brain tumor pediatric patients (under 21 years old).Among the 265 patients who received RT (others received surgical treatment), there were 19 ischemic events (8 ischemic strokes and 11 TIAs) in 14 patients.Among these 14 patients, 13 of them received radiation.More specifically, 12 received radiation in the Circle of Willis area.The hazard ratio (H.R.) of ischemic events after cranial RT was 8.0.Patients who received RT at the Circle of Willis area had a higher HR (9.0) than focal, patients who underwent non-Circle of Willis area RT (HR 3.4) in developing stroke or TIA. [1]Surgery and chemotherapy did not exhibit an association with stroke/TIA.In summary, cranial radiation, especially when administered to the Circle of Willis region, represents a significant risk factor for ischemic cerebral vascular events in children with brain tumors.
Moyamoya disease is a vasculopathy that presents as a progressive thickening and narrowing of intracranial blood vessels, which leads to a reduction in blood flow to the brain tissues.Moyamoya syndrome (MMS) refers to moyamoya vasculopathy associated with another disease or trigger. [32]Cranial RT has been established as a contributing factor for MMS in pediatric patients.A study analyzed 54 pediatric patients who developed MMS after radiation with a median age at an initial RT of 3.8 years.The study determined that individuals who underwent radiation therapy to the parasellar region during childhood (under 5 years of age) were at the highest risk of developing MMS.Neurofibromatosis type 1 (NF1) predisposes the pediatric patient to have MMS after radiation.The incidence of developing MMS increases after RT (95% of cases occur within 12 years). [33]In a retrospective study in Taiwan, which enrolled 391 pediatric patients with primary brain tumors treated with cranial RT, eight (2%) cases of post-RT MMS were identified.The median latency was three years post-RT (40-54 Gy).This study also identified that lower radiotherapy doses might induce MMS after a long latency. [34]A different case review established a statistically significant association between higher doses of radiation and earlier onset of cerebral vasculopathy in pediatric patients who were diagnosed with MMS. [35]A review study that analyzed 54 reported cases of radiation-induced MMS identified that the diagnosis of optic glioma is a strong predictor of the development of this syndrome. [34]However, because many pediatric optic glioma patients are also NF1 patients, whether optic glioma is a direct risk factor for RT-induced MMS needs further study.In summary, higher cranial RT dose, radiation at the Circle of Willis area, and received RT at a younger age are the risk factors for the development of radiation-induced Ischemic vasculopathy.In addition to higher cranial RT dose, received radiation at the parasellar region, NF1, and optic glioma are associated with developing MMS.

Carotid Artery Vasculopathy
Cranial RT is also associated with large intra or extra-cranial arteriopathy.Researchers have identified the correlation between ionizing radiation and atherosclerosis disease in carotid arteries in pediatric patients.A study followed 30 pediatric cancer patients, those who received neck RT, and found the average intimamedia thickness in the radiation group is 0.46 mm compared to the healthy control group which is 0.41 mm.The atherosclerotic plaque was found in 18% of the carotid arteries that were exposed to radiation. [36]Female gender, nonwhite ethnicity, family history of ischemic stroke, coronary artery disease, high body weight, hyperlipidemia, cancer recurrence, and years of treatment are identified as risk factors in this study.In another study that followed 115 pediatric brain tumor patients with annual follow-up through MRA, ten patients (8.7%) with large vessel arteriopathy were identified.The incidence of developing RT-induced angiopathy was 5.4% after a 5 year follow-up and 16% after a 10 year follow-up.Among the ten patients, five (50%) developed carotid artery narrowing or occlusion. [37]In another retrospective study that enrolled 75 pediatric brain tumor patients who received proton RT, 5 of 75 patients (6.7%) were identified with large cerebral vessel vasculopathy. [38]Carotid vasculopathy (#1 severe right ICA stenosis, # 2 left ICA occlusion, #3 right ICA stenosis) presents in three (60%) of five patients.Among pediatric patients with large vessel cerebral vasculopathy, the overall carotid artery vasculopathy rate is 53.3%, making it important for the clinician to closely follow up on the carotid artery condition in pediatric patients receiving cranial RT. [38]

Radiation-Induced Hemorrhagic Vasculopathy
Intracerebral hemorrhage (ICH) is another post-RT complication.Radiation causes ICH in several ways, including causing hemorrhage from tumor hemorrhagic necrosis, remodeling of vessels, aneurysms, and other vascular malformations like cavernoma and moyamoya syndrome.After a relatively high radiation dose, acute vessel wall necrosis increases the risk of vascular rupture in the acute phase, whereas telangiectasia formation and hemorrhagic infarcts could develop for a long time following low radiation doses. [21] study reviewed previous publications that included 77 delayed radiation-induced cerebrovasculopathy and 32 intracerebral bleeding cases in pediatric patients.Among the 32 cases of ICH, 7 cases were found to have cerebral aneurysms, and two cases were complicated with both cerebral aneurysms and Moyamoya disease.In addition, 75% of these patients received radiation when they were younger than 11 years old.The median interval between receiving radiation to the development of ICH is ≈7 years. [35]Another study included a large number of pediatric cancer survivors (N = 1362) who were diagnosed between 1966 and 1996 and received cranial radiation.Among these patients, 28 experienced the first symptomatic stroke (≈25 years median latency from cancer diagnosis).Thirty-six percent (10 out of 28) patients had an ICH, with 6 out of the 10 resulting from cavernous malformations. [41]The percentage reported in this study for pediatric cancer survivors is higher than the percent (10%-20%) documented for the general population. [42,43][46] A study enrolled 40 patients who had childhood brain tumors, performed cranial MRI, and found 90% of them affected by cerebral microbleeds.Thirty-three percent of patients have clinical symptoms, and those who experienced cerebral microbleeds were more severely disabled.They also found that increased follow-up duration and irradiation doses correlate with more total lesion counts. [47]Another retrospective study that analyzed a hundred children with primary brain tumors treated with RT showed a similar conclusion.Young age when receiving radiation, high maximum radiation doses, and a large part of the brain exposed to high dose (≥30 Gy) radiation are major risk factors for cerebral microbleeds development. [48]The above data imply that cranial RT in pediatric patients is associated with both intracerebral hemorrhage and cerebral microbleeds.A younger age when radiation is given is associated with increased risks for both ICH and cerebral microbleeds.Radiation dose and interval are not associated with ICH but are significant risk factors for cerebral microbleeds.

Radiation-Induced Other Vascular Malformations
In addition to the vasculopathy discussed in the previous sections, cranial RT has also been reported to induce other vascular malformations, including intracranial cavernous malformation and aneurysms in pediatric patients.
One of the long-term complications of cranial radiation therapy, particularly in children, is intracerebral cavernous malformations (ICMs). [49,50]Despite most patients with cavernous malformations being asymptomatic, ICH caused by these lesions may present and cause disabilities.It has been reported that the risk of bleeding may be significant among pediatric patients with RT-induced ICM. [51]In research that followed 239 www.advanced-bio.compediatric oncology patients who underwent ionizing radiation with available subsequent brain MRI scanning results, ten of the 239 patients were diagnosed with ICM.The median latency time for detecting ICMs after cranial RT was 12 years at a median age of 21.4 years.The cumulative incidence was 3% at ten years postcranial RT and 14% at 15 years. [52]An analysis of 36 survivors of childhood cancer who underwent cranial radiation was conducted through a recent long-term retrospective follow-up.Eighteen patients (50%) showed radiation-induced cavernomas.The tumor origin and cumulative radiation dose are found to be major risk factors of radiation-induced cavernomas. [53]

Ischemic Vasculopathy
Acute ischemic stroke is a major complication for adult brain tumor survivors. [54]The major pathophysiology of RT-induced ischemic vasculopathy in adults is the progressive steno-occlusive change of cerebral arteries after radiation therapy. [56]Although the advancement of radiation therapy technology and steroid treatment have decreased the incidence of microvascular ischemic disease but not in medium and large vessel stenoocclusive changes. [55]As adult brain cancer patients live longer, acute ischemic stroke becomes more clinically relevant.Currently, there is limited research to guide the management of radiation-induced acute ischemic stroke.
A study of 6862 patients older than 65 showed that patients with head and neck cancers treated only with radiotherapy had an increased risk of cerebrovascular events than those treated with surgery or surgery and radiotherapy. [56]In a retrospective study, 99 studies were analyzed to assess the incidence of stroke, TIA, or carotid stenosis in patients with a history of RT for head and neck cancers.The data indicate that the relative risk of TIA or ischemic stroke is at least doubled by radiation. [57]The ionizing radiationinduced atherosclerosis disease and injury to vasa vasorum are the main underlying pathophysiology.Studies with prospective follow-up reported no incidence of ischemic stroke after stereotactic radiosurgery and Gamma-knife surgery methods. [58,59]In a cohort study of 456 nonfunctioning pituitary adenoma patients, the rate of ischemic stroke was 11.6% with conventional or stereotactic radiosurgery techniques.Still, no distinction was made between them in the analysis. [60]These data indicate applying more accurate radiation to target tumors will reduce the risk of ischemic vasculopathy in adult patients.Another study examined small vessel disease after radiation therapy.Molad et al. analyzed data from 110 patients treated with RT for primary or metastatic brain tumors with MRI and calculated the annual incidence of cerebral microinfarction.They showed no significant differences in the annual incidence of cerebral microinfarcts between radiated patients and the general populations. [61]icrovascular injury is another complication of cranial RT.Different from major symptomatic ischemic events, the microvascular disease gradually builds up, usually identified by brain MRI.White matter changes can be used to represent cerebral vascular disease.One study of glioblastoma patients has identified that conventional cranial RT induces subventricular white matter changes. [62]Another study also reported that patients would have white matter injury after RT, which is associated with cognitive decline. [63]However, the white matter injury after RT has a mixed pathology with RT-induced oligodendrocyte/myelin, astrocytes, and microvessels injury.It is not only an indicator of microvascular injury but also a marker of a direct RT injury to subcortical structures.

Carotid Artery Vasculopathy
Studies in adult patients have identified the correlation between RT and carotid artery vasculopathy.In a study that followed 367 adult patients with head and neck cancer who underwent high-dose RT, there was a tenfold rise in carotid-related strokes compared to the general population. [64]In another cross-section study, carotid artery disease is found in 12%-40% of adult patients who have a history of head and neck radiation therapy. [36]ncreasing age and time from radiation therapy have been reported as risk factors. [64,65]A pooled analysis of eight studies in a systematic review showed a significantly higher incidence of mild and severe (>70% in ultrasound) extra-cranial carotid artery stenosis among patients who have a history of RT involving neck. [66]Cheng et al., in a randomized control trial, demonstrated that radiation could progress carotid artery stenosis rapidly from less than 50% to more than 50% in comparison to the nonradiated group (annualized rate: 15.4%, compared with 4.8%) in a mean follow up of 36 months.Still, they found no differences in progressing new symptoms or mortality between the groups. [67]n a clinical trial of cervical carcinomas, the rate of critical stenosis (more than 70%) was 16%.In contrast, the control group experienced no critical stenosis after a mean follow-up of about 80 months. [68]A study of 217 adult head and neck cancer survivors who received RT and two years follow up with duplex ultrasound revealed that patients with a total plaque score ≥ seven after RT are more prone to progress carotid artery stenosis to >50% and as a secondary outcome to ischemic stroke. [69]Given the well-established correlation between RT and carotid artery steno-occlusive disease, close follow-up and secondary preventive management are necessary for adult patients who received head and neck RT.
Carotid blowout syndrome, also known as carotid artery rupture, is a rare but life-threatening condition characterized by the rupture or injury of the carotid arteries in the neck.The main causes of carotid blowout syndrome include erosion or invasion of the carotid artery by a tumor, previous radiation therapy damaging the arterial wall, or trauma to the neck region.Different from other RIVs, the risk of carotid blowout syndrome is significantly increased when there is a combination of surgery and RT.Studies have shown that carotid blowout syndrome ranges from 3% to 4.5% in the general population after major head and neck oncological surgeries. [39]However, when those surgical patients have undergone previous radiation therapy, the incidence of carotid blowout syndrome rises from 4.5% to 21.1%, compared to patients who have not received radiotherapy but only oncological surgeries 0% to 2.4%. [39]The incidence of carotid blowout syndrome is minimally increased with planned preoperative radiotherapy at moderate doses (<45 Gy).The extracranial carotid artery rupture would cause oropharyngeal hemorrhage, a rare but life-threatening complication.A study included 139 patients diagnosed with oropharyngeal squamous cell carcinoma who underwent RT.Ten of the 139 patients developed life-threatening, arterial oropharyngeal hemorrhage.After multiple logistic regression analyses, the advanced T category is statistically significant with the development of oropharyngeal hemorrhage.Among the patients who experienced hemorrhaging, nine out of ten had tumors classified as T category 3 or 4. [40]

Hemorrhagic Vasculopathy
In addition to the steno-occlusive vascular changes, ICH and microbleeds are also observed in adult patients after radiation therapy.According to a study, 25.9% and 43.25% of adult brain tumor patients who underwent RT developed ICH in the 3 year and 5 year follow-up images, respectively. [70]The number of intracerebral hemorrhages per patient positively correlates with the followup time.In contrast, no significant changes were observed in the size of the intracerebral hemorrhages throughout follow-up.Leclerc et al. found a significantly higher incidence of remote microhemorrhages or remote hematoma in 58 glioma patients who received RT Remote hematoma developed in four patients (7%), all of whom received radiation. [71]In this study, patients with at least one remote microhemorrhage were significantly more likely to present with a remote hemorrhage during follow-up (16% versus 0%).Patients with a high number of microhemorrhages were significantly more likely to present with an ICH (p = 0.005). [71]nother study reviewed 113 primary brain patients and showed similar results that all patients who received cranial RT had intracranial microbleeds, of which the rate was significantly higher than the nonradiated group.Post-RT cranial microbleeds' total number and volume increased over time after RT. [72] Angiogenesis inhibitor is found to decrease the intracranial microbleeds in patient who received cranial radiation. [73]he presence of hemorrhagic vasculopathy in post-RT patients raises physician concerns about long-term anticoagulant use.A study of 41 patients treated with anticoagulant therapy during single-fraction stereotactic radiosurgery for brain metastasis revealed no relevant risk of ICH. [74]These findings were similar to a meta-analysis of ICH's risk in brain metastases. [75]In summary, cranial RT increases the adult risk of ICH or cerebral microbleeds.The total number of cranial microbleeds and hemorrhages increased over time after RT Anti-angiogenic therapy decreases the risk of post-RT cerebral microbleeds.

Other Vascular Malformation
Although rare, there are some case reports of cavernous malformation in the adult years after radiation. [76,77]A study analyzed 32 radiation-induced cavernous malformation patients (13 adults, 19 children).Pediatric patients were diagnosed with cavernous malformation at a considerably younger age compared to adult patients, with a median age of 24.0 years versus 49.4 years, respectively. [78]The low occurrence rates and the older median age of cavernous malformation in an adult indicate children are more susceptible than adults to developing this vascular malformation after radiation.Compared to radiation-induced occlusive changes, the prevalence of cerebral aneurysms after radiation therapy is uncommon. [79]Vessel wall weakness caused by radiation-induced endothelial injury is likely the pathogenesis of radiation-induced aneurysms. [80,81]In 2014, a comprehensive literature review examined radiation-induced intracranial aneurysms in a cohort of 46 patients, comprising a total of 69 intracranial aneurysms.Of the total, 83% were categorized as saccular aneurysms, 9% were classified as fusiform aneurysms, and the remaining 9% were regarded as pseudo-aneurysms.The rupture rate of radiation-induced aneurysms is higher than congenital saccular aneurysms, despite the size of aneurysms. [82]he mortality rate for this kind of aneurysm after rupture is also high. [81,82]Different from the primary saccular aneurysm, the radiation-induced aneurysm is prone to arise from the trunk of an artery.[85] A study analyzed 67 RT-induced brain aneurysms, including ten pediatric brain tumor patients and 57 adult patients, and recognized the internal carotid artery (34%) is the most vulnerable artery. [86]he researchers found the anterior circulation is more sensitive to radiation-induced injury.Interestingly, the aneurysm development in posterior circulation exhibited a good univariate association with the lower radiation dosage compared to anterior circulation.High radiation (especially higher than 50 Gy) doses decreased the latency of multiple aneurysm formation. [86]In 2019, a 10 year follow-up study enrolled 70 691 pediatric and adult head and neck tumor patients and demonstrated cerebral aneurysm is more common in nasopharyngeal carcinoma patients who received cranial RT compared to patients with other head and neck cancers. [87]Similar to primary aneurysms, hypertension is also a risk factor.This study also emphasizes that radiation-induced aneurysms have a higher risk of rupture, and anterior circulation is more sensitive to aneurysmal change after radiation. [85]

Prevention and Management
According to published studies, radiation therapy-induced vascular damage can be prevented or minimized by reducing radiation dose and precise tissue targeting during radiation. [88]Strategies and new technologies such as particle therapy, 3D conformal radiotherapy, and stereotactic body radiation therapy could help reduce radiation therapy-induced vascular damage in the brain. [89]Proton therapy, the most common form of heavy particle therapy, has multiple advantages compared to conventional photon therapy. [90]Compared with traditional photon therapy, which uses high-energy X-rays or gamma rays to destroy cancer cells, the photons are generated by linear accelerators.They are delivered to the tumor from different angles.Protons have mass and a positive charge, which allows them to penetrate tissues up to a certain depth before releasing most of their energy.Protons deposit minimal energy as they enter the body but release most of their energy at a specific depth known as the Bragg peak.In this way, it offers the advantages of precise targeting, higher dose delivery to the target tissue, absence of an exit dose, and lower radiation exposure of nearby healthy tissues (Proton beam therapy).As a result, proton therapy can be especially beneficial for treating tumors located near critical structures or in pediatric patients, where minimizing radiation exposure to healthy tissues is important. [91]In a prospective study of 174 pediatric glioma patients treated with proton therapy between 2007 and 2017, only two patients (1.1%) developed symptomatic vasculopathy. [92]Although RT-induced vasculopathy has been reported in fewer patients with proton therapy, further studies that systemically compare the risk between proton therapy and photon therapy are needed in the future.
In addition, preclinical studies suggest that statins may have a preventative and protective effect on radiation-induced vascular injury. [93,94]Potential cellular and molecular mechanisms of statin include an anti-inflammatory [95] and anti-oxidative [96] effect by modulating the interaction between immune cells (e.g., monocyte) and endothelial cells.For example, Captopril (angiotensin-converting enzyme [ACE] inhibitor) reduces radiation-induced TGF-1 secretion from endothelial cells. [97]ther compounds may also be used to prevent or reduce radiation therapy-induced vascular damage in the brain.Simvastatin (HMG Co-A reductase inhibitor) reduces endothelial cell permeability by maintaining tight junctions. [98]While preclinical studies showed a promising effect of statins in inhibiting radiation-induced vascular damage, [93,94] carefully designed clinical trials regarding statins are needed in the future.In a retrospective study of RT-induced cerebral vascular complications, statin use after radiation therapy was found to associate with a reduction (32%) in stroke. [99]However, even with secondary stroke prevention management, 35.7% of pediatric brain cancer patients still had recurrent ischemic events (stroke or TIA). [1]Further studies on how to prevent and manage RT-induced vasculopathy are still in demand.
As the utilization of cranial RT in cancer treatment becomes more prevalent and patient survival rates improve due to advancements in therapy, it becomes progressively crucial to focus on the development of RIV.Identifying the pathophysiology and risk factors of RT-induced vasculopathy will assist the physician in deciding how closely to follow up and investigate possible early signs of vasculopathy in different patient populations.Identifying the pathophysiology and risk factors of RT-induced vasculopathy will assist the physician in deciding how closely to follow up and investigate possible early signs of vasculopathy in different patient populations.Currently, there are no clinical trials that can provide the proper frequency of surveillance angiograms after cranial RT, nor are studies showing the benefits of such surveillance vascular imaging.Most patients were found to have vasculopathy after symptomatic cerebrovascular disease developed or incidentally from brain imaging.However, given the identified risk factors of RIV, we should closely monitor the patients with a higher risk of developing RT-induced vasculopathy.Oncology patients who receive RT are supposed to have surveillance imaging for their tumor treatment.Guidelines from the National Comprehensive Cancer Network (NCCN) advised conducting a follow-up MRI scan in individuals diagnosed with a high-grade glioma around four weeks after the completion of RT, with repeating the MRI every two to four months for a duration of two to three years.Those patients with extra RIV risk factors will benefit from adding MRA imaging while they have the MRI scanning.This way, patients do not need extra imaging appointments or referrals to a vascular specialist to schedule the imaging study.As a result, we recommend that patients with one or more RIV risk factors in Table 1 have extravascular imaging on top of routine brain imaging (for tumor recurrence monitor).For example, a young patient (<5 years old) with optic glioma who received a high dose of RT at the Circle of Willis area will need closer followup and more aggressive secondary stroke prevention compared to an older patient who was treated with a low dose of RT that spare the Circle of Willis area.However, further clinical studies to identify the proper surveillance imaging frequency and their clinical benefits are needed.Regarding the importance of single RT dose versus total dose, current studies did not identify strong association between vasculopathy and the single RT dose.The aggregation of the total RT dose is the risk factor, instead of the single dose volume.
chronic inflammation and abnormal cytokine secretion (IL-1, IL-6, TGF-, TNF-, and VEGF) contribute to the formation of vasculopathy, suppressing the aberrant inflammation and cytokines production in cerebral vasculature after RT may be a future direction of management.Studies have demonstrated that statins can reduce inflammatory cell infiltration in atherosclerotic plaques and effectively hinder various other inflammatory processes. [100]esting if statin will halt or reduce the process of radiationinduced vasculopathy will be one of the focuses of the field.In summary, the prevention and management RIV need a thorough understanding of the pathophysiology, prevalence, and risk factors of this condition (Table 2; Table S1, Supporting Information).Further clinical studies are required to examine the beneficial role of statin and antiaggregant therapy in combination with surveillance imaging in different subgroups of patients.

Figure 1 .
Figure 1.The schematic graph of the pathophysiology of radiation-induced vasculopathy.

Figure 2 .
Figure 2. The schematic graph of the pathophysiology and corresponding pathologies in acute and chronic phase after radiation therapy.RT: radiation therapy; ICH: intracerebral hemorrhage; MMS: moyamoya syndrome.

Table 1 .
Summary of RIV risk factors.

Table 2 .
Summary of RIV subtypes, prevalence, risk factors, and management in pediatric and adult patients.