The incidence of radiation necrosis has increased secondary to combined modality therapy for brain tumors and stereotactic radiosurgery. The pathology of progressive brain radiation necrosis (RN) primarily includes inflammation and angiogenesis in which cytokines, chemokines, and vascular endothelial growth factors are upregulated. Combined multiparametric imaging, including lesional metabolism, spectroscopy, and blood flow, could enhance diagnostic accuracy compared with a single imaging study. Nevertheless, a substantial risk of bias restricts firm conclusions about the best imaging technique for diagnosing brain RN. Bevacizumab shows promising results of improving radiographic edema and post-gadolinium enhancement with associated symptomatic improvement. However, this was based on small double-blinded randomized controlled trials, which introduces a high risk of bias due to the small sample size despite the high-quality trial design. Edaravone combined with corticosteroids also resulted in a more significant reduction in radiographic edema than corticosteroids alone but had no impact on reducing the enhancing lesion. There is a great need for further prospective randomized controlled trials (RCTs) to treat brain RN.
- radiation necrosis
- brain metastases
- brain tumors
- brain injury
For years, radiation therapy (RT) has played a critical role in the treatment of primary brain tumors (PBT) and brain metastases (BM). Different techniques can be used depending on the clinical setting, including brachytherapy, fractionated stereotactic radiotherapy, and stereotactic radiosurgery. The use of RT in brain tumors has been related to improved progression-free survival as well as overall survival, especially in patients with high-risk low-grade gliomas . As with different cytotoxic treatment approaches, the use of cranial irradiation comes with the possibility of specific side effects known as radiation toxicity that can be acute (early toxicity) or late. Usually, early toxicity symptoms are reversible and treatable with proper supportive care; these symptoms include fatigue, headache, alopecia, dermatitis, nausea, and vomiting. Radiation necrosis (RN) is one of the leading late toxicity clinical manifestations. It usually occurs between 1–3 years after RT in the location that received the most radiation (tumor location) or a nearby area.
Clinical manifestations of RN will depend on the location of its development . Signs and symptoms of focal neurologic deficits might occur, seizures are also present in approximately 20% of patients . Depending on the region of the brain that is affected, different sets of symptoms might be present, including but not limited to motor deficits (2.9%), sensory deficits (1.3%), cognitive deficits (1%), speech deficits (1.3%), visual disturbances (0.6%), ataxia (1.6%) and general symptoms like headache (5%), nausea (1%) and hemorrhage (5%) . This chapter will discuss the epidemiological features of RN, its risk factors, its pathophysiology, its diagnosis, and treatment.
2. Incidence of radiation necrosis
The current true incidence of RN is hard to estimate. According to Vellayappan
In a study made by Kohutek
Studies where pathological confirmation of RN was done reported the least incidence, a clear example is an investigation made by Chin
3. Pathophysiology of radiation necrosis
Vascular and white matter (myelinated tissue) injury have been stated as the genesis of RN. Since the second half of the 20th century, anecdotal clinical literature argued about the existence of delayed radiation-induced necrosis of the brain; however, scarce evidence was available regarding the exact mechanisms of disease . In the 1970s and 1980s, two main pathogenetic theories were formulated. The first one was the glial cell theory, in which radiation injury was presumed to induce damage of glial cells, specifically of oligodendrocytes, which will induce a cascade of events that will end in tissue necrosis . The other theory stated that endothelial cell injury induced by radiation was the only cause explaining ischemia and further tissue necrosis. Different experimental studies performed in rats and dogs found data that supported both theories, and today we consider that RN arises as a multifactorial process in which glial cells, endothelial cells, and other cell types result injured by radiation generating different inflammatory and scarring processes that end in tissue necrosis [13, 14, 15].
Both theories are currently accepted as part of one single process in which vascular injury precedes glial cell damage. After brain tissue is exposed to radiation, avascular insult occurs within the first 24 hours, followed by parenchymal brain injury . Reactive oxygen species develop because of ionizing radiation, leading to single- and double-stranded DNA damage. Regulatory cell mechanisms are activated and will drive the endothelium to cell cycle arrest and further apoptosis . Ionizing radiation of more than 8 Gy will also induce activation of acid sphingomyelinase in endothelial cells [18, 19], leading to ceramide synthesis and ceramide-induced apoptosis . The injured tissue will also induce inflammation, producing the release of TNF-alpha , a molecule that has been shown to disrupt the blood–brain barrier (BBB) in multiple physiological and pathological situations [22, 23, 24]. Increased expression of VEGF and ICAM-1 has also been shown [25, 26]. The result of this inflammatory cascades is the development of intravascular thrombi and fibrinoid necrosis, leading to vessel lumen narrowing and further ischemia and necrosis and disrupting, even more, the BBB homeostasis , leading to cerebral edema and further demyelination . Thus, vascular injury induces oligodendrocyte injury, but at the same time, the initial ionizing radiation can also directly damage glial cells, generating inflammation and gliosis. In the early-delayed phase of this process, edema might resemble tumor progression or pseudoprogression on imaging findings . Research has also shown that ischemia-induced hypoxia in the perilesional area can induce HIF-α, which also induces VEGF expression generating angiogenesis of weak, leaky capillaries that aggravate edema, necrosis, and demyelination. Figure 1 shows the pathophysiological characteristics for the development of the RN.
4. Risk factors related to radiation necrosis
As a result of different epidemiological, clinical, and genomic studies related to radiation-associated brain injury, different risk factors for RN have been identified.
4.1 Dose-volume interplay
The incidence of RN increases as dose and volume increase. Different studies have tried to find the ideal dose for different tumor diameters. Lesions of 20 mm or less can be safely treated with 24 Gy, 21–30 mm lesions with 18 Gy, and lesions between 31–40 with 15 Gy. The cumulative incidence of RN at 12 months for these measurements is 8% . In the case of SRS, it has been demonstrated that the brain parenchyma that is irradiated with >10–12 Gy has a greater risk of developing RN. This risk is even higher when V10 > 10.5 cm3 or V12 > 7.9 cm3 .
4.2 Prior radiation exposure
Another essential risk factor for RN is prior radiation exposure, whether as whole-brain radiation therapy (WBRT) or SRS. A study performed by Sneed
Radiosensitization with cytotoxic agents is a common practice in the treatment of different tumors and metastatic diseases . In the same study by Sneed
4.5 Tyrosine-kinase inhibitors
4.6 Brain location
Even though most studies did not find a correlation between brain location and RN risk, some observations by Flickinger
Specific histological subtypes of tumors might be related to an increased risk of RN. Miller
4.8 Planning target volume (PTV) margin
A higher PTV might be related to an RN’s increased risk. A study by Kirkpatrick
4.9 Intrinsic radiosensitivity
A possible genetic radiosensitivity might also underly some of the risk burdens of some patients that develop RN. One
5. Radiation necrosis imaging
The pathology of progressive brain RN primarily includes inflammation and angiogenesis in which cytokines, chemokines, and vascular endothelial growth factors are upregulated [12, 15, 42, 43]. Distinguishing between RN and tumor progression is somewhat challenging on conventional imaging. Besides, obtaining tissue samples is invasive even in stereotactic biopsies, although pathological diagnosis remains the gold standard. Moreover, needle biopsy poses a risk of misdiagnosis because RN is typically a heterogeneous lesion with coexisting radiation necrosis and tumor cells . Currently, RN is diagnosed by relatively less-invasive radiological examinations that evaluate the whole lesion, compared with needle biopsy. Strategies can be divided into two categories, the use of conventional radiological imaging [computed tomography (CT) and magnetic resonance imaging (MRI)], and nuclear medicine studies [single photon emission CT (SPECT) and positron emission tomography (PET)] .
Brain RN may occur during therapy (acute injury), a few weeks to 3 months after therapy (early-delayed injury), or more than three months after treatment (late injury). After conventional radiotherapy, RN typically involves large areas of the brain and may not be amenable to surgery . On the contrary, the injury secondary to radiosurgery tends to be restricted to the site of treatment and, consequently, may respond well to surgical resection . Computed tomography was found to be unreliable in this regard quite early [46, 48, 49]. The most cited MRI features are necrotic foci, contrast enhancement, and perilesional edema [50, 51]; Changes are most evident in T2-weighted and fluid-attenuated inversion recovery sequences. Unfortunately, these features are commonly present with recurrent tumors as well. Some MRI features have been thought to suggest radiation necrosis in previous reports: contrast enhancement with ill-defined borders and little or no mass effect and a “Swiss cheese” or “soap bubble” pattern (“cut green pepper”). On the other hand, Dequesada
Years ago, some suggested that advanced imaging modalities might prove to be more reliable than MRI in the differential diagnosis of tumor versus necrosis. Taylor et al.  found that magnetic resonance spectroscopy (MRS) reliably identified 5 of 7 patients with active tumor and 4 of 5 patients with radiation necrosis. Others have found that MRS reliably distinguished pure tumor from pure necrosis but that no values could distinguish mixed specimens [54, 55].
Almost two decades ago, Tsuyuguchi
Since then, the use of MRS, MR perfusion, and PET has been consolidated as effective techniques to help increase diagnostic confidence. These techniques are discussed below.
5.1 MR perfusion
Viable tumor has intact vasculature and thus higher perfusion and blood volume than necrotic tissue. An increased relative cerebral blood volume (rCBV) based on dynamic susceptibility-weighted MRI has been used for differentiating tumor from necrosis . Sugahara
However, much of the published information is retrospective and inconsistent. Barajas
MRS provides additional information on the metabolic composition within an area of tissue by comparing several metabolites’ relative concentrations. Ando
Impaired BBB is considered the leading diagnostic indicator of brain tumors and metastases on contrast-enhanced MRI and CT. Similarly, many PET tracers that can identify tumor cells at various sites in the body would only reach the brain if the BBB is disrupted. Therefore, the development of specific tracers that do not depend on BBB damage, such as fluorodeoxyglucose (18F-FDG) and labeled amino acids (aa) that are transferred by specific transporters across the intact BBB was introduced. Different studies showed that 18F-FDG is unhelpful in differentiating tumor progression from RN. Even though 18F-FDG alone has a low sensitivity (43%), its combination with other imaging techniques like MRI might increase its diagnostic usefulness . The fact that tumoral or highly inflamed tissue might have an increased uptake of amino acids , and the relatively low uptake of normal brain tissue would provide a considerable tissue contrast. Compared to 201Tl, 18F-FDG is more specific but less sensitive to detect tumor recurrence since the former, before its uptake through the Na+-K+ ATPase pump, has a non-specific accumulation due to BBB breakdown. The latter lacks sensitivity because of the physiological uptake of normal brain . More specifically, in the differentiation of tumor recurrence and RN, 18F-FDG also has low specificity, ranging from 40 to 94%, mainly during the first few weeks post-therapy, with a study that showed a sensitivity of 81–86%. Therefore, it is recommended to perform 18F-FDG PET no less than 3 months after the end of RT, also because it can cause inflammatory changes that can last up to 6 months after therapy but slowly decreases over time, for example, in the lung parenchyma, which will take up FDG and make it difficult to differentiate from the recurrent tumor .
Other amino acids have been studied, including fluoro-1-thymidine, fluoroethyltyrosine (18F-FET), 3,4-Dihydroxy-6-18F-fluoro- l -phenylalanine (FDOPA), l-[Methyl- 11 C] methionine (11C-MET), 3-Deoxy-30-18F-fluorothymidine (18F-FLT) and carbon-11 choline. Floeth
18F-FDOPA is an amino acid tracer that has been used at the beginning for the evaluation of movement disorders by assessing the integrity of the striatal dopamine pathway. Recently, 18F-FDOPA it is studied in the imaging of brain tumors. In this scenario, one of the main pros of 18F-FDOPA lays in the crossing of the BBB thanks to a specific neutral amino acid transporter, which grants a better uptake ratio also because tracer accumulation does not depend on BBB breakdown . In a non-conventional meta-analysis, Yu
11C-MET is a PET amino acid isotope characterized by a relatively short half-life that in tumors determine the high density and activity of amino acid transporters. Instead, it can accumulate due to active transport and cell proliferation, but in RN, passive diffusion via BBB damage is the most probable uptake mechanism . Therefore, the difference in terms of accumulation mechanisms could be a way to distinguish the two clinical settings. Concerning its role in the differentiation of recurrence from RN, Hustinx
Moreover, in the case of high-grade gliomas, 11C-MET uptake is higher than in low-grade tumors; therefore, it could be used for monitoring purposes to assess anaplastic transformation . In a recent study of 18 lesions from 15 patients with metastatic brain tumors who underwent gamma knife radiosurgery, the authors showed that 11C-MET was superior in terms of both sensitivity and specificity as an imaging technique for differentiating RN and recurrent metastatic tumors after gamma-knife compared with diffusion-weighted imaging (DWI), MR permeability imaging and 18F-FDG. However, it is not widely available yet for clinical use due to its physical limitations . Another study showed that 11C-MET could differentiate recurrence from RN based on the PET/Gd volume ratio and the PET/Gd overlap ratio as these ratios were significantly lower in patients with RN than in patients with glioblastoma recurrence (p < 0.05) (analysis were done based on a pathological assessment) .
18F-FLT is a radiolabeled analog that has been used to indicate tumor proliferation since thymidine is a nucleoside encountered only in DNA; therefore, it reflects tissue proliferation rate. 18F-FLT transport is mediated mainly by active Na + −dependent carriers through nucleoside transporters (salvage thymidine pathway) and passive diffusion. Enslow
6. Pathological assessment
Histopathology is currently the gold standard to diagnose tumor recurrence or RN. A significant difference in histologic findings exists between these two conditions. Macroscopically, RN shows as a firm-like mass or sometimes as a soft cystic lesion. A yellow-to-brown necrotic core is usually accompanied by significant hemorrhage, gliosis, and tissue atrophy . In the case of RN, fibrinoid necrosis, hemorrhage, hyalinization and, blood vessel thrombosis can be seen, with a visible hypoxic injury of the surrounding tissue . The necrotic area is usually paucicellular, characterized by the presence of inflammatory ghost cells and focal perivascular lymphocytes, and surrounded by gliotic brain tissue corresponding mainly to GFAP-reactive astrocytes (reactive gliosis) . Inside the lesion, other cell types like foamy macrophages and hemosiderophages can be seen. A low nuclei-cytoplasmic ratio is characteristic. On the other hand, tumor recurrence shows a high cellularity with a ghost cell outline, demonstrating a high nuclei-cytoplasmic ratio. In brain metastases, careful examination of the blood vessels is essential as residual tumor cells might be seen around the Virchow Robin spaces. An immunohistochemistry panel will reveal the usual immunophenotype of the suspected tumor recurrence according to the patient’s history. Histopathological assessment is not routinely performed unless an invasive approach to the lesions is needed for other purposes like therapeutic interventions. Figure 4 shows the main pathological features of radiation injury, including cytological atypia, fibrinoid necrosis, and the marked inflammatory infiltrate.
7. Management of radiation necrosis
Since the 1970s, RN can be controlled with advanced images and left under observation. Wang
For patients with symptomatic brain RN, steroids are typically the first-line treatment, as they effectively reduce symptoms associated with brain edema and also inhibit the pro-inflammatory cascade involved in radiation injury. However, withdrawal of corticosteroids may result in a rebound of the edema and related symptoms and prolonged use of corticosteroids can be associated with significant toxicity including steroid myopathy, iatrogenic Cushing’s syndrome and glucose intolerance .
There have been several recent reviews addressing the use of bevacizumab for brain RN [89, 90] that included data from both retrospective and prospective studies. Lubelski
A recent systemic review found only three clinical trials with pharmacological interventions to reduce the clinical and radiological features of brain RN . The first one is a randomized, double-blind, placebo-controlled trial of bevacizumab 7.5 mg/kg every three weeks for 2 cycles versus placebo tested in adults treated with radiotherapy for the brain or head and neck neoplasm and with radiological diagnosis of brain RN based on MRI criteria. Included patients were allowed to be taking corticosteroids before study participation, but they were required to be using a stable dose for at least one week before receiving study treatment. The primary endpoint was the radiological response, defined as at least a 25% reduction in brain edema at six weeks of treatment compared with pre-treatment; this was measured as the volume of hyperintensity on T2-FLAIR MR images . This trial reported that 100% (7/7) of participants on bevacizumab had a reduction in brain edema (T2 hyperintense volume) by at least 25% and a reduction in post-gadolinium enhancement.
In contrast, all those receiving placebo had clinical and/or radiological progression (five participants in the placebo arm experienced progressive clinical symptoms while two patients had radiological progression without progressive symptoms). Three severe adverse events were noted with bevacizumab which included aspiration pneumonia, pulmonary embolus, and superior sagittal sinus thrombosis .
The second was an open-label trial of patients treated with methylprednisolone 500 mg intravenously for three days followed by prednisone orally on a tapering schedule over 30 days, as tolerated, with or without the addition of edaravone 30 mg orally twice daily for 14 days. Eligible patients were adults (> 18 years old) treated with radiotherapy at least six months before study enrollment with radiographic evidence of RN based on MRI features. This trial also defined response as at least 25% reduction in the volume of T2-hyperintensity, and the primary endpoint was evaluated at three months following the start of treatment . This study demonstrated a more significant reduction in brain edema in the edaravone plus corticosteroid group than in the corticosteroid alone group (mean difference was 3.03, 95%CI 0.14–5.92), although the result approached borderline significance (p = 0.04). There was no evidence of any critical difference in the reduction in post-gadolinium enhancement between arms (mean difference 0.47, 95% CI -0.80-1.74). Similarly, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone measured using the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic (LENT-SOMA) scale (OR 2.51, 95%CI 1.26–5.01). No differences in treatment toxicities were observed between arms, and no severe adverse events were reported.
Besides, one prospective non-randomized study allowed patients to choose between vitamin E 1000 IU twice daily for one year or no active treatment. Eligible cases were adults treated with radiotherapy for nasopharyngeal carcinoma with no evidence of recurrence for at least five years who have developed radiological evidence of unilateral or bilateral temporal lobe necrosis without mental impairment. Unlike the two randomized studies, serial imaging was not evaluated in this study. Patients were assessed at baseline and one year using a battery of in-house and more widely utilized neuropsychological tests, including the Cantonese version of the Mini-Mental Status Examination (CMMSE), Hong Kong List Learning Test (HKLLT), Visual Reproduction subtest of the Wechsler Memory Scale III (WMS-III VR), Category Fluency Test (CFT) and computerized Cognitive Flexibility Test . Evaluating cognitive function in patients at baseline and after one year of treatment, a 5.3% improvement in global cognitive function on CMMSE was seen in patients who received vitamin E compared with no improvement in the control group (P = 0.007). Assessment of verbal learning using the Hong Kong List Learning Test (HKLLT) demonstrated that the treatment group had a 27.2% improvement at one year versus no improvement in the control group.
Similarly, improvements were seen for visual memory and recall for the group treated with vitamin E. There was no difference in attention, language, or executive function between the two groups at baseline or at one year. Corticosteroid requirements and adverse events to treatment were not reported in this study .
Another integrative study gathered the information from two prospective, seven retrospective, and three case report studies involving 89 patients with RN treated with bevacizumab . In total, 93% of patients had a recorded radiographic response to antiangiogenic therapy, and 6.7% had experienced RN progression. Seven studies (n = 73) reported mean volume reductions on gadolinium-enhanced T1 (mean 47%, +/− 24) and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI images (mean 62%, +/− 23). Pooling together the T1 and T2 MRI reduction rates revealed a mean of 48 (95% CI 38–59) for T1 reduction rate and 62 (95% CI 52–72) for T2W imaging studies. Eighty-five patients presented with neurological symptoms at bevacizumab exposure, since when nine (10%) had stable symptoms, 39 (48%) had improved, and 34 (40%) patients had complete resolution of their clinical impairment. Similarly, dexamethasone discontinuation or reduction in dosage was observed in 97% of patients who had recorded dosage before and after bevacizumab treatment .
Considering the use of alternative ways for the administration of bevacizumab in patients with RN, Dashti
Although surgery is frequently used in clinical practice to address progressive resectable RN lesions, no prospective trials of surgical resection for brain RN were identified in this review. A retrospective series of 24 adult patients who underwent craniotomy and resection of contrast-enhancing lesions in the temporal lobes (16 unilateral and eight bilateral) following radiotherapy for nasopharyngeal carcinoma reported a reduction in the extent of brain edema observed on either CT or MRI (in those cases who had serial imaging). Only one patient required a repeat resection for recurrent necrosis . In patients who were treated with radiosurgery, a retrospective series of 15 patients treated with surgical resection for RN reported improvement in brain edema resulting in either a partial or complete taper off corticosteroids as well as symptom improvement in the majority of patients .
7.5 Pentoxifylline and vitamin E
Pentoxifylline (PTX) is a methylxanthine derivative that decreases blood viscosity, increasing blood circulation and tissue oxygenation. Vitamin E (or tocopherol) acts as a free-radical scavenger. In a small retrospective study of 11 patients with brain RN following radiotherapy for brain metastases, meningioma, and AVMs, the combination of PTX and vitamin E resulted in radiological improvement in all but one patient, who was eventually confirmed to have tumor recurrence .
7.6 Hyperbaric oxygen
There are limited small retrospective case reports and case studies reporting the outcomes of Hyperbaric oxygen (HBO) therapy for brain RN. Pasquier
7.7 Laser-induced thermal therapy (LITT)
Only one single-arm study of a LITT reported promising local control of 75.8% (13 of 15 lesions) and dramatic reductions in lesion volume to less than 10% of the pre-treated volume in seven of the treated lesions . However, as this was a single-arm study with a limited number of patients, a further prospective investigation is required to compare this treatment’s effectiveness against current management approaches. Figure 5 shows a proposed algorithm for the diagnostic and therapeutic approach of NR.
Despite the rising incidence of RN because of increased utilization of stereotactic radiosurgery and reirradiation, there remain significant challenges in diagnosing this complex brain injury. To date, there is no established standard to diagnose RN noninvasively. Over the past few years, there are, however, more treatment options, particularly with bevacizumab. More studies are needed to define who is at risk and how to minimize these risks; to diagnose radiation necrosis more accurately with imaging, blood tests, or other noninvasive techniques; and to treat these patients quickly before neurological signs and symptoms develop and progress.