Journal of Radiation and Cancer Research

: 2017  |  Volume : 8  |  Issue : 3  |  Page : 135--140

Adverse radiation effect in the brain during cancer radiotherapy

Andrew J Fabiano1, Dheerendra Prasad2, Jingxin Qiu3,  
1 Department of Neurosurgery, Roswell Park Cancer Institute; Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
2 Department of Radiation Oncology, Roswell Park Cancer Institute, University at Buffalo, State University of New York, Buffalo, New York, USA
3 Department of Pathology, Roswell Park Cancer Institute, University at Buffalo, State University of New York, Buffalo, New York, USA

Correspondence Address:
Andrew J Fabiano
Department of Neurosurgery, Roswell Park Cancer Institute; Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York


Adverse radiation effect (ARE) in the brain is the reactive inflammation, vasculitis, and necrosis that occurs as a complication of radiotherapy. There are two main categories of ARE that result in vasogenic cerebral edema: first, a residual irritant mass of the targeted lesion; and second, radiation-damaged perilesional normal brain tissue in a reactive state. Radiation injury leads to fibrinoid and coagulative necrosis of different cell types and fibrinoid necrosis and hyalinization of vessels. The clinical consequence of ARE is neurologic impairment secondary to vasogenic edema in the normal brain. Neuroimaging may aid in differentiating tumor recurrence from ARE. However, imaging studies are not definitive, and their utility in this setting remains controversial. The management of patients with ARE is dictated by symptom occurrence. The definitive management of symptomatic ARE is craniotomy and resection. Alternative therapies include bevacizumab, laser-interstitial thermal therapy, and reirradiation.

How to cite this article:
Fabiano AJ, Prasad D, Qiu J. Adverse radiation effect in the brain during cancer radiotherapy.J Radiat Cancer Res 2017;8:135-140

How to cite this URL:
Fabiano AJ, Prasad D, Qiu J. Adverse radiation effect in the brain during cancer radiotherapy. J Radiat Cancer Res [serial online] 2017 [cited 2023 Mar 23 ];8:135-140
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The framework for modern fractionated radiation therapy was described by the French physician Coutard in 1937.[1] Therapeutic brain radiation began in the 1950s and has continued to evolve since that time.[2],[3] Today, external beam intensity-modulated radiation therapy is used to deliver ionizing radiation to treat a variety of intracranial pathologies including primary brain tumors, brain metastases, intracranial lymphoma, and atypical meningiomas.[4],[5],[6],[7],[8] Treatments are individualized with a typical conformal intensity-modulated radiation therapy field for glioblastoma receiving 60 gray (Gy) in 30 fractions, and a typical whole-brain radiation treatment (WBRT) for brain metastases delivered as 30 Gy in 10 fractions.[2],[4]

Lars Leksell pioneered the use of stereotactic radiosurgery (SR) to treat brain lesions. He first described this technique in the 1940s, and his work culminated in the creation of a cobalt-60 machine at the Karolinska Institute in Stockholm, Sweden, in 1968.[9],[10] The cornerstone of SR is the accurate delivery of a high radiation dose to a specific brain target while minimizing the amount of radiation to the surrounding normal brain tissue.[11] Today, methods of SR delivery include cobalt-60–based machines, linear accelerators, and cyclotrons.[11],[12] SR is a proven and effective therapy for a variety of intracranial pathologies including brain metastasis, meningioma, vestibular schwannoma, arteriovenous malformation, and trigeminal neuralgia.[13],[14],[15],[16],[17]

Adverse radiation effect (ARE) in the brain is the reactive inflammation, vasculitis, and necrosis that occurs as a complication of radiotherapy. The term ARE includes the conditions alternatively described as radiation necrosis, radiation-induced small vessel vasculitis, and pseudoprogression.[18],[19],[20] In common parlance, ARE is typified by these postradiation inflammatory reactions; however, it is an inclusive term that may also be used to describe delayed radiation-induced large-vessel vasculopathy and leukoencephalopathy.

 Radiation Biology

The neocortex is histologically composed of neurons in a laminar organization.[21] Brain capillaries and surrounding astrocytes form the structural matrix of the brain. Oligodendrocytes insulate white matter tracts and regulate cell metabolism.[21] All anatomic components of the brain ultrastructure are susceptible to injury secondary to brain irradiation.

Radiation treatment results in cell death by causing DNA injury including double-strand DNA breaks, micronuclei formation, and chromosome aberrations.[22] Additional damage occurs to other cellular elements including microtubules.[22],[23] As cells progress through the cell cycle, the apoptotic program is initiated, resulting in cell death.[22],[24] In the human brain, p53-mediated apoptosis and tumor necrosis factor alpha cytotoxicity have been demonstrated to contribute to radiation-induced cell death.[25],[26] Apoptosis is an active process of cell death contrasting with the passive cell destruction that occurs in necrosis.[22]

A definitive description of the cellular pathogenesis of brain injury following irradiation has yet to be described. Brain irradiation can result in early brain injury secondary to transient white matter demyelination or a delayed brain injury characterized by a reduction in neurons and white matter necrosis.[27] Radiation-induced vascular injury can lead to ischemia and secondary white matter necrosis.[27] A combination of reactive astrocytosis and sustained microglial activation secondary to irradiation can result in a sustained pro-inflammatory state resulting in neuronal toxicity.[28] Due to the limited capacity for neurogenesis in adults, cellular damage from brain irradiation is often permanent.

 Adverse Radiation Effect Pathophysiology

There are two main categories of ARE that result in vasogenic cerebral edema: a residual irritant mass of the targeted lesion and radiation-damaged perilesional normal brain tissue in a reactive state.[11],[18] Following irradiation, a treated lesion may remain in the brain and stimulate the inflammatory cascade. Cytokine release results in endothelial cell permeability and subsequent vasogenic cerebral edema. Further, when treating cancer with radiation, the tumor cells may avoid apoptotic cell death and undergo necrosis secondary to the radiation therapy.[29] Necrosis results in the release of cellular contents into the intracellular space, again resulting in an inflammatory cascade and cytokine release. Ultimately, the patient's immune response is required to remove the treated cells and prevent them from stimulating a persistent inflammatory reaction within the brain. Restricting the immune-mediated removal of lesional tissue can allow ARE to develop or persist, as is observed in patients undergoing SR while receiving immune therapy for a systemic cancer.[30],[31]

Radiation damage to the perilesional brain parenchyma can also incite ARE. Injury to brain parenchyma is considered a radiotherapy late-response because these target cells are gradually proliferating with a slow rate of cell loss.[22] Radiation injury leads to fibrinoid and coagulative necrosis of different cells types and fibrinoid necrosis and hyalinization of vessels [Figure 1].[11] As necrotic cell debris is released, cytokine-mediated endothelial cell leakage results in vasogenic cerebral edema. Macrophage infiltration of the interstitial space occurs to digest necrotic debris. This process is rapidly propagated due to a local vascular endothelial proliferation that occurs in the ARE perilesional brain.[11],[32] The resultant inflammatory reaction obstructs the removal of inciting cellular debris and allows ARE to persist.{Figure 1}

The timing of ARE following radiotherapy is variable. For lesions treated with SR, ARE typically occurs 3 to 18 months postprocedure, peaking 9–12 months post-SR.[11],[33] Patients undergoing multiple treatments to the same region (SR/SR, WBRT/SR) may experience a 3-month peak.[34] ARE may initiate a rapid growth distinguishable from tumor recurrence growth that would be expected to follow a logarithmic growth model.[35] This ARE growth pattern highlights the self-propagating ARE inflammatory cascade.

 Clinical Presentation

The clinical consequence of ARE is neurologic impairment secondary to vasogenic edema in the normal brain. Although direct neuronal or oligodendroglial damage may occur, primary cell damage from ARE that results in a clinical manifestation is exceedingly rare. This has significant clinical ramifications because effective treatment of symptomatic ARE can lead to symptom resolution. Initial presentation is variable and is dependent on the location of the ARE-induced edema within the brain. Neurologic deficit (such as mixed aphasia), headache, and seizure are common presentations [Figure 2]. Asymptomatic ARE may be detected on routine surveillance neuroimaging.{Figure 2}


ARE is a diagnosis made on the basis of pathologic findings. A noninvasive test to definitively diagnose ARE does not exist.[11] Neuroimaging may aid in differentiating tumor recurrence from ARE; however, imaging studies are not definitive, and their utility in this setting remains controversial.[36] Standard magnetic resonance imaging will show the enlargement of a gadolinium-enhancing lesion with surrounding vasogenic edema in instances of ARE [Figure 2] and [Figure 3]. A gadolinium-enhancing vessel neighboring the enlarging lesion is often identified. T1/T2 mismatching is a useful method for evaluating a suspected area of ARE.[37] T1/T2 mismatch can be expressed quantitatively with the lesion quotient equal to the maximal cross-sectional area of the postgadolinium T1-weighted contrast enhancement divided by the T2-weighted hyperintensity.[38] A lesion quotient of <0.3 was found in 80% of cases of ARE, whereas a lesion quotient of >0.6 was found in the tumor. Positron emission testing may demonstrate increased glucose metabolism with both ARE and tumor growth, thus its use to evaluate tumor progression versus ARE is discouraged.[11] Perfusion-weighted imaging and arterial spin labeling images have shown promise for distinguishing ARE from tumor progression.[36],[39],[40] Further study of these modalities, correlated with pathologic specimens, is warranted.{Figure 3}

The best method for evaluating an enlarging lesion in the setting of potential ARE is a careful, side-by-side review of all patient images over time. Fully understanding the behavior timeline of the lesion in the context of all radiotherapy treatments offers the greatest insight into distinguishing ARE from recurrent tumor. Patients undergoing WBRT often experience an acute episode of ARE 6–8 weeks following the completion of their fractionated treatment. Conversely, SR-induced ARE should be considered when lesion growth occurs during the 3 or 9–12 months post-SR peaks. Delayed ARE secondary to WBRT occurs 6–24 months following the completion of therapy. SR-induced ARE should be included in the differential diagnosis when a tumor initially contracts after SR and then rapidly grows in a delayed fashion.


The management of patients with ARE should be initially dictated by symptom occurrence. In patients who are asymptomatic, serial neuroimaging is recommended with an interval determined by lesion location and clinical scenario. The natural history of ARE is abatement over time; thus, in asymptomatic patients, close monitoring may be sufficient until the lesion resolves. The duration of ARE can vary so the clinician must be mindful that it is difficult to judge where along the peak of edema a given lesion resides until a decrease in lesion size is observed. A stereotactic biopsy is an option in situ ations where the diagnosis of recurrent tumor would necessitate additional treatment. Alternatively, in some clinical situations, the lesion can be monitored with neuroimaging until it causes the patient to have symptoms. Corticosteroids should not be routinely prescribed to asymptomatic patients. If neuroimaging demonstrates vasogenic edema in an epileptogenic area of the brain, antiepileptic prophylaxis is optional.

Initial management of symptomatic ARE patients can include corticosteroid administration. Corticosteroids decrease vasogenic cerebral edema by reducing endothelial cell permeability through an effect on cytoskeletal and tight junction proteins.[41] Corticosteroid therapy should only be viewed as a temporizing measure in the treatment of ARE due to significant treatment toxicities. Toxicities may include weight gain, cosmetic deformities, gastric ulcer, bowel perforation, osteoporosis, bone fracture, hyperglycemia, peripheral edema, increased risk for infection, hypertension, pancreatitis, and psychosis.[42] Corticosteroid therapy may be continued during a short course of observation to manage symptoms or until definitive treatment is rendered. A primary purpose of the treatment of symptomatic ARE is to obviate the need for corticosteroid therapy. In addition, maintenance of corticosteroids may prohibit the use of certain chemo- and immune therapies necessary to manage a patient's systemic disease.

The definitive management of symptomatic ARE is craniotomy and resection [Figure 3]. This should be particularly considered for superficial lesions in noneloquent areas of the brain. Many factors influence this clinical decision, including overall prognosis, age, and medical status of the patient, and the degree of impairment caused by the patient's symptoms. The upfront surgical resection of symptomatic ARE may result in symptom resolution and maintenance of a high functional performance status. When ARE abuts eloquent cortex, a small amount of lesional tissue may be left in place so as not to disturb the underlying normal cortex. If most of the lesion is resected, the symptomatic vasogenic edema should resolve with the small residual ARE abating over time. Delaying a craniotomy may cause a patient's condition to deteriorate such that a craniotomy is no longer a treatment option.

Additional treatment options exist for symptomatic ARE patients who are not strong candidates for craniotomy and resection. Deep-seated lesions may be amenable to laser-interstitial thermal therapy (LITT).[43],[44] Resolution of cerebral edema is protracted after LITT as compared to edema resolution after a craniotomy for resection.[45] Patients who are not surgical candidates may be treated with bevacizumab or reirradiation.[46],[47] The combination of pentoxifylline and Vitamin E may have a marginal effect on the duration of ARE, whereas evidence to support the use of hyperbaric oxygen for ARE is sparse.[11] Newer immune therapies cross the blood–brain barrier and may offer a treatment option for ARE; further study in this area is warranted.[48]


ARE is a frequent occurring pathologic process in a neuro-oncology practice. Knowledge of pathophysiology and temporal behavior of ARE will aid the practitioner in distinguishing ARE from tumor progression. Asymptomatic ARE can be closely monitored, whereas symptomatic ARE is often best treated by craniotomy and removal. Corticosteroids should be viewed as a temporizing therapy for ARE and their prolonged administration avoided.


We thank Paul H Dressel BFA for preparation of the illustrations, Elaine C Mosher MLS and Debra J Zimmer for editorial assistance.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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