eMedicine Specialties > Neurology > Neuro-oncology

Radiation Necrosis

Michael J Schneck, MD, Associate Professor, Departments of Neurology and Neurosurgery, Stritch School of Medicine, Loyola University; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center
Anna Janss, MD, PhD, Associate Professor of Pediatric Neuro-oncology, Emory University School of Medicine; Consulting Neuro-oncologist, Children's Healthcare of Atlanta

Updated: Feb 24, 2010

Introduction

Background

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 eMedicine articles 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.

Recent 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 ]}

Pathophysiology

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.^{[4 ]}

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

United States

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.^{[5 ]}

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.

Clinical

History

• 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.^{[6 ]}
• 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.

Physical

• 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.

Causes

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 below 50 Gy in 25 fractions.^{[7 ]}
• Other predisposing factors include the following:
  • 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.

Differential Diagnoses

Other Problems to Be Considered

Patients with a diagnosis of either a primary or metastatic brain tumor with a CNS event should undergo a meticulous review of their histories for other possible causes.

Sagittal sinus thrombosis
Neurologic complications related to antineoplastic treatments
Radiation-induced neoplasm
Brainstem syndromes
Complex partial status epilepticus
Increased intracranial pressure
Vascular dementia

Workup

Laboratory Studies

No specific tests of the serum or cerebrospinal fluid are indicated.

Imaging Studies

A fundamental problem in 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.

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 recurrent tumor is difficult. Most of the research has been focused on recurrent astrocytoma.

MRI of a patient with symptoms of gait unsteadiness 1 year after being diagnosed with a posterior fossa primitive neuroectodermal tumor (PNET). Treatment during the 1-year interval prior to this MRI consisted of surgical resection, craniospinal radiation of 2340 cGy, boost dose given to the posterior fossa for a total of 5500 cGy, chemotherapy (vincristine, cis-platinum, and cyclohexylchloroethylnitrosurea [CCNU]), and dexamethasone therapy.

Positron emission tomography with [18F]-labeled fluorodeoxyglucose (PET-FDG) performed following the MRI of a patient with symptoms of gait unsteadiness 1 year after being diagnosed with a posterior fossa primitive neuroectodermal tumor (PNET). Treatment during the 1-year interval prior to these studies consisted of surgical resection, craniospinal radiation of 2340 cGy, boost dose given to the posterior fossa for a total of 5500 cGy, chemotherapy (vincristine, cis-platinum, and cyclohexylchloroethylnitrosurea [CCNU]), and dexamethasone therapy. PET-FDG demonstrates hypometabolism consistent with probable radiation necrosis. Four years later, the patient is stable and without evidence of tumor progression.

• 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.^{[8 ]}
  • Dequesada et al noted that lesions containing radiation necrosis never displayed gyriform lesion/edema distribution, marginal enhancement, or solid enhancements.^{[9 ]}
  • 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 recurrent tumor and a quotient of 0.3 or less was seen in 4 of 5 cases of radiation necrosis.^{[9 ]}
  • T1, T1 with gadolinium, T2, T2- fluid-attenuated inversion recovery (FLAIR), and proton density do not adequately enable differentiation of radiation necrosis from tumors.
  • 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:
    • Nonenhancing 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 higher-grade tumor.
    • Enhancing lesions that develop some distance from a primary glioma but within the radiation field may be indicative of radiation necrosis.
    • Enhancing focus in the periventricular white matter, particular 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.
• CT scan
  • CT scan is not helpful in making the diagnosis of radiation necrosis.
  • It is most useful in the acute, clinical decline of a patient with brain tumor to differentiate acute hemorrhage from increased intracranial pressure, obstructive hydrocephalus, or a herniation syndrome.
• 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 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.^{[10 ]}
  • 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.^{[11 ]}
  • Thallium metabolic activity is due to its similarity to potassium.
  • Thallium SPECT reflects 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 healthy brain. A ROI located in one hemisphere is compared to a similar area in the contralateral hemisphere.
  • For bihemispheric lesions, a 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^{[12 ]}
  • 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 astrocytoma 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, 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).^{[5 ]}
  • A ROI less than 1.6 cm lowers sensitivity and specificity in the differentiation of radiation necrosis from tumor recurrence.^{[13 ]}
  • A ROI located in the temporal lobes and brain stem may have poor resolution due to artifact 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.^{[14 ]}
• 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 an anaplastic astrocytoma, glioblastoma multiforme, primary CNS lymphoma, or metastasis.
• 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 -acetylaspartate (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; good correlation between MRS and lesion biopsy findings was reported from a study by Rock et al.^{[15 ]}

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

Procedures

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

• Diagnosing radiation necrosis is problematic. The diagnosis depends on obtaining adequate biopsy findings and is prone to sampling error.
• 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.

Histologic Findings

• 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.

Treatment

Medical Care

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.^{[16,17 ]}
• Hyperbaric oxygen promotes perfusion and angiogenesis.
  • Oxygen is delivered at 20-24 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.^{[16 ]}
  • Hyperbaric oxygen can be provided in conjunction with anticoagulation.

Surgical Care

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.

Medication

Medical therapy focuses on 2 mechanisms: controlling vasogenic edema and/or controlling vessel thrombosis.

Corticosteroids

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.

Dosing

Adult

Cerebral edema: 10 mg IV initial, followed by 4 mg q6h until symptoms subside; if response noted in 2-24 h, reduce dose
Consider increasing dose if no response in 24 h

Pediatric

Administer as in adults

Interactions

Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effects of salicylates and vaccines used for immunization

Contraindications

Documented hypersensitivity; active bacterial or fungal infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use; increase standing dose for patients who are subjected to physiologic stress; provide GI protection with H2 antagonists or antacids

Anticoagulants

Because radiation necrosis pathophysiology involves vessel thrombosis and subsequent occlusion, anticoagulant use has been proposed.^{[18 ]}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.

Dosing

Adult

80 U/kg (5000 U for 68-kg male) IV bolus initially, followed by 18 U/kg/h continuous IV infusion

Pediatric

50 U/kg initially; 100 U/kg IV q4h or continuous 20,000 U/m²/24h maintenance

Interactions

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity

Contraindications

Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock; periodically monitor platelet counts and hemoccult stool testing during heparin therapy; bleeding time usually is unaffected by heparin; thrombocytopenia is a potential complication; may develop new thrombus formation due to irreversible thrombus aggregation in relationship to thrombocytopenia (white lot syndrome); may lead to severe thromboembolic complications of skin necrosis, gangrene of the extremities, and multisystem infarction; new thrombus in association with thrombocytopenia indicates heparin should be discontinued; patients whose aPTTs cannot be increased despite dosage adjustments should be evaluated for heparin resistance, which is encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, MI, cancer, and postsurgical patients; increased risk of bleeding in elderly women

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.

Dosing

Adult

Radiation necrosis: PT 1.5 times the control

Pediatric

Administer as in adults

Interactions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate; medications that may increase anticoagulant effects of warfarin include oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac

Contraindications

Documented hypersensitivity; severe liver or kidney disease; GI ulcers; preeclampsia; eclampsia; recent surgery; recent trauma; bleeding tendencies; overt bleeding; puncture and diagnostic procedures with increased risk of uncontrollable bleeding are contraindicated in patients with elevated PT/INR; may increase release of atheromatous/cholesterol plaque emboli; necrosis secondary to local thrombus may occur within a few days after initiating therapy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; only use IM injections when absolutely necessary; restrict injections to the upper limb, where manual compression can be performed; educate patients about avoiding contact sports, maintaining good nutrition with minimal variation in vitamin K-containing foods, and quickly reporting flulike and GI illnesses; address contraception issues

Monoclonal antibodies

Agents in this category are used to decrease blood supply to a tumor by inhibiting angiogenesis.

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.^{[19 ]}
Fifteen patients with malignant brain tumors were treated with bevacizumab or bevacizumab combination n in one study.^{[20 ]}

Dosing

Adult

Not established; 5 mg/kg IV q2wk or 7.5 mg/kg IV q3wk suggested

Pediatric

Not established: Use as per adult dose suggested

Interactions

Coadministration with 5-fluorouracil increases incidence (2-fold) of serious and fatal arterial thromboembolic events (ie, CVA, MI, TIAs, angina)

Contraindications

Documented hypersensitivity to antibody; major surgery within 28 days; unhealed surgical wounds; GI perforation; history of GI, pulmonary, or cerebral hemorrhage; hypertensive crises; nephritic syndrome; history of venous or arterial thromboembolism (ie stroke or MI); caution should be taken in patients with history of uncontrolled hypertension, proteinuria, CHF, or other cardiac disease, age >65

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

GI perforations; GI, pulmonary, or cerebral hemorrhage; fistula formation; wound healing complications; arterial thromboembolic events; venous thromboembolic events; hypertensive crises; posterior reversible leukoencephalopathy syndrome; neutropenia; infection; proteinuria; nephritic syndrome; congestive heart failure; immunogenicity to the drug

Follow-up

Further Inpatient Care

• 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.

Further Outpatient Care

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

Prognosis

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.

Multimedia

Media file 1: MRI of a patient with symptoms of gait unsteadiness 1 year after being diagnosed with a posterior fossa primitive neuroectodermal tumor (PNET). Treatment during the 1-year interval prior to this MRI consisted of surgical resection, craniospinal radiation of 2340 cGy, boost dose given to the posterior fossa for a total of 5500 cGy, chemotherapy (vincristine, cis-platinum, and cyclohexylchloroethylnitrosurea [CCNU]), and dexamethasone therapy.

Media file 2: Positron emission tomography with [18F]-labeled fluorodeoxyglucose (PET-FDG) performed following the MRI of a patient with symptoms of gait unsteadiness 1 year after being diagnosed with a posterior fossa primitive neuroectodermal tumor (PNET). Treatment during the 1-year interval prior to these studies consisted of surgical resection, craniospinal radiation of 2340 cGy, boost dose given to the posterior fossa for a total of 5500 cGy, chemotherapy (vincristine, cis-platinum, and cyclohexylchloroethylnitrosurea [CCNU]), and dexamethasone therapy. PET-FDG demonstrates hypometabolism consistent with probable radiation necrosis. Four years later, the patient is stable and without evidence of tumor progression.

References

1. Lai R, Abrey LE, Rosenblum MK, DeAngelis LM. Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study. Neurology. Feb 10 2004;62(3):451-6. [Medline].

2. Liu AK, Macy ME, Foreman NK. Bevacizumab as therapy for radiation necrosis in four children with pontine gliomas. Int J Radiat Oncol Biol Phys. Nov 15 2009;75(4):1148-54. [Medline].

3. Barajas RF Jr, Chang JS, Segal MR, Parsa AT, McDermott MW, Berger MS, et al. Differentiation of recurrent glioblastoma multiforme from radiation necrosis after external beam radiation therapy with dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology. Nov 2009;253(2):486-96. [Medline].

4. Kureshi SA, Hofman FM, Schneider JH, Chin LS, Apuzzo ML, Hinton DR. Cytokine expression in radiation-induced delayed cerebral injury. Neurosurgery. Nov 1994;35(5):822-9; discussion 829-30. [Medline].

5. Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation injury. J Nucl Med. Nov 2000;41(11):1861-7. [Medline].

6. Cheng KM, Chan CM, Fu YT, Ho LC, Cheung FC, Law CK. Acute hemorrhage in late radiation necrosis of the temporal lobe: report of five cases and review of the literature. J Neurooncol. Jan 2001;51(2):143-50. [Medline].

7. Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys. Jun 1 2006;65(2):499-508. [Medline].

8. Asao C, Korogi Y, Kitajima M, et al. Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence. AJNR Am J Neuroradiol. Jun-Jul 2005;26(6):1455-60. [Medline].

9. Dequesada IM, Quisling RG, Yachnis A, Friedman WA. Can standard magnetic resonance imaging reliably distinguish recurrent tumor from radiation necrosis after radiosurgery for brain metastases? A radiographic-pathological study. Neurosurgery. Nov 2008;63(5):898-903; discussion 904. [Medline].

10. Miyashita M, Miyatake S, Imahori Y, Yokoyama K, Kawabata S, Kajimoto Y, et al. Evaluation of fluoride-labeled boronophenylalanine-PET imaging for the study of radiation effects in patients with glioblastomas. J Neurooncol. Sep 2008;89(2):239-46. [Medline].

11. Xiangsong Z, Weian C. Differentiation of recurrent astrocytoma from radiation necrosis: a pilot study with 13N-NH3 PET. J Neurooncol. May 2007;82(3):305-11. [Medline].

12. Mogard J, Kihlstrom L, Ericson K, Karlsson B, Guo WY, Stone-Elander S. Recurrent tumor vs radiation effects after gamma knife radiosurgery of intracerebral metastases: diagnosis with PET-FDG. J Comput Assist Tomogr. Mar-Apr 1994;18(2):177-81. [Medline].

13. Kahn D, Follett KA, Bushnell DL, et al. Diagnosis of recurrent brain tumor: value of 201Tl SPECT vs 18F-fluorodeoxyglucose PET. AJR Am J Roentgenol. Dec 1994;163(6):1459-65. [Medline].

14. Chung JK, Kim YK, Kim SK, et al. Usefulness of 11C-methionine PET in the evaluation of brain lesions that are hypo- or isometabolic on 18F-FDG PET. Eur J Nucl Med Mol Imaging. Feb 2002;29(2):176-82. [Medline].

15. Rock JP, Hearshen D, Scarpace L, et al. Correlations between magnetic resonance spectroscopy and image-guided histopathology, with special attention to radiation necrosis. Neurosurgery. Oct 2002;51(4):912-9; discussion 919-20. [Medline].

16. Chuba PJ, Aronin P, Bhambhani K, et al. Hyperbaric oxygen therapy for radiation-induced brain injury in children. Cancer. Nov 15 1997;80(10):2005-12. [Medline].

17. Ashamalla HL, Thom SR, Goldwein JW. Hyperbaric oxygen therapy for the treatment of radiation-induced sequelae in children. The University of Pennsylvania experience. Cancer. Jun 1 1996;77(11):2407-12. [Medline].

18. Glantz MJ, Burger PC, Friedman AH, Radtke RA, Massey EW, Schold SC Jr. Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology. Nov 1994;44(11):2020-7. [Medline].

19. Wong ET, Huberman M, Lu XQ, Mahadevan A. Bevacizumab reverses cerebral radiation necrosis. J Clin Oncol. Dec 1 2008;26(34):5649-50. [Medline].

20. Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys. Feb 1 2007;67(2):323-6. [Medline].

21. Buchpiguel CA, Alavi JB, Alavi A, Kenyon LC. PET versus SPECT in distinguishing radiation necrosis from tumor recurrence in the brain. J Nucl Med. Jan 1995;36(1):159-64. [Medline].

22. Cerghet M, Redman B, Junck L, Forman J, Rogers LR. Prolonged survival after multifocal brain radiation necrosis associated with whole brain radiation for brain metastases: case report. J Neurooncol. Oct 2008;90(1):85-8. [Medline].

23. Chen W. Clinical applications of PET in brain tumors. J Nucl Med. Sep 2007;48(9):1468-81. [Medline].

24. de Vries B, Taphoorn MJ, van Isselt JW, Terhaard CH, Jansen GH, Elsenburg PH. Bilateral temporal lobe necrosis after radiotherapy: confounding SPECT results. Neurology. Oct 1998;51(4):1183-4. [Medline].

25. Deshmukh A, Scott JA, Palmer EL, Hochberg FH, Gruber M, Fischman AJ. Impact of fluorodeoxyglucose positron emission tomography on the clinical management of patients with glioma. Clin Nucl Med. Sep 1996;21(9):720-5. [Medline].

26. Ishikawa M, Kikuchi H, Miyatake S, Oda Y, Yonekura Y, Nishizawa S. Glucose consumption in recurrent gliomas. Neurosurgery. Jul 1993;33(1):28-33. [Medline].

27. Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatment. Radiology. Nov 2000;217(2):377-84. [Medline].

28. Lee AW, Foo W, Chappell R, et al. Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. Jan 1 1998;40(1):35-42. [Medline].

29. McPherson CM, Warnick RE. Results of contemporary surgical management of radiation necrosis using frameless stereotaxis and intraoperative magnetic resonance imaging. J Neurooncol. May 2004;68(1):41-7. [Medline].

30. Nelson MD Jr, Soni D, Baram TZ. Necrosis in pontine gliomas: radiation induced or natural history?. Radiology. Apr 1994;191(1):279-82. [Medline].

31. Nelson SJ, Huhn S, Vigneron DB, et al. Volume MRI and MRSI techniques for the quantitation of treatment response in brain tumors: presentation of a detailed case study. J Magn Reson Imaging. Nov-Dec 1997;7(6):1146-52. [Medline].

32. Olivero WC, Dulebohn SC, Lister JR. The use of PET in evaluating patients with primary brain tumours: is it useful?. J Neurol Neurosurg Psychiatry. Feb 1995;58(2):250-2. [Medline].

33. Omuro AM, Leite CC, Mokhtari K, Delattre JY. Pitfalls in the diagnosis of brain tumours. Lancet Neurol. Nov 2006;5(11):937-48. [Medline].

34. Packer RJ, Zimmerman RA, Kaplan A, et al. Early cystic/necrotic changes after hyperfractionated radiation therapy in children with brain stem gliomas. Data from the Childrens Cancer Group. Cancer. Apr 15 1993;71(8):2666-74. [Medline].

35. Peterson K, Clark HB, Hall WA, Truwit CL. Multifocal enhancing magnetic resonance imaging lesions following cranial irradiation. Ann Neurol. Aug 1995;38(2):237-44. [Medline].

36. Posner JB. Side effects of radiation therapy. Neurologic Complications of Cancer. No. 54. Philadelphia, Pa: FA Davis; 1995:311-37.

37. Rizzoli HV, Pagnanelli DM. Treatment of delayed radiation necrosis of the brain. A clinical observation. J Neurosurg. Mar 1984;60(3):589-94. [Medline].

38. Slizofski WJ, Krishna L, Katsetos CD, et al. Thallium imaging for brain tumors with results measured by a semiquantitative index and correlated with histopathology. Cancer. Dec 15 1994;74(12):3190-7. [Medline].

Keywords

leukoencephalopathy, radiation therapy, adverse effects of radiation therapy, radiotherapy effects, radiation therapy complications, radiotherapy complications, whole-brain radiation, radiation injury, radionecrosis

Contributor Information and Disclosures

Author

Michael J Schneck, MD, Associate Professor, Departments of Neurology and Neurosurgery, Stritch School of Medicine, Loyola University; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center
Michael J Schneck, MD is a member of the following medical societies: American Academy of Neurology, American Society of Neuroimaging, Neurocritical Care Society, and Stroke Council of the American Heart Association
Disclosure: boehringer-ingelheim Honoraria Speaking and teaching; sanofi/bms Honoraria Speaking and teaching; pfizer Honoraria Speaking and teaching; genentech Honoraria Speaking and teaching; ucb pharma Honoraria Speaking and teaching; talecris Consulting fee Other; nmt medical  Independent contractor; NIH Grant/research funds Independent contractor; vernalis Grant/research funds Independent contractor; sanofi Grant/research funds Independent contractor

Coauthor(s)

Anna Janss, MD, PhD, Associate Professor of Pediatric Neuro-oncology, Emory University School of Medicine; Consulting Neuro-oncologist, Children's Healthcare of Atlanta
Anna Janss, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Association for Cancer Research, American Medical Association, Children's Oncology Group, International Association for the Study of Pain, Pennsylvania Medical Society, Society for Neuro-Oncology, and Society for Neuroscience
Disclosure: Nothing to disclose.

Medical Editor

Frederick M Vincent Sr, MD, Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine
Frederick M Vincent Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners, American College of Legal Medicine, American College of Physicians, and Michigan State Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Jorge Kattah, MD, Head, Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
Jorge Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, and New York Academy of Sciences
Disclosure: Biogen Honoraria Consulting; Bayer Corporation Honoraria Consulting

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Robert Wilson, MD to the development and writing of this article.

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