Radiation Necrosis

Radiation necrosis, a focal structural lesion that usually occurs at the original tumor site, is a potential long-term central nervous system (CNS) complication of radiotherapy or radiosurgery. Edema and the presence of tumor render the CNS parenchyma in the tumor bed more susceptible to radiation necrosis. Radiation necrosis can occur when radiotherapy is used to treat primary CNS tumors, metastatic disease, or head and neck malignancies. It can occur secondary to any form of radiotherapy modality or regimen.

In the clinical situation of a recurrent astrocytoma (postradiation therapy), radiation necrosis presents a diagnostic dilemma. Astrocytic tumors can mutate to the more malignant glioblastoma multiforme. Glioblastoma multiforme's hallmark histology of pseudopalisading necrosis makes it difficult to differentiate radiation necrosis from recurrent astrocytoma using MRI. See Medscape Reference articles Neurologic Manifestations of Glioblastoma Multiforme and Low-Grade Astrocytoma.

Therapeutic effects of radiotherapy

Radiation creates ionized oxygen species that react with cellular DNA. Tumor cells have less ability than healthy cells for DNA repair. Thus, between fractionation doses, healthy cells have a greater probability than tumor cells of repairing themselves. With each subsequent mitosis, the cumulative effects of unrepaired DNA result in apoptosis (cell death) of these tumor cells.

Central nervous system syndromes secondary to radiotherapy

Radiation necrosis is part of a series of clinical syndromes related to CNS complications of radiotherapy. These syndromes occur in a distinct chronologic order and have characteristic pathophysiology. While the term radiation necrosis is used to refer to radiation injury, pathology is not limited to necrosis and a spectrum of injury patterns may occur.

Acute encephalopathy occurs during and up to 1 month after radiotherapy. This acute encephalopathy is due to disruption of the blood-brain barrier.

Early delayed complications occur 1-4 months after radiotherapy. Early delayed complications are caused by white matter injury characterized by demyelination and vasogenic edema. Early delayed changes may produce a somnolence syndrome in children, reappearance of the initial tumor's symptomatology, temporary decline in long-term memory, and encephalopathy. In early delayed complications, patients may have increased edema and contrast enhancement on MRI (both symptomatic and asymptomatic) that may resolve spontaneously over a few months. Both the acute and early delayed complications are steroid responsive.

Treatment-induced leukoencephalopathy is the leading toxicity after primary CNS lymphoma and may be seen both early[1] and as a delayed consequence of treatment. It may be seen in greater than 90% of patients older than 60 years who have been successfully treated with combination chemotherapy and whole-brain radiation. A relationship between increased blood-brain barrier permeability and radiation therapy has been posited to contribute to this leukoencephalopathy and to methotrexate-induced vasculopathy. This also may be an etiology for the changes seen with radiation necrosis.

Radiation necrosis and diffuse cerebral atrophy are considered long-term complications of radiotherapy that occur from months to decades after radiation treatment. As opposed to the focal nature of radiation necrosis, diffuse cerebral atrophy is characterized by bihemispheric sulci enlargement, brain atrophy, and ventriculomegaly. Diffuse cerebral atrophy clinically is associated with cognitive decline, personality changes, and gait disturbances.

Studies

Liu et al reported that in children with pontine gliomas, a nearly always fatal brain tumor, bevacizumab may provide both therapeutic benefit and diagnostic information. They note that although radiation therapy can provide some palliation in such patients, it can also result in radiation necrosis and neurologic decline. In a study of 4 children, 3 children showed significant clinical improvement with bevacizumab and were able to discontinue steroid use, which, according to the authors, can have numerous side effects that significantly compromise a patient's quality of life. In 1 child who continued to decline on bevacizumab, it was later determined that the patient had disease progression, not radiation necrosis. In all cases, according to the investigators, bevacizumab was well tolerated[2] .

Barajas et al attempted, in a study of 57 patients, to determine whether T2-weighted dynamic susceptibility-weighted contrast material-enhanced (DSC) MRI can differentiate radiation-therapy-induced necrosis from glioblastoma multiforme. They found that mean, maximum, and minimum relative peak height and relative cerebral blood volume were significantly higher in patients with recurrent glioblastoma multiforme than in patients with radiation necrosis. In addition, they determined that mean, maximum, and minimum relative percentage of signal intensity recovery values were significantly lower in patients with recurrent glioblastoma multiforme than in patients with radiation necrosis[3] .

Levin et al designed a class 1 double-blind study to compare the treatment of cerebral radiation necrosis with bevacizumab or placebo in 14 patients. Their protocol use, clinical, imaging, and other measures clearly demonstrated a beneficial effect of bevacizumab. They used 4 cycles at 3-week intervals. The dose was 7.5 mg/kg. Theoretically, bevacizumab blocks the effect of vascular endothelial growth factor (VGEF) and decreases vascular permeability, a critical component of radiation-mediated injury in the brain. The long-term benefit is not known. One of the study patients required an additional dose[4] .

Plimpton et al used MRI to retrospectively study 101 children with solid brain tumors. Median follow-up for all patients was 13 months (range 3-51 mo). They concluded that findings in pediatric patients treated with radiotherapy for solid brain tumor suggests children may have an increased likelihood to develop radiation necrosis compared with adults[5] .

Radiation necrosis is coagulative and predominantly affects white matter. This coagulative necrosis is due to small artery injury and thrombotic occlusion. These small arteries demonstrate endothelial thickening, lymphocytic and macrophagic infiltrates, presence of cytokines, hyalinization, fibrinoid deposition, thrombosis, and finally occlusion.

The primary mechanism of the delayed injury in radiation associated with necrosis is secondary to vascular endothelial injury or direct damage to oligodendroglia. As a result, white matter tissue is often more affected than gray matter tissue. Radiation may have effects on fibrinolytic enzyme systems, with an absence of tissue plasminogen activator and an excess in urokinase plasminogen activator impacting tissue fibrinogen and extracellular proteolysis with subsequent cytotoxic edema and tissue necrosis. Whether immune-mediated mechanisms may also contribute to radiation-induced neurotoxicity is unclear, but an autoimmune vasculitis has been postulated as a secondary host response to tissue damage.

Animals exposed to radiation and given antibodies to cytokines (tumor necrosis factor, interleukin-1, tissue growth factor) have decreased survival compared to animals that do not receive these antibodies. These cytokines may be involved in initially protecting healthy tissue from the effects of radiation. With prolonged radiation exposure, these particular cytokines are overexpressed and result in a cascade of inflammatory events and vascular injury[6] .

In addition to vessel occlusion with resultant tissue necrosis, telangiectatic vessels, which may hemorrhage, occasionally form. Demyelination, oligodendrocyte dropout, axonal swelling, reactive gliosis, and disruption of the blood-brain barrier also can be observed.

Frequency

Natural history of the tumor in terms of prognosis and survival may affect the occurrence of radiation necrosis in a particular tumor population. In glioblastoma multiforme or metastatic disease with a poor long-term prognosis, the patient may not live long enough to develop radiation necrosis. Radiation necrosis can occur as soon as a few months or as long as decades after treatment. It generally occurs 6 months to 2 years after radiation therapy. Radiation injury may occur in 5-37% of patients treated for intracranial neoplasms[7] .

Mortality/Morbidity

Radiation necrosis can be fatal. It also can cause problems associated with a mass lesion, such as seizures, focal deficits, increased intracranial pressure, and herniation syndromes.

Radiation necrosis is a focal process that occurs at the initial tumor site.

• The history generally reflects a subacute or chronic re-emergence of the initial tumor symptoms.

• Occasional reports exist of patients developing diffuse areas of necrosis away from the initial tumor site.

• When obtaining a history, include questions to exclude stroke and infection, which can cause a tumorlike appearance on MRI.

Breakthrough or new seizures may occur. These seizures may be partial, complex partial, or partial with secondary generalization (grand mal).

Depending on the tumor location and rate of growth, radiation necrosis can present with signs of mass effect, elevated intracranial pressure, obstructive hydrocephalus, or one of the herniation syndromes.

Hemorrhage in late radiation necrosis is a rare but described phenomenon.[8]

Radiation necrosis involving the frontal or temporal lobes may produce cognitive and personality changes.

• In nasopharyngeal carcinoma, the anteromedial aspects of the temporal lobes are located in the radiation port.

• A patient with radiation necrosis in this location may develop symptoms of personality change, memory loss, amnesia, and/or Klüver-Bucy syndrome.

• Radiation necrosis resulting from radiotherapy for ocular and maxillary cancer can affect the frontal lobes. This can cause hemiparesis, apathy, and/or personality changes.

Evaluate mental status and cortical functioning in patients with radiation necrosis who have a supratentorial lesion or signs of increased intracranial pressure. In cortical testing, examine for aphasia, apraxia, attention, neglect, visuospatial skills, recognition, short-term recall, and calculation.

With the possibility of increased intracranial pressure, examine the fundus for possible papilledema and/or decreased or absent spontaneous venous pulsations.

Since radiation necrosis is a focal lesion, tailor the neurologic exam to look carefully for focality, lateralization, or asymmetry in motor, sensory, or coordination testing.

Since radiation necrosis occurs in the same region as the initial tumor bed, evaluate functions specific to that area of the CNS.

Multiple risk factors are thought to play a role in the development of radiation necrosis (RN). These include the cumulative radiation dose, fractionation size, treatment duration, treated volume, prior cranial radiation, and the use of adjuvant therapies. Additionally, probabilistic variables, such as the genetic profile of the radiated tumors or the host may also influence the risk of developing RN.[9]

Brain lesions > 1cm in diameter exhibit the greatest risk of developing RN.[9] Occurrence generally is related to total radiation doses and fractionation size. The risk increases with increasing doses and larger radiation fraction sizes.

• Tolerable total radiation dose to the brain is 6500–7000 cGy.

• Patients who have received a total dose of 5500 cGy have a 3–5% occurrence of radiation necrosis.

• Fractionation daily dose exceeding 200 cGy also increases risk.

• Cerebral necrosis is unlikely at doses less than 50 Gy in 25 fractions.[10]

• Hypofractionation is an effective strategy for treating recurrent high-grade gliomas without increasing the risk of RN.[11]

• A dose-dependent risk is also seen with stereotactic radiosurgery, where doses > 10 Gy to > 10.5 mL volume carry a 35% risk of RN,[12, 13] and up to 50% risk with 13 Gy to > 10 mL surface area.[13]

• A systematic review showed no correlation between the duration from initial radiotherapy to re-irradiation and the risk of RN.[14]

Other predisposing factors include the following:

• Adjunctive therapies such as the use of BRAF inhibitors with SRS, which in one study caused a 22% risk of RN compared to 11% in SRS alone.[15]

• Other vasculopathic risk factors (eg, diabetes mellitus, hypercholesterolemia).

• Chemotherapy: Chemotherapy increases the risks of necrosis even when adjusting for length of follow-up or initial radiation therapy dose.

• A study of 5747 brain lesions by Miller et al. provided novel insight into the relationship between tumor biology and risk of RN. They found that metastatic renal and small-cell lung carcinomas were correlated with a greater likelihood of RN. Furthermore, HER2-amplification, BRAF V600+ mutational status, and ALK rearrangement appeared to be significantly associated with RN.[16]

• Individual risk factors, such as variations in genetic radiosensitivity, also contribute to the risk of RN. Wang et al. identified the gene Cep128 as a radiation injury susceptibility gene.[17]

A fundamental problem in the diagnosis of radiation necrosis is that most imaging studies do not preclude the need for surgical brain biopsy or craniotomy for diagnosis. The typical appearance of brain radiation injury is similar to that of brain tumors, with a contrast-enhancing mass surrounded by edema and mass effect.[18]

With conventional MRI, CT scan, positron emission tomography with [18 F]-labeled fluorodeoxyglucose (PET-FDG), and thallium 201 spectroscopy (single-photon emission CT [SPECT]), differentiating radiation necrosis from the recurrent tumor is difficult.[19]  Recently many advanced imaging techniques like diffusion-weighted images (DWI), perfusion-weighted Images (PWI), and Magnetic resonance spectroscopy (MRS) have been used to differentiate radiation necrosis from pseudoprogression or progression of the tumor. Most of the research has been focused on recurrent astrocytoma. See the images below.

CT scan

CT scan is not helpful in making the diagnosis of RN.

It is most useful in the acute, clinical decline of a patient with a brain tumor to differentiate acute hemorrhage from increased intracranial pressure, obstructive hydrocephalus, or a herniation syndrome.

Conventional MRI

MRI signal changes in radiation necrosis cannot be differentiated from tumor-related changes.

In a study by Asao et al, diffusion-weighted MRI sequences of radiation necrosis were associated with marked and spotty hypointensity compared with recurrent tumors, with maximal apparent diffusion coefficient values in each lesion being smaller for recurrent tumors versus radiation necrosis.[20]

Dequesada et al noted that lesions containing radiation necrosis never displayed gyriform lesion/edema distribution, marginal enhancement, or solid enhancements. [21]

Dequesada et al reported that the lesion quotient (which is the ratio of the nodule as seen on T2 imaging as compared to the total enhancing area on T1 imaging) was associated with a quotient of 0.6 or greater in all cases of the recurrent tumor and a quotient of 0.3 or less was seen in 4 of 5 cases of radiation necrosis.[21]

T1, T1 with gadolinium, T2, T2- fluid-attenuated inversion recovery (FLAIR), and proton density do not adequately enable differentiation of radiation necrosis from tumors.

Reddy el al concluded that enhancement patterns on MRI were just as accurate in predicting pathologic diagnosis as MR spectroscopy.[22]

Previously, radiation necrosis was believed to have greater peripheral than central enhancement with gadolinium. However, this peripheral enhancement pattern is not a consistent finding in radiation necrosis. Tumors also may display a greater peripheral than central enhancement.

MRI patterns that may signal but are not diagnostic for the possibility of radiation necrosis include the following:

• Non-enhancing tumors prior to surgery that have enhancing foci that subsequently develop within and circumscribed to the tumor bed may represent necrosis rather than progression to the higher-grade tumor.

• Enhancing lesions that develop some distance from a primary glioma but within the radiation field may be indicative of radiation necrosis.

• The enhancing focus in the periventricular white matter, particularly within the corpus callosum or the top of the ventricles, may represent necrosis because the periventricular white matter is highly susceptible to radiation necrosis.

• Consider radiation necrosis if a new MRI enhancing lesion has a soap-bubble or Swiss-cheese appearance.

Perfusion weighted images (PWI)

Dynamic susceptibility contrast (DSC), dynamic contrast-enhanced (DCE), and arterial spin labelling (ASL) are the three MRI perfusion imaging techniques used. DSC and DCE rely on the injection of intravenous contrast agent whereas the ASL uses magnetically labeled blood as an endogenous contrast media.[23]  DSC is the most employed technique with the best diagnostic performance among the three. Regional cerebral blood volume (rCBV) measurement in DSC demonstrates a significant elevation in the setting of tumor progression compared to radiation necrosis. Mean rCBV thresholds in the range of 0.9 to 2.15 and maximum rCBV between 1.49 and 3.10 have predicted tumor progression with more than 95% accuracy.[24]  Quantitative hemodynamic indices like the transfer constant (Ktrans ) and fractional plasma volume (Vp )  measured in DCE showed higher values in true progression compared to radiation necrosis[24, 25]  (Figures 2A and 2B).

Diffusion-weighted images (DWI)

Homogeneous or multifocal high signal intensity on diffusion-weighted images was observed in tumor progression compared to peripheral or no hyperintensities in cases of pseudoprogression and radiation necrosis.[24, 26]

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) offers a new, quantitative approach to help differentiate radiation necrosis from tumor recurrence.

A few studies with histologic confirmation demonstrate the potential of MRS in differentiating radiation necrosis from tumor recurrence.

Future studies will determine the usefulness of MRS in avoiding biopsy or craniotomy for definitive diagnosis. MRS measures various brain metabolic markers, as follows:

• Creatine is indicative of cellular bioenergetics

• Choline (Cho) compounds reflect membrane metabolism

• Lactate (Lac) reflects anaerobic metabolism

• N -acetyl aspartate (NAA) is an amino acid marker of neurons

• Gliomas have high peaks in Cho and even higher peaks in creatine when compared to healthy brain tissue

• Radiation necrosis has decreased peaks in Cho, NAA, and creatine compared to healthy brain tissue

• MRS may be of particular use in distinguishing pure tumor from pure necrosis. Knowledge of the choline/creatine and lipid-lactate/choline ratios may allow one to distinguish between tumor and necrosis; the good correlation between MRS and lesion biopsy findings was reported from a study by Rock et al.[27]

The multimodal assessment using a combination of the above modalities may have a better predictive ability in differentiating progression from radiation necrosis.[24] A low apparent diffusion coefficient (ADC), high regional cerebral blood volume (rCBV), high transfer constant (Ktrans), high fractional plasma volume (Vp), and high choline: creatinine ratio in multiparametric MRI suggested tumor recurrence rather than radiation necrosis.[24, 28]

Dynamic testing

Dynamic testing (eg, PET-FDG, SPECT) detects differences in tissue metabolism.

Tumors have greater metabolism (ie, increased uptake of PET-FDG and SPECT) than healthy brain parenchyma and areas of radiation necrosis.

Radiation necrosis is hypometabolic (ie, decreased uptake of FDG and thallium) compared to healthy brain parenchyma.

PET-FDG uses glucose transport and glycolysis as markers of metabolic activity.

Other PET imaging tracers have been proposed, including fluoride-labeled boronophenylalanine and other amino-acid tracers. These may be more useful in the detection of tumors because the background protein metabolism activity is lower than sugar and the background activity of brain glucose metabolism may complicate interpretations of PET-FDG.[29]

13 N-NH3 PET may also be useful because this compound is associated with high uptake in even low-grade astrocytomas, thus possibly allowing clinicians to distinguish between recurrent astrocytoma and radiation necrosis.[30]

Thallium metabolic activity is due to its similarity to potassium.

Thallium SPECT reflects the metabolic activity of sodium/potassium ATP-dependent membrane transport, chloride transport, and calcium channels.

In dynamic testing, a region of interest (ROI) is compared to a similar area of a healthy brain. An ROI located in one hemisphere is compared to a similar area in the contralateral hemisphere.

For bihemispheric lesions, an ROI is compared to an equivalent region in the anterior-posterior or posterior-anterior areas of brain parenchyma.

Most medical centers use qualitative assessments of ROI rather than quantitative assessments.

Despite diagnostic benefits and limitations of dynamic testing, histology often demonstrates mixed findings of malignant cells and radiation necrosis.

Advantages of PET-FDG [31]

PET-FDG correlates with prognosis and survival for newly diagnosed astrocytoma. Astrocytoma research has demonstrated that increased FDG uptake correlates with decreased survival.

Increased FDG activity on PET is more indicative of higher-grade astrocytomas such as anaplastic astrocytoma or glioblastoma multiforme.

PET-FDG also has assisted in guiding brain biopsy sites. Since brain biopsies are subject to sampling error, PET-FDG can assist the surgeon in obtaining the most metabolically active tissue to allow more accurate tumor staging.

PET-FDG is diagnostically useful in evaluating a tumefactive lesion (ie, a structural lesion on MRI that suggests tumor) when clinical history suggests another diagnosis (eg, stroke, demyelination, abscess).

Despite the potential of this tool in a newly diagnosed brain tumor, PET-FDG becomes problematic when differentiating radiation necrosis from tumor recurrence.

Disadvantages of PET-FDG

Its sensitivity and specificity in differentiating radiation necrosis from tumor recurrence are related to various factors. Overall, the sensitivity of FDG-PET has been reported as 80-90%, but the specificity is lower (50-90% depending on the series).[7]

An ROI of less than 1.6 cm lowers sensitivity and specificity in the differentiation of radiation necrosis from tumor recurrence.[32]

An ROI located in the temporal lobes and brain stem may have poor resolution due to artifacts from nearby bony structures.

Inflammatory cells in areas of radiation necrosis may show increased metabolic activity, which falsely can indicate tumor recurrence.

Tumor cells also may be present in areas of low glucose activity on PET-FDG.

Brain tissue used for comparison to the ROI can become depressed metabolically from radiotherapy and/or chemotherapy.

Carbon C 11–methionine PET scanning may be a complementary study to FDG-PET. In one series, 31 of 35 brain tumors showed increased11 C-methionine despite isometabolism or hypometabolism on FDG-PET scans, and 10 benign lesions (of which 2 were cases of radiation necrosis) showed decreased or normal uptake of11 C-methionine. [33]

Thallium single-photon emission CT scan

Except for being more readily available at more medical centers than PET-FDG, thallium SPECT has the same limitations in dynamic testing.

A thallium index greater than 1.5 generally correlates with anaplastic astrocytoma, glioblastoma multiforme, primary CNS lymphoma, or metastasis. Overall, imaging studies provide additional information, but they cannot provide a definitive diagnosis (ie, to avoid biopsy or craniotomy).

Overall, imaging studies provide additional information, but they cannot provide a definitive diagnosis (ie, to avoid biopsy or craniotomy).

The similarities of radiation necrosis and tumor recurrence in clinical presentation and diagnostic imaging make performing a brain biopsy critical for diagnosis.[18]

Diagnosing radiation necrosis is problematic. The diagnosis depends on obtaining adequate biopsy findings and is prone to sampling errors up to15%.[34]

A brain biopsy sample must be large enough to exclude tumor recurrence without causing clinically significant neurologic deficits. Areas to avoid include the deep central areas of the thalamus, the motor strip, occipital lobe, and speech centers.

There is preliminary evidence that indicates the promising role of liquid biopsy as a diagnostic alternative to intracranial biopsies. Quantitative assays of Annexin V-positive microvesicles that are secreted into the bloodstream by GBM can aid in differentiating between tumor progression and pseudoprogression.[35]  Similarly, the ratio of myeloid suppressor cell-derived biomarkers HLA-DR and vascular noninflammatory molecule 2 expressions on CD14+ monocytes, termed the DR-Vanin Index (DVI) has been shown to distinguish RN from tumor progression with adequate certainty.[36]

Radiation necrosis tissue samples demonstrate necrotic tissue without predominance of malignant cells.

Irradiated tumor may contain necrosis, which does not necessarily signify radiation necrosis.

Some biopsy findings of radiation necrosis show both malignant cells and radiation necrosis.

A hallmark of radiation necrosis is involvement of the white matter with demyelination and oligodendrocyte dropout.

In addition to necrotic tissue, biopsy findings of radiation necrosis may demonstrate thickened vessels with endothelial proliferation and/or hyalinization with fibrosis and moderate infiltration of lymphocytes and macrophages.

Probably the most important factor in providing good care is the clinician's confidence of diagnosis. Exposing a patient with radiation necrosis to unwarranted antineoplastic treatment is not desirable.

A conservative option in treating a patient with radiation necrosis is observation. This may be appropriate for a patient found to have an asymptomatic necrotic mass on follow-up MRI. If the patient is asymptomatic and definitive diagnosis of radiation necrosis or recurrent glioma does not make a difference in clinical management, the patient should be monitored clinically and with serial MRI scans.

For patients with signs and symptoms of mass effect, increased intracranial pressure, or neurologic disability, consider other treatment options. Consider surgical evaluation, steroids, anticoagulation, or hyperbaric oxygen therapy separately or in combination.[37, 38, 39]

A study of 14 patients with radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs responded to bevacizumab with decreases in T(2)-weighted fluid-attenuated inversion recovery and T(1)-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. This trial provided class I evidence of the efficacy of bevacizumab as a treatment for CNS radiation necrosis.[40]

In another study of the efficacy of bevacizumab, researchers reviewed 14 lesions in 11 patients treated with bevacizumab for brain RN secondary to SRS for their brain metastases. The mean percentage decrease in RN volume seen on T1 post-Gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI at first follow-up, at a mean of 26 days (range, 15-43 days), was 64.4% and 64.3%, respectively.[41]

Hyperbaric oxygen promotes perfusion and angiogenesis.

• Oxygen is delivered at 2-3 atm for 20-30 sessions. Each session lasts approximately 90-120 minutes.

• Hyperbaric oxygen therapy is expensive, time-consuming, and not readily available at most medical centers.

• Efficacy is not well documented.

• Small case studies exist, but many of these patients also were receiving concomitant steroid therapy. These clinical series showed resolution of a lesion on MRI.[37]

• Hyperbaric oxygen can be provided in conjunction with anticoagulation.

In addition to providing potential histologic diagnosis, surgery has other therapeutic benefits. Surgical debulking of the lesion can relieve increased intracranial pressure and improve disability. Patients with obstructive hydrocephalus may require a shunting procedure. Surgery, however, is associated with a high risk of complications or neurologic deficit and should be reserved for symptomatic patients in whom medical therapy fails.

Laser interstitial thermal therapy

Laser interstitial thermal therapy (LITT) can be used in cases where medical management has failed, and surgical treatment is either contraindicated due to high surgical risks or the lesion is in a surgically inaccessible location. In these cases, LITT can help control the perilesional edema and potentially reduce the dose of steroids required. LITT can help obtain a simultaneous biopsy, particularly in asymptomatic patients with serial imaging showing a progression. A few anecdotal pieces of evidence suggest that the LITT can completely resolve the radiation necrosis, improve overall survival, and have a better long-term reduction of lesional volume.[42, 43, 44]

Medical therapy focuses on two mechanisms: controlling vasogenic edema and/or controlling vessel thrombosis.

Class Summary

Steroid therapy has only a temporary role in relieving neurologic decompensation and deficits. It relieves any symptomology related to vasogenic edema and disruption of the blood-brain barrier. While administering steroid therapy, the clinician must implement another medical or surgical therapy to treat radiation necrosis and to protect the patient from long-term complications.

Dexamethasone (Decadron, Dexasone)

Glucocorticoids such as dexamethasone have potent anti-inflammatory effects in many disorders. In addition to metabolic effects, they modify immune system response. Lacks salt-retaining property of hydrocortisone.

Patients can be switched from an IV to PO regimen in a 1:1 ratio.

Class Summary

Because radiation necrosis pathophysiology involves vessel thrombosis and subsequent occlusion, anticoagulant use has been proposed.[45] To date, few case studies have addressed use in this condition; the evidence for anticoagulation is very limited. Patients with radiation necrosis may also be at risk of intracranial hemorrhage, further limiting the presumptive benefits of this therapy. In most of these studies, histologic verification of radiation necrosis was present. Patients received 6 mo of IV heparin, then warfarin with aPTT and PT adjusted to 1.5 times the control. Patients had significant resolution of deficits. When anticoagulation was stopped, symptoms reemerged. Almost immediate resolution of symptoms occurred when anticoagulation was restarted. Before starting anticoagulation therapy, careful diagnostic evaluation and management are needed.

Heparin

Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Check aPTT after the first 6 h, then periodically q4-6h in early treatment. Dosage is therapeutic when aPTT is adjusted to 1.5 times normal.

Warfarin (Coumadin)

Inhibits synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) and anticoagulants (proteins C and S). Vitamin K is a cofactor for postribosomal synthesis of vitamin K-dependent clotting factors, which promote synthesis of gamma-carboxyglutamic acid (necessary for proper coagulation). Reportedly interferes with vitamin K epoxide regeneration. Peak anticoagulant effect is 72-96 h. Like other anticoagulants, warfarin has no effect on a preexisting thrombus.

Individualize dose in response to PT/INR and therapeutic goal. Periodic determination of PT/INR is required.

Class Summary

Agents in this category are used to decrease blood supply to a tumor by inhibiting angiogenesis.[46, 47]

Bevacizumab (Avastin)

A recombinant, humanized antibody that inhibits vascular endothelial growth factor (VEGF). VEGF has a significant role in angiogenesis and maintenance of existing blood vessels. By inhibiting VEGF, the antibody would interfere with the blood supply to a tumor, which is thought to be critical to tumor metastasis. By preventing VEGF from reaching leaky capillaries that are associated with brain swelling, bevacizumab may also help in radiation necrosis.

Fifteen patients with malignant brain tumors were treated with bevacizumab or bevacizumab combination n in one study.

Many neuro-oncology patients have significant cognitive and neurologic disabilities. These may require physical therapy, occupational therapy, social work support, and home nursing.

Consider the special medical needs of immobilized patients with a decreased level of consciousness and paralysis. They are more susceptible to deep venous thrombosis, pulmonary embolism, pneumonia, sepsis, malnutrition, and skin breakdown.

Depending on lesion site and treatment effects, patients with brain tumors may be more predisposed to cognitive difficulties and dementia, which in turn increase the risk of delirium and cognitive difficulties. Prevention and treatment of delirium includes reorientation techniques, frequent interactions with familiar personal contacts (eg, family members), minimal or no exposure to psychotropic medications, control of noxious visual and auditory stimuli, correction of underlying metabolic derangements, and maintenance of a normal sleep-wake schedule.

Prognosis is related to the natural history of underlying tumor and the idiosyncratic nature of radiation necrosis. Some lesions may show no interval growth while others require multiple resections to relieve disability. While long-term survival is uncommon, prolonged survival in the context of radiation necrosis has been described.