ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Delayed complications of cranial irradiation

Delayed complications of cranial irradiation
Literature review current through: Jan 2024.
This topic last updated: Jan 09, 2024.

INTRODUCTION — Cranial irradiation is used to treat patients with primary or metastatic brain tumors and as prophylaxis for selected patients at high risk of neoplastic involvement of the nervous system. A full understanding of the potential consequences associated with cranial irradiation is needed both to manage potential complications and to properly counsel patients prior to treatment.

The late complications of fractionated cranial irradiation will be reviewed here. Early complications of brain radiation therapy and complications of spinal cord and peripheral nerve irradiation are discussed separately.

(See "Acute complications of cranial irradiation".)

(See "Complications of spinal cord irradiation".)

(See "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy'.)

(See "Lumbosacral plexus syndromes", section on 'Radiation plexopathy'.)

PATHOPHYSIOLOGY — Brain irradiation has global effects as well as tissue- and compartment-specific effects on brain vasculature as well as neuroglial cells and their precursors, including stem cells [1]. In addition, inflammation and blood-brain barrier disruption, induced by radiation, may also cause or enhance direct or indirect cellular damage by other mechanisms [2].

In preclinical studies, endothelial damage occurs within the first 24 hours after a large single dose of radiation [3]. The exact mechanism is not known, but endothelial cell apoptosis appears to play a major role. Preclinical studies further suggest that radiation may act directly on the plasma membrane of several cell types, activating acid sphingomyelinase and generating ceramide, an initiator of apoptosis [4]. Endothelial damage can lead to subsequent disruption of the blood-brain barrier and other late vascular effects, such as telangiectasias, microvascular dilatation, thickening and hyalinization of the vessel wall, and development of cavernomas or aneurysms. As a result, ischemic strokes or brain hemorrhage, including microbleeds, may occur months to years after brain radiation [5]. (See 'Cerebrovascular effects' below.)

Tissue necrosis is a distinct syndrome of radiation toxicity, thought to be the consequence of vascular endothelial cell damage, resulting in fibrinoid necrosis of small vessels and direct brain parenchymal necrosis. Occlusion of small blood vessels results in focal coagulative necrosis, capillary leakage, and demyelination of the surrounding brain parenchyma [6,7]. The disruption of the blood-brain barrier (as visualized by gadolinium imaging) may be mediated in part through vascular endothelial growth factor (VEGF) that is released in response to hypoxia. Evidence supporting the role of VEGF in the pathogenesis of radiation necrosis comes from the observation that the imaging abnormalities seen with radiation necrosis may be reversed in patients treated with bevacizumab, a monoclonal antibody that binds VEGF. (See 'Brain tissue necrosis' below.)

Radiation induces an inflammatory response characterized by an increase in activated microglia [2] and cytokine release, such as tumor necrosis factor alpha and interleukin-1 beta [3]. The precise role of this inflammatory response in vascular and cellular damage is unknown and may be caused both by cellular damage and by perpetuation of injury-induced inflammation, leading to a cycle of further cellular toxicity and tissue damage.

Evidence from animal models suggests that radiation is cytotoxic to proliferating neuroglial progenitor cells with disruption of gliogenesis and neurogenesis, resulting in a decrease in the number of newly formed neurons in areas of the brain with neurogenic potential. For instance, the hippocampus contains a neural stem cell niche important to memory formation that is potentially quite radiosensitive [2]. Other regions vulnerable to the effects of radiation and relevant to brain plasticity include the periventricular area (subventricular zone) and white matter tracts harboring oligodendrocyte precursor cells, which have been shown to be sensitive to the effects of radiation. In humans, the cognitive impact of damage to areas of neurogenesis is becoming clearer, with clinical trials demonstrating preservation of both tested and patient-reported cognitive function when these areas receive lower doses of radiation during whole brain radiation therapy (WBRT) [8]. The contribution of impaired white matter integrity to such cognitive dysfunction is also becoming better understood [9,10]. Loss of neurogenesis could lead to delayed cognitive deficits, even in the absence of identifiable changes on magnetic resonance imaging (MRI) [11]. (See 'Neurocognitive effects' below.)

When treating brain tumor patients, advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT) or proton beam therapy, have shown benefits in preserving cognitive function either by sparing specific neurogenic niches, such as the hippocampus, during WBRT or by sparing a larger volume of normal brain parenchyma during partial-brain radiotherapy [12,13]. (See 'Prevention' below.)

RISK FACTORS — The primary risk factors influencing the likelihood of developing complications include the volume of normal brain tissue treated, the total radiation dose, the fractionation schedule, the use of concurrent medications, prior and concomitant therapeutic interventions including surgery and chemotherapy, and underlying host- and tumor-related variables.

The likelihood of brain damage increases in the very young (ie, <5 years old) and in older adults. Use of concurrent or sequential chemotherapy, targeted agents, and immune checkpoint inhibitors may increase the incidence and severity of radiation-induced toxicity [14]. As an example, patients, especially those >60 years old, with primary central nervous system lymphoma (PCNSL) treated with fractionated whole brain radiation therapy (WBRT) and chemotherapy are at particularly high risk for the development of severe cognitive impairment with imaging findings of significant white matter toxicity [15]. In patients with metastatic disease, the use of immune checkpoint inhibition concurrent with radiosurgery, particularly from melanoma, has been associated with increased risk of posttreatment imaging changes [16].

Genetic factors may make certain individuals more susceptible to otherwise safe doses of radiation [17]. For example, a study of 15 families with radiation-induced meningiomas after treatment for tinea capitis identified several genes as potential risk factors [18]. Other genetic markers have also been found to enhance susceptibility to radiation toxicity when specific organs are irradiated [19-22]. A history of multiple sclerosis may also raise the risk of radiotherapy-induced neurotoxicity [23].

BRAIN TISSUE NECROSIS

Clinical features — Treatment-induced brain tissue necrosis (also referred to as radiation necrosis) is a serious complication that typically develops one to three years after radiation, although the range is quite broad and cases have been reported more than 10 years after radiation [24]. The dose that causes a higher than 5 percent risk of focal radiation necrosis using conventional 2 gray (Gy) fractionation is usually estimated to be 72 Gy, but this may be an oversimplification, and the dose that causes necrosis may vary by region of the brain as well [25]. Tissue necrosis is more likely to occur when high doses per fraction are administered and perhaps with concurrent chemotherapy or radiosensitizers [26]. The risk of tissue necrosis after stereotactic radiosurgery (SRS) has been reported to be higher, with a steep dose-response relationship [27-29]. (See "Overview of the treatment of brain metastases", section on 'Complications of SRS'.)

Tissue necrosis typically develops at or adjacent to the original site of tumor, the location that received the highest radiation dose [30]. Tissue necrosis can also develop in part of the normal brain parenchyma that was included in the treatment field of a tumor originating outside the brain, such as temporal lobe necrosis that develops in some patients treated for nasopharyngeal cancer or clival chordoma [31]. In this setting, brain tissue necrosis typically results in new focal neurologic signs, and imaging studies such as computed tomography (CT) or MRI may show an enhancing mass lesion with edema [32]. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Treatment-related complications'.)

Symptoms produced by localized brain necrosis depend upon the location of the lesion and can include focal neurologic deficits or more generalized signs and symptoms of increased intracranial pressure. Approximately 20 percent of patients have seizures [33]. Brainstem necrosis can produce severe clinical sequelae, including gait and balance problems, as well as multiple cranial neuropathies.

Diagnosis — Differentiating recurrent tumor from tissue necrosis can be very difficult by imaging, and the two entities are mostly indistinguishable on conventional structural MRI [34]. Conventional MRI typically shows a contrast-enhancing mass lesion with central necrosis and reactive edema within or immediately adjacent to the site of the original tumor and/or the site of highest dose of radiation. These imaging features almost entirely overlap with the radiographic appearance of high-grade primary brain tumors and brain metastases, and therefore image interpretation can be challenging.

Conventional imaging features that may be more suggestive of radiation necrosis than tumor include lack of a clearly defined T2 mass lesion [35] and high edema to enhancing lesion volume ratio [36]. The test of time can be the most helpful feature, since spontaneous improvement in edema and lesion volume over time is generally inconsistent with active tumor and very suggestive of evolving radiation necrosis. Conversely, worsening imaging features are nonspecific and can be associated with either process. Follow-up imaging after one to two months can be helpful to evaluate for rapid interval changes and to guide further management decisions.

Other imaging modalities have been investigated in an attempt to differentiate radiation necrosis from active tumor; however, no single imaging modality has proven to be sufficiently specific to establish a diagnosis. Perfusion-weighted MRI may show decreased cerebral blood volume (CBV) associated with radiation necrosis, whereas active tumor is more likely to be associated with increased CBV [37,38]. Restricted diffusion on diffusion-weighted MRI suggests active tumor [39]. A high lipid peak on magnetic resonance spectroscopy suggests necrosis [40-45]. Increased uptake with fluorodeoxyglucose (FDG) [46-51] or methionine [52] positron emission tomography (PET) or thallium chloride-201 single-photon emission computed tomography (SPECT) [53] all suggest tumor, whereas lack of uptake is more suggestive of necrosis.

Ultimately, biopsy of the suspicious lesion may be required for a definitive diagnosis, particularly in patients who are symptomatic and have worsening imaging findings over time.

Treatment — The clinical course of brain tissue necrosis is highly variable [34]. No causal therapies have been established, and management is primarily symptomatic. The treatment decisions require a balance between the often-competing goals of symptom control and avoidance of side effects.

In some cases, tissue necrosis is an asymptomatic, self-limited process that can be managed conservatively without intervention. In patients who are symptomatic, we suggest initial treatment with a moderate dose of glucocorticoid (eg, 4 to 8 mg of oral dexamethasone daily), which usually produces prompt symptomatic improvement by reducing cerebral edema. Once symptoms are controlled, glucocorticoids can then be gradually tapered over the course of several weeks. Follow-up imaging after one to two months is generally recommended.

In patients who do not achieve symptomatic response to glucocorticoids, or when glucocorticoids cannot be tapered without return of symptoms, a variety of other nonsurgical treatment options have been explored, including bevacizumab and laser interstitial thermal therapy (LITT) [54-56].

Bevacizumab – Retrospective case series and two small randomized trials indicate that bevacizumab is useful in selected cases of cerebral tissue necrosis [57-65].

In a double-blind clinical trial, 14 patients with radiographic- or biopsy-confirmed cerebral radiation necrosis were randomly assigned to bevacizumab (dose of 7.5 mg/kg every three weeks for four doses) or a saline placebo [60]. All patients assigned to bevacizumab had improvement in neurologic symptoms or imaging findings based upon MRI criteria. No responses were seen in those initially treated with placebo, but all patients who progressed on placebo did respond to bevacizumab during treatment crossover.

A larger open-label trial compared bevacizumab (dose of 5 mg/kg every two weeks for four doses) with glucocorticoids (methylprednisolone 500 mg intravenously daily for three days followed by gradual prednisone taper) in 112 patients with mostly temporal lobe radiation necrosis after nasopharyngeal cancer therapy [65]. Important exclusions included a history of bleeding related to tumor or radiation therapy; active central nervous system hemorrhage; recent intraabdominal fistula, perforation, or abscess; and inadequately controlled hypertension. Compared with glucocorticoids, bevacizumab resulted in higher rates of radiographic response (66 versus 32 percent) and clinical improvement (62 versus 43 percent) at 60 days, although the recurrence rate at six months was similar (29 versus 27 percent). Hypertension was the most common adverse effect (approximately 20 percent in both groups, all grade 1 to 2); there were two treatment-related serious adverse effects (ischemic stroke in the bevacizumab arm and infection in the glucocorticoid arm). Bevacizumab was associated with hemorrhage in four patients, including one nonserious cerebral hemorrhage and three nonserious nose bleeds.

The optimal dose and duration of bevacizumab for treatment of brain tissue necrosis have not been established. As more than half of patients in the available studies have responded durably to a four-dose course of bevacizumab (either 7.5 mg/kg every three weeks or 5 mg/kg every two weeks), we favor using one of these regimens and stopping after four doses in most patients. A gradual glucocorticoid taper can typically begin after the first dose of bevacizumab. We obtain an MRI after two and four doses for monitoring and then every two to three months for six months. Symptomatic and/or radiographic relapse is not uncommon, and some patients require retreatment with bevacizumab [61,62,66].

Further studies are needed to determine the safety of bevacizumab in certain patient populations, such as patients with prior intracranial hemorrhage and those who require anticoagulation, as well as those with low platelet counts. There is at least one report of worsening of clinical symptoms with bevacizumab therapy [67]. The risks and side effects of bevacizumab therapy for other indications are discussed separately. An ongoing clinical trial seeks to further define the clinical benefit of the use of bevacizumab for this indication. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Surgical resection – Surgical resection of the necrotic tissue is sometimes required, particularly in cases in which there is diagnostic uncertainty as to whether the radiographic changes are indicative of tumor progression or treatment-induced tissue necrosis, or in patients with severe necrosis who have contraindications to bevacizumab. Surgery often achieves palliative benefit by reducing mass effect and decreasing steroid requirements postoperatively [56,68,69].

Laser interstitial therapy – Minimally invasive LITT has also been explored as a therapeutic intervention [55,70] and is increasingly being adopted in practice; biopsies can be obtained during the same procedure [54,71]. Limited clinical follow-up data suggest that enhancement and cerebral edema can worsen significantly in the first several months after treatment, and clinicians should be cautious of rapid glucocorticoid tapers in this setting [72]. One retrospective case series has shown safety and utility of LITT in lieu of craniotomy for selected cases of cerebral tissue necrosis but more rapid resolution of preoperative neurologic deficits with craniotomy [73].

Unproven therapies – Therapeutic anticoagulation, antiplatelet therapy, and hyperbaric oxygen therapy have been reported to provide benefit in small case series [74-76], but their efficacy has not been established prospectively.

PSEUDOPROGRESSION — Pseudoprogression is a term used to refer to subacute treatment-related effects that can mimic tumor progression, typically in the setting of combined radiotherapy and temozolomide for high-grade or low-grade glioma, but also seen with immune checkpoint inhibitors (and particularly anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] agents) in combination with radiation for brain metastases. Imaging studies in patients with pseudoprogression demonstrate increased contrast enhancement and vasogenic edema, usually occurring within three months of completion of chemoradiation, which later stabilize or subside on follow-up studies without a change in therapy (image 1). Symptoms may or may not be present. Pseudoprogression is discussed in more detail separately. (See "Management of recurrent high-grade gliomas", section on 'Early progression versus pseudoprogression' and "Overview of the treatment of brain metastases", section on 'Complications of SRS'.)

NEUROCOGNITIVE EFFECTS — Cranial irradiation can result in a spectrum of neurocognitive deficits in the years following treatment in children and in adults. Important data on the impact of radiation therapy on neurocognitive function have been derived from studies in adults with primary brain tumors and brain metastases, as well as in survivors of childhood malignancies.

Cranial irradiation in children warrants special attention in view of the potential for impairment of growth and development of the central nervous system. The toxicity of cranial irradiation in children has been studied in a variety of settings, with the highest doses being used in children treated for primary tumors of the central nervous system, and somewhat lower doses used in children receiving prophylactic cranial irradiation (PCI) as part of their treatment for acute lymphoblastic leukemia. These issues are discussed in detail separately. (See "Treatment and prognosis of medulloblastoma", section on 'Neurocognitive impairment' and "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Central nervous system, mental health, and cognition' and "Overview of the management of central nervous system tumors in children", section on 'Long-term morbidity'.)

Whole brain radiation — Whole brain radiation therapy (WBRT) has both early-delayed and long-term effects on neurocognitive function. Early-delayed effects typically impact learning and memory up to three months to one year following WBRT, whereas more significant long-term effects that broadly impact cognition can occur greater than one year after WBRT.

Early and selective effects on short-term recall and verbal fluency, as measured by tests such as the Hopkins Verbal Learning Test (HVLT), have been best described in prospective trials of standard WBRT for brain metastases and PCI for lung cancer [77-80]. None of these historical trials included contemporary approaches to WBRT using neuroprotective strategies. (See 'Prevention' below.)

A small randomized trial found that adding WBRT to stereotactic radiosurgery (SRS) increased the likelihood of HVLT decline [77]. In this study, 52 percent of patients who received SRS plus WBRT experienced a drop of ≥5 points in the HVLT at four months. While the HVLT results of this study may have been influenced in part by the inferior overall survival of patients receiving SRS plus WBRT, a similar decline in HVLT at 3, 6, and 12 months post-treatment was appreciated in a large multicenter study of PCI versus observation for non-small cell lung cancer [78]. Another study found similar and selective effects on recall at four months in patients with brain metastases treated with WBRT [79].

A larger randomized trial of SRS plus WBRT versus SRS alone in patients with one to three brain metastases corroborates these findings [80]. In this trial, cognitive impairment, defined as a decline >1 standard deviation (SD) from baseline in any of six neurocognitive test batteries at three months, was more likely in the WBRT plus SRS group (92 versus 64 percent). On individual measures, the addition of WBRT led to more pronounced decline in immediate recall (30 versus 8 percent), delayed recall (51 versus 20 percent), and verbal fluency (19 versus 2 percent) compared with the group treated with SRS alone.

In a randomized trial comparing tumor bed radiosurgery versus WBRT following resection of a brain metastasis, patients assigned to postoperative WBRT experienced greater early decline in HVLT scores and were more likely to show cognitive deterioration at six months compared with those assigned to radiosurgery alone (85 versus 52 percent) [81].

In addition to learning and memory decline, WBRT has also been shown to impact patient-reported quality of life, as measured by the cognitive component of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (QLQ-C30). In a large multi-institutional trial of patients with one to three brain metastases, WBRT added to SRS was associated with greater decline in patient-reported cognitive functioning at one year compared with SRS alone [82]. Similar results were also reported in a pooled secondary analysis of multicenter trials of PCI for lung cancer [83].

While these studies have clearly demonstrated early-delayed effects of WBRT on cognitive function, characterization of long-term effects (ie, one year or longer) is complicated by the fact that most patients with brain metastases survive less than six months after WBRT. In addition, there are multiple factors that may impact cognition in these patients, including brain metastases themselves, concurrent treatment modalities (surgery, chemotherapy), the effects of medications, baseline neurocognitive dysfunction, and comorbidities (eg, vascular risk factors and diabetes) [11].

With these limitations, the available data suggest that nonspecific diffuse white matter changes can be seen on MRI in nearly all patients receiving WBRT doses of 20 gray (Gy) or higher and who survive longer than one year [84,85]. The risk of white matter changes and neurocognitive decline following WBRT is higher in patients with baseline white matter changes [10,86].

Most patients are asymptomatic, at least initially, but the incidence and severity of symptoms appear to correlate with the severity of radiographic changes [87]. When severe, these radiographic changes can be associated with the clinical syndrome of leukoencephalopathy involving ataxia, confusion, memory loss, dementia, and rarely death [88]. Severe leukoencephalopathy occurs in less than 5 percent of patients and is influenced by the use of large fraction sizes for WBRT. This can be associated with hydrocephalus, in which case it may respond at least transiently to ventriculoperitoneal shunting [89,90]. Cerebral atrophy may become evident with additional follow-up [87,91].

Partial brain radiation — Partial brain radiation may also have long-term effects on neurocognitive function, although the risk is significantly less than with WBRT, and observed effects may be due to additional factors such as the tumor itself, surgery, or antiseizure medication therapy [92,93]. An understanding of the risks of neurocognitive dysfunction after partial brain radiation in adults is derived primarily from patients with low-grade gliomas who have received involved field radiation therapy. The effects of cranial irradiation upon neurocognitive function in these patients are particularly important, since patients often have extended survival.

Collectively, existing clinical studies suggest that in adults with brain tumors, early cognitive dysfunction is often related to the tumor itself. In long-term survivors, however, focal radiation may impair cognitive function in a significant subset of patients, even when fraction size is limited and contemporary, image-guided technologies are used to deliver highly conformal radiation [12]. Significant and progressive structural brain changes (eg, cortical thinning, decreased whole-brain and gray matter volume, increased ventricular volume) have been demonstrated as early as four weeks following focal radiation with concurrent temozolomide in patients with glioblastoma [94,95] and appear to be progressive, at least in a subset of patients [96].

In an observational study with the longest follow-up, 195 patients with low-grade glioma, including 104 who had received radiation therapy, were compared with a control group of healthy individuals [97].

Six years after initial treatment, the low-grade glioma patients had lower ability in all cognitive domains compared with controls. However, the use of radiation was not associated with poorer cognitive function, except among patients who received a daily radiation dose greater than 2 Gy, where compromised memory was observed. In the same study, anticonvulsant medication was associated with a sixfold increase in risk of compromised capacity for perceptual tasks and inattention and executive function, effects that may be attributed to either medications or seizures. Details concerning the total dose and volume treated in patients who received greater than 2 Gy per fraction were not provided, and there might have been unrecognized negative selection biases, since patients with more extensive disease might have been treated with higher doses per fraction in view of an expectation of a poorer prognosis.

A subsequent study by the same group evaluated the effects of radiation in a subset of 65 patients who were assessed for cognitive effects at a mean of 12 years after initial treatment [98]. All patients were considered clinically stable since their first assessment. Radiation had been part of the original treatment in 32 patients (49 percent). In all but two cases this had consisted of focal radiotherapy rather than WBRT, and in all but three cases, the fraction dose was ≤2 Gy. At the second assessment, patients who had received radiation had significant impairment compared with patients who did not receive radiation as part of their original treatment in three cognitive domains: executive functioning, information processing speed, and attention. Detailed analyses suggested that these deficits could not be attributed exclusively to dose fraction or anticonvulsant usage, and that these deficits were at least in part attributable to radiation.

One potential source of bias, however, is that patients who were treated with radiation immediately after diagnosis were compared with patients who had survived without a recurrence. Patients not treated initially with radiation who recurred prior to the second analysis were excluded from the comparison cohort. Thus, it is not possible to know the average degree of cognitive impairment in a population of patients with low-grade glioma who were not treated with radiation initially when potentially adverse effects of tumor recurrence are factored in.

In a prospective study of 203 patients with low-grade glioma who were randomized to receive either a lower dose (total of 50.4 Gy in 28 fractions) or a higher dose (total of 64.8 Gy in 36 fractions) of postoperative radiation therapy, most patients maintained stable neurocognitive function over time as measured by the Folstein Mini-Mental State Examination (MMSE) [99]. Five percent of those without tumor progression had a significant decline in MMSE scores (>3 points) five years after treatment, however, all in the low-dose radiation arm. Importantly, the MMSE has significant limitations for assessing neurocognitive function due to a lack of sensitivity [100], and therefore these study findings may represent an underestimation of the actual degree of radiation-associated cognitive decline. On the other hand, neurocognitive batteries detect small degrees of cognitive decline that may not always be clinically significant [80]. The impact of the volume of normal brain parenchyma irradiated on cognitive dysfunction in patients with isocitrate dehydrogenase (IDH)-mutant low-grade glioma is currently being evaluated in a randomized combinatorial radiotherapy-temozolomide trial (NRG BN005, NCT03180502), in which intensity-modulated radiation therapy (IMRT) is compared with proton therapy.

The potential contributing effects of other anticancer treatments, particularly systemic chemotherapy, must also be considered. Limited data in low-grade glioma patients are potentially reassuring, however. Cognitive function was assessed using the MMSE in 251 patients with high-risk low-grade gliomas who were randomly assigned to receive either radiation alone or radiation in combination with procarbazine, lomustine, and vincristine (PCV) [101]. After five years of follow-up, no significant difference could be detected in cognitive function between the groups. As discussed above, the poor sensitivity of MMSE testing in neurocognitive assessment remains a significant limitation of this study.

Evaluation — Neurocognitive dysfunction in patients who have received cranial irradiation is often multifactorial. An initial evaluation should include a thorough history to identify potential contributing factors other than prior radiation, such as medication side effects, underlying mood disorders, and sleep disturbances. Mental status and cognition function should be assessed clinically in each patient. (See "The mental status examination in adults".)

Formal neurocognitive and neuropsychological testing is not generally necessary but can be useful in some patients in order to establish a baseline of neurocognitive function, since symptoms might progress over time. An underlying mood disorder might be uncovered by detailed neuropsychological assessment. In addition, detailed neurocognitive testing helps to identify the exact pattern of cognitive deficits, which can guide further therapeutic interventions, such as neurocognitive rehabilitation.

Recent neuroimaging should be reviewed to identify alternative, and potentially reversible, causes of cognitive decline that occur with increased frequency in patients with brain tumors and prior radiation, such as hydrocephalus. An extensive laboratory evaluation is typically of low yield aside from screening for common vitamin deficiencies (eg, vitamin B12 deficiency), metabolic abnormalities, and thyroid dysfunction. (See "Evaluation of cognitive impairment and dementia".)

Prevention — In patients who require WBRT for treatment of brain metastases, we recommend use of hippocampal avoidance IMRT as well as memantine to decrease the risk of neurocognitive toxicity [102-104]. Memantine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, which mediate synaptic plasticity and memory in the brain, particularly in the neurons of the hippocampus. Hippocampal avoidance uses IMRT to reduce the dose delivered to the hippocampal dentate gyrus by approximately threefold during WBRT. Rare patients with metastases within 5 mm of the hippocampus are not eligible for hippocampal avoidance IMRT.

Supporting evidence includes the following studies:

A randomized trial in 508 patients with brain metastases undergoing conventional WBRT found that the addition of memantine during and for up to six months after WBRT led to a 22 percent relative reduction in the risk of cognitive toxicity compared with placebo (hazard ratio [HR] 0.78, 95% CI 0.62-0.99) [105]. Only 149 patients were evaluable for the primary endpoint of delayed recall at 24 weeks, and the difference in scores was not statistically significant (p = 0.06). Additional analyses demonstrated that memantine improved executive function, processing speed, and delayed recognition. Patient attrition significantly reduced the power of the study.

In practice, we use a slow up-titration of memantine, beginning at 5 mg daily with initiation of radiation and increasing once a week by 5 mg to reach a target dose of 10 mg of memantine twice daily. The most common side effects of memantine are fatigue and gastrointestinal symptoms (nausea, vomiting, cramping, loose stools).

In a subsequent randomized trial in 518 patients with brain metastases, the use of IMRT for hippocampal avoidance led to an additional 26 percent relative reduction in risk of cognitive toxicity compared with conventional WBRT (HR 0.74, 95% CI 0.58-0.95); both groups received memantine during WBRT and for up to six months afterwards [8]. Specific benefits were seen in patient-reported cognitive symptoms and neurologic symptom interference as well as executive function at four months and learning and memory at six months. Patients in the hippocampal avoidance group also reported less difficulty remembering things, less difficulty speaking, and greater improvement in fatigue at six months. No differences in intracranial progression-free survival (HR 1.14, 95% CI 0.93-1.41) or overall survival (6.3 versus 7.6 months; HR 1.13, 95% CI 0.90-1.41) were observed between the treatment arms. Cognitive and neurologic symptom benefits in the hippocampal avoidance arm continued to be evident in patients who completed 12-month follow-up exams and questionnaires [106].

In a single-blinded randomized phase II trial in 70 patients with brain metastases, the use of IMRT for hippocampal avoidance was associated with better six-month preservation of memory function as assessed by HVLT total recall and recognition compared with conventional WBRT. In this trial, none of the patients were treated with memantine. There were no differences in progression-free survival in brain (HR 1.17, 95% CI 0.69-1.98) or overall survival (HR 1.32, 95% CI 0.73-2.38) [107].

Hippocampal avoidance IMRT in patients with small cell lung cancer who require PCI is reviewed separately. (See "Prophylactic cranial irradiation for patients with small cell lung cancer", section on 'Standard PCI versus hippocampal avoidance'.)

In the setting of partial-brain radiation, one large prospective study demonstrated better neurocognitive and neuroendocrine outcomes following more conformal radiotherapy using stereotactic techniques compared with conventional radiotherapy techniques for low-grade and benign brain tumors [12]. Sparing of a larger volume of brain tissue with conformal radiotherapy techniques was associated with improvement in full-scale IQ and performance IQ scores over a period of five years.

Similarly, retrospective case series have demonstrated potential protective benefits of proton therapy related to its capacity to spare more normal brain tissue during partial-brain radiotherapy [13,108-111]. A randomized trial of proton therapy versus IMRT in adults with IDH-mutant gliomas (NRG BN005) is underway [112].

Treatment — Several pharmacologic interventions have been tested in randomized trials to minimize or improve cognitive function in patients treated with focal or whole brain radiation [113]. Results have been mixed, however, with some studies showing no benefit and others showing modest improvements in selected outcomes. Lacking better options, drugs such as methylphenidate, donepezil, and memantine are generally well tolerated and may be beneficial in a subset of patients, along with neurocognitive rehabilitation aimed at compensatory strategies [114]. (See "Cognitive function after cancer and cancer treatment", section on 'Behavioral interventions'.)

Treatment decisions must be individualized, taking into account patient preferences, the pattern and severity of deficits, comorbidities, potential side effects, and cost. A trial of a neurostimulant (eg, methylphenidate, modafinil) is often worthwhile in patients with profound fatigue, impaired attention and concentration, and poor motivation. In patients with prominent memory impairment, either donepezil or memantine may be offered as part of the treatment strategy.

Clinical data have yielded mixed results on the impact of treatment with methylphenidate or wake-promoting agents (eg, modafinil, armodafinil) on neurocognitive function, fatigue, and quality of life following cranial irradiation [115-120].

A randomized, double-blind clinical trial evaluated 83 children who were long-term survivors of either acute lymphoblastic leukemia or malignant brain tumors and who had documented neurocognitive impairment [116]. The patients received a three-week crossover course of treatment with methylphenidate (either 0.3 or 0.6 mg/kg) or placebo. The lower dose of methylphenidate therapy was associated with improvements in attention and social deficits compared with placebo, but no advantage was seen with the higher dose.

In another small trial that was terminated prematurely, 68 patients with primary or metastatic brain tumors were randomly assigned to receive methylphenidate or placebo during radiation therapy [117]. Eight weeks after completion of radiation, there was no difference in fatigue or cognition compared with placebo.

Armodafinil was studied in a multicenter randomized trial of 54 primary brain tumor patients undergoing radiation therapy [121]. Armodafinil at a dose of 150 mg was given once daily during radiation and for an additional four weeks after radiation therapy. In both groups, fatigue worsened by the end of radiation and improved by four weeks after radiation. However, there were no significant differences in fatigue, sleepiness, cognition, or quality of life between armodafinil and placebo on any outcome measure. In a post hoc analysis, armodafinil was associated with improved fatigue in patients with higher baseline levels of fatigue.

In a larger multicenter randomized trial of 328 adult patients with high-grade glioma and moderate to severe fatigue, armodafinil at 150 or 250 mg daily did not lead to a clinically meaningful reduction in fatigue [122].

While these data do not support the routine use of armodafinil, it may be worth trying in patients suffering from severe fatigue when nonpharmacologic strategies have failed.

The rationale for use of acetylcholinesterase inhibitors in patients with cognitive dysfunction after cranial radiation is primarily extrapolated from trials in patients with Alzheimer disease and other forms of dementia, which have shown modest benefits on cognition, behavior, and activities of daily living (see "Cholinesterase inhibitors in the treatment of dementia"). Prospective studies of donepezil in brain tumor patients include the following:

In a phase II study, 24 patients with low-grade gliomas were treated with donepezil for a total of 24 weeks [123]. Donepezil significantly improved several parameters of cognitive functioning (including attention, concentration, and verbal memory) and mood compared with baseline and the washout evaluation six weeks after completion of treatment [123].

In a confirmatory phase III study, 198 patients with primary or metastatic brain tumors and a history of partial or whole brain radiotherapy >6 months prior to study entry were randomly assigned to donepezil 5 to 10 mg/day or placebo for 24 weeks [124]. Patients in both groups showed improved cognitive function at 24 weeks compared with baseline, but there was no significant difference in the primary outcome (a composite score of cognitive performance, subjective confusion, and fatigue) between patients who received donepezil compared with those who received placebo. In subset analyses, patients with low baseline cognitive scores seemed to derive more benefit from donepezil than those with higher baseline scores.

CEREBROVASCULAR EFFECTS — Cerebrovascular disease, including occlusive vascular disease and stroke, intracranial hemorrhage, and cavernous malformations, is an increasingly recognized long-term complication of cranial irradiation.

Vasculopathy and ischemic stroke — Children are probably more susceptible to radiation-induced vasculopathy than adults, and the supraclinoid region of the internal carotid artery and the circle of Willis seem especially vulnerable. Additional risk factors for neurovascular toxicity include administration of chemotherapy, young age at the time of radiotherapy, radiation dose (eg, whole brain radiation dose ≥24 Gy), and comorbid neurofibromatosis type 1 [125-129].

Both focal arteriopathies and moyamoya arteriopathy can occur, with an estimated cumulative incidence of up to 12 percent at 10 years among childhood brain tumor survivors [128,130,131]. In a review of 54 cases of post-radiation moyamoya, 56 percent were in children younger than five years of age, 26 percent had neurofibromatosis type 1, and 69 percent had a low-grade glioma [130]. The median time from radiation to onset of symptoms was 40 months. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".)

The risk of stroke following radiation in survivors of childhood leukemia and brain tumors was illustrated in a report from the Childhood Cancer Survivor Study, which analyzed 4828 leukemia survivors, 1871 brain tumor survivors, and 3846 siblings of cancer survivors [126]. Late-occurring stroke occurred in 37 leukemia survivors (0.8 percent) at a median of 10 years from diagnosis. Among brain tumor survivors, 3.4 percent had a late-occurring stroke at a median of 14 years from diagnosis. The stroke rate was highest among brain tumor survivors who had received both cranial irradiation and alkylating agents (6.5 percent), but it was also elevated compared with sibling controls in cancer survivors who had not received cranial irradiation.

Radiation fields that include the circle of Willis confer higher risk for neurovascular events than focal brain radiation to other areas [125,132,133]. In a prospective cohort study of over 3000 five-year childhood cancer survivors, patients who received any brain radiation were at increased risk for stroke (relative risk [RR] 8.5, 95% CI 6.3-11.0). The dose of radiation to the circle of Willis was the strongest predictor, with an RR as high as 15.7 for those who received ≥40 gray (Gy) to this area [133]. The cumulative incidence of stroke continued to rise with longer follow-up, reaching 11 percent by age 45 years in those who had received 10 Gy or more to the circle of Willis. In a separate study, unexplained recurrent headache also increased risk of subsequent stroke or transient ischemic attack (TIA; hazard ratio [HR] 4.7), independent of other risk factors [134].

Cerebrovascular mortality also appears to be elevated in brain tumor survivors, particularly among those who receive radiation to central areas of the brain [132,135]. In a population-based study of over 19,500 brain tumor patients of any age (excluding glioblastoma), long-term cerebrovascular mortality was significantly increased by cranial irradiation in the subset of patients with centrally located tumors (HR 2.8) [132]. The observed 10- and 20-year cerebrovascular mortality rates in patients with centrally located tumors who received radiation were 0.6 and 1.1 percent, respectively.

Although radiation to a large volume of the carotid arteries is uncommon during the treatment of intracranial tumors, it is common in the management of head and neck cancers and some other tumors that can involve lymph nodes in the neck and may increase the risk of stroke in these patients. However, radiation fields that include the lower common carotid artery as part of treatment to supraclavicular or internal mammary lymph nodes for breast cancer have not been associated with an increased incidence of stroke [136]. (See "Management of late complications of head and neck cancer and its treatment", section on 'Carotid artery injury'.)

Secondary stroke prevention measures, including antiplatelet therapy and management of other cardiovascular risk factors, have not been well studied in this setting, but should be considered in individual patients [137]. A multidisciplinary expert panel from the United States and Canada reached consensus on the following recommendations in childhood cancer survivors treated with cranial irradiation [129]:

Screening – Screening neuroimaging should be performed in high-risk patients (eg, radiation field included the circle of Willis, whole brain radiation dose ≥24 Gy) beginning by five years after completion of radiation and continuing at least every five years indefinitely. Most panelists agreed that screening should consist of both brain MRI and magnetic resonance angiography (MRA) to adequately assess for cerebrovascular disease. Survivors should also have laboratory testing to screen for modifiable risk factors of stroke in the general population (eg, lipid panel, hemoglobin A1C, serum glucose).

Specialty referral – Patients with evidence of small vessel disease, large vessel disease, and/or cavernous malformations with prior hemorrhage should be referred to a specialist (neurology/neurosurgery) for evaluation and risk assessment.

Stroke prevention – Patients with prior small vessel stroke and those with large vessel disease (with or without prior stroke) should receive aspirin for stroke prevention. There was no consensus on the role of antiplatelet therapy in other patient groups. Additional preventive considerations in patients with cerebrovascular disease are reviewed separately. (See "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".)

Microbleeds and cavernous malformations — Intracerebral microbleeds and cavernous malformations commonly develop after cranial irradiation with a median latency of several years, primarily in regions of the brain that have received >30 Gy [138-141]. With high-sensitivity magnetic susceptibility imaging, the cumulative incidence of microbleeds in retrospective uncontrolled studies ranges from 40 to 90 percent by 5 to 10 years after radiation, with the range likely dependent in large part upon the sensitivity of the imaging technique [5,140-143].

As with other cerebrovascular complications, children appear to be at higher risk than adults [5,138,144]. The risk of bleeding is not well studied but appears to be low; some lesions may enlarge over time. (See "Vascular malformations of the central nervous system", section on 'Cavernous malformations'.)

MIGRAINE-LIKE HEADACHE (SMART) SYNDROME — A rare late effect of radiation is a reversible syndrome characterized by migraine-like headaches often accompanied by focal neurologic signs and/or seizures lasting days to weeks. The disorder, called SMART (stroke-like migraine attacks after radiation therapy) syndrome, usually occurs many years or even decades after receipt of radiation, although cases within two years after proton radiation have been described [145]. Episodes may be associated with transient gadolinium enhancement and changes in diffusivity of focal areas of the cortex, and thus be confused with recurrent tumor or subacute stroke (image 2) [145-147]. The exact mechanism is unknown but cerebral vascular reactivity appears to be normal during the attack [148]. Transient regional cerebral hyperperfusion preceding seizures and cortical MRI abnormalities have been described [149].

It can be difficult to distinguish this clinical syndrome from transient ischemic attack (TIA), stroke, or seizure without neuroimaging and electroencephalography (EEG), at least upon initial presentation. Patients with a history of brain irradiation are at increased risk for each of these. MRI and vascular imaging should be performed to rule out acute stroke or recurrent tumor, and follow-up imaging may be required to interpret the significance of certain findings (eg, cortical gadolinium enhancement, focal diffusion restriction) [145]. Extended EEG monitoring may be indicated in patients with ongoing symptoms, even if prior routine EEG was uninformative, to rule out nonconvulsive seizures or status epilepticus [147].

The recurrence risk of SMART episodes is not well characterized. As it is not always possible to distinguish SMART from seizure (and they can coexist), antiseizure medication therapy is often appropriate, especially if the initial event is severe or prolonged. It is not known whether drugs with effectiveness in migraine prophylaxis, such as verapamil, propranolol, valproate, or topiramate, can help to reduce the frequency or severity of attacks in patients with recurrent episodes, but these are the agents most frequently tried in this setting [150].

EFFECTS ON THE EYES AND OPTIC PATHWAYS — Radiation therapy may have a series of acute and delayed effects on the eyes and optic pathways. As an example, during treatment, radiation may stimulate the retinal photoreceptors, causing patients to transiently perceive light sensations immediately after radiation treatment to fields that include segments of the optic pathways.

Cataracts — Radiation-induced cataracts may result after low doses of radiation to the lens of the eye. Patients typically present with painless visual impairment two to eight years following radiation therapy. In a retrospective study of over 1000 patients who received total body irradiation for bone marrow transplantation, either 10 gray (Gy) in one fraction or 12 Gy in conventional fractionation, 60 percent of the patients receiving one dose and 43 percent of the patients receiving fractionated radiation developed cataracts [151]. Cataract development is strongly correlated with the chronic use of steroids in these patients. The treatment is the same as in nonradiation-induced cataracts, namely cataract removal and prosthetic lens placement.

Optic neuropathy — Optic neuropathy typically presents with painless monocular or bilateral visual impairment developing over one to several weeks and beginning around 6 to 24 months after radiation. The incidence of mild, transient radiation effects on the optic nerves is not well reported. At fraction sizes <2 Gy, severe optic neuropathy after cranial irradiation is unusual with doses less than 55 Gy, but increases to 3 to 7 percent with doses of 55 to 60 Gy and 7 to 20 percent for doses >60 Gy [152,153].

Fraction size greatly impacts the incidence of optic neuropathy, with larger fraction sizes associated with higher rates of neuropathy. In a study of 55 patients receiving 45 to 55 Gy for pituitary adenomas or craniopharyngiomas, 18 percent of patients receiving fraction sizes larger than 2.5 Gy developed optic neuropathy, while no patients receiving fraction sizes less than 2.5 Gy developed optic neuropathy [154]. In the more severe cases of optic neuropathy, steroids are unlikely to provide benefit. Hyperbaric oxygen has provided limited success [155]. Anticoagulation is sometimes tried, with uncertain results. (See "Hyperbaric oxygen therapy".)

Late onset of optic neuropathy has been reported in three cases of patients who were treated with bevacizumab for glioblastoma [156]. Assessment of this risk requires additional data from ongoing glioblastoma trials. (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Bevacizumab'.)

Optic neuropathy has also been reported with lower doses of radiation as a complication of prophylactic chemotherapy plus cranial irradiation for acute lymphoblastic leukemia [157].

Xerophthalmia — Xerophthalmia (dry eyes) can be a complication of radiation to the eye. This is generally mild and has been most frequently reported in patients treated for lymphoid malignancies of the orbit and ocular adnexa [158,159]. The incidence and severity varies with the radiation dose to the lacrimal gland as the rate of dry eyes increases with doses above 30 Gy [160].

Retinopathy — Retinal injury due to retinal ischemia can also occur after radiation. Radiation retinopathy is often asymptomatic and is found incidentally on funduscopic exam. If symptomatic, it presents as painless loss of vision months to years after radiation. Risk factors for radiation retinopathy include radiation dose, prior chemotherapy, and diabetes. In one study of 64 patients receiving radiation for head and neck tumors, 27 eyes in 26 patients developed symptomatic radiation retinopathy resulting in visual acuity of 20/200 or worse [161]. Fourteen of the injured eyes developed rubeosis iridis and/or neovascular glaucoma. No patient receiving less than 45 Gy developed retinal complications, but the incidence of retinopathy increased with higher doses.

OTOTOXICITY — Tinnitus and high-frequency hearing loss are adverse effects that occasionally occur during cranial irradiation [162]. These early symptoms are often due to radiation-induced otitis media, causing mucosal vasodilatation and eustachian tube edema. Symptoms typically resolve spontaneously, but occasional patients need myringotomy for symptomatic relief.

Hearing loss months to years after radiation is usually due to sensorineural damage [163-166]. This was illustrated by a review of 325 patients treated for head and neck tumors between 1964 and 2000 at a single institution [163]. Sensorineural hearing loss was observed in 15 percent of patients, and multivariate analysis showed that age and radiation dose to the cochlea were significant risk factors. For patients who were receiving doses over 60.5 gray (Gy), the five-year risk of clinically overt hearing loss was 37 percent.

Late sensorineural hearing loss also has been reported in children who are treated with cranial irradiation for brain tumors [167,168]. In a study of 78 children who were assessed by audiometry and who had not received platinum-based chemotherapy, hearing loss was documented in 11 cases (14 percent) [167]. Ototoxicity was related to the dose of radiation to the cochlea, with higher frequencies being more sensitive to lower radiation doses. A cumulative cochlear dose less than 35 Gy was recommended for patients receiving a total tumor dose of 54 to 59.4 Gy in 30 to 33 fractions. Childhood cancer survivors who have received ≥30 Gy of cranial irradiation with or without concurrent carboplatin or cisplatin should be followed with audiograms into adulthood to monitor for hearing loss (table 1).

Hearing loss can also occur with fractionated stereotactic radiotherapy or radiosurgery for vestibular schwannomas (acoustic neuromas). (See "Vestibular schwannoma (acoustic neuroma)".)

Cisplatin chemotherapy — Cisplatin, which itself may cause hearing loss, results in synergistic ototoxicity with radiation, especially in the high-frequency speech range [169,170]. In a randomized trial of 115 patients treated for nasopharyngeal carcinoma, hearing thresholds at 4 kHz were significantly worse for patients receiving combined-modality therapy compared with those treated with radiation alone [170]. Impairment began shortly after treatment and then stabilized after one year. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Ototoxicity'.)

Approximately 40 to 60 percent of long-term survivors of childhood medulloblastoma experience moderate to severe hearing loss, although the incidence may be lower with modern radiation techniques that spare key structures [171]. Cochlear implantation can be considered in patients with complete deafness after radiation therapy [172]. (See "Treatment and prognosis of medulloblastoma", section on 'Hearing loss'.)

The treatment of patients with advanced head and neck cancers may include radiation to cranial nerve VIII or the cochlea in some cases. In this setting, the ototoxicity of combined treatment with cisplatin and radiation is significant [173,174]. This was illustrated by a randomized trial in which patients were randomly assigned to cisplatin administered either intraarterially or intravenously, and radiation was given to a total dose of 70 Gy in 35 fractions [173]. Both regimens induced significant hearing loss, which was worse at higher frequencies. More ears required hearing aids after intravenous cisplatin (72 of 148 [49 percent] versus 51 of 143 [36 percent], with intraarterial chemotherapy).

ENDOCRINOPATHIES

Hypothalamus and pituitary gland — Hypothalamic and pituitary endocrinopathies occur in up to 80 percent of adults following radiation therapy that includes these structures [175-182]. Such injury may occur after doses as low as 20 gray (Gy) [183], and therefore patients who receive pituitary as well as nonpituitary cranial radiation are at risk. Where possible, approaches to reduce radiation exposure to the uninvolved endocrine axis are used to lower the risk of endocrine dysfunction [12].

The time course of endocrine dysfunction after radiation to the hypothalamic and pituitary region is variable, with patients typically having abnormal serum hormone levels long before clinical symptoms develop. Abnormalities can develop as early as one year after completion of therapy, and the prevalence rises over time. As a result, patients who have received radiation to the hypothalamus or pituitary region should have a baseline endocrine evaluation within a year of completing radiation and annual blood work to screen for dysfunction of the hypothalamic-pituitary axis. (See "Diagnostic testing for hypopituitarism".)

The prevalence of hypopituitarism was illustrated by a systematic review that included eight studies of long-term endocrine function in adults who had received cranial radiation for primary nonpituitary tumors, including nasopharyngeal tumors [182]. The prevalence of any degree of hypopituitarism ranged from 37 to 77 percent, with a follow-up time of 3 to 13 years after radiation. The most common abnormality was growth hormone (GH) deficiency (50 percent), followed by gonadotropin deficiency (25 percent), hyperprolactinemia (24 percent), adrenocorticotrophic hormone (ACTH) deficiency (19 percent), and central hypothyroidism (16 percent).

Hypothyroidism — Hypothyroidism develops in 15 to 20 percent of adult patients after cranial irradiation [182]. This may be a manifestation of either central hypothyroidism, due to irradiation of the pituitary through the cranial fields, or primary hypothyroidism due to irradiation of the thyroid from the spinal fields. Patients who have received cranial radiation should therefore undergo structured periodic monitoring of both thyroid stimulating hormone (TSH) and free T4. (See "Central hypothyroidism", section on 'Diagnosis'.)

SECONDARY TUMOR FORMATION — Following cranial irradiation, there is an increased risk of secondary meningiomas, malignant gliomas, nerve sheath tumors, and sarcomas; the risk of meningiomas and gliomas is proportional to the dose of cranial irradiation. The evidence linking these secondary brain tumors is discussed separately. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Ionizing radiation' and "Risk factors for brain tumors", section on 'Ionizing radiation'.)

As with standard fractionated radiation, stereotactic radiosurgery (SRS) can be associated with the development of secondary malignancies [184,185]. Although the overall incidence appears very low, it is likely that the number of reported cases will increase as additional patients are treated and observed for extended periods. Techniques that limit dose exposure to normal structures, such as proton therapy, also appear to lower the risk of secondary malignancies compared with conventional techniques [186].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Hair loss from cancer treatment (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pathophysiology – Cranial irradiation can have deleterious effects on the vasculature of the brain as well as on neuroglial cells and their precursors. Inflammation and blood-brain barrier disruption may also indirectly contribute to cellular damage. (See 'Pathophysiology' above.)

Brain tissue necrosis – Treatment-induced brain tissue necrosis (radiation necrosis) typically develops one to three years after radiation. Symptoms produced by localized brain necrosis and reactive edema depend upon the location of the lesion and can include focal neurologic deficits or more generalized signs and symptoms of increased intracranial pressure. The risk increases with higher doses per fraction. (See 'Brain tissue necrosis' above.)

Initial treatment – For patients with symptomatic brain tissue necrosis, we suggest initial treatment with glucocorticoids to decrease cerebral edema (Grade 2C). A typical dose of dexamethasone is 4 to 8 mg daily or divided twice daily until clinical improvement. (See 'Treatment' above.)

Role of surgery – Surgical resection of the necrotic tissue is sometimes required, particularly in cases in which there is diagnostic uncertainty as to whether the radiographic changes are indicative of tumor progression or tissue necrosis, or in patients with severe necrosis who have contraindications to bevacizumab. Laser interstitial thermal therapy (LITT) is an option in this context but is less preferred in patients with preoperative neurologic deficits. (See 'Treatment' above.)

Refractory necrosis – For nonsurgical patients who do not achieve symptomatic response to glucocorticoids, or when glucocorticoids cannot be tapered without return of symptoms, we suggest a course of bevacizumab (Grade 2C). We avoid use of bevacizumab in certain patient populations for which safety data are currently inadequate, such as those with recent intracranial hemorrhage. (See 'Treatment' above.)

Neurocognitive effects – Both focal brain radiation and whole brain radiation therapy (WBRT) are associated with a decline in neurocognitive function over time in some patients, which adversely impacts quality of life. Preventive strategies are available for patients who require WBRT. (See 'Neurocognitive effects' above.)

Prevention – For patients undergoing WBRT for brain metastases, in order to decrease the risk of neurotoxicity, we recommend use of hippocampal avoidance intensity-modulated radiation therapy (IMRT) (Grade 1B); we also suggest use of memantine (Grade 2C). Patients with metastases within 5 mm of the hippocampi should receive conventional WBRT. We use a slow up-titration of memantine, beginning at 5 mg daily with initiation of WBRT and increasing once a week by 5 mg to reach a target dose of 10 mg twice daily. Memantine is continued for up to six months after completion of WBRT. (See 'Prevention' above.)

Supportive care – Treatment of neurocognitive dysfunction after brain radiation is individualized, and no medications are proven to be beneficial. Supportive therapies that may benefit selected patients include cognitive rehabilitation and use of stimulants or wake-promoting agents for those with prominent deficits in attention, concentration, and motivation. (See 'Treatment' above.)

Cerebrovascular effects – Cranial irradiation has been associated with a variety of cerebrovascular complications, including occlusive vascular disease resembling moyamoya disease, ischemic stroke, and intracerebral cavernous malformations that may cause intracranial bleeding. (See 'Cerebrovascular effects' above.)

Eye, ear, and endocrine effects – Additional well-described late complications of cranial irradiation include cataracts, optic neuropathy, xerophthalmia, retinopathy, ototoxicity, and endocrinopathies. (See 'Effects on the eyes and optic pathways' above and 'Ototoxicity' above and 'Endocrinopathies' above.)

Secondary tumors – Following cranial irradiation, there is an increased risk of secondary tumors, such as meningiomas, malignant gliomas, and nerve sheath tumors. Survivors of childhood cranial or craniospinal radiation are at increased risk for intracranial tumors as well as myeloid neoplasms. This risk can be lowered by decreasing the total intracranial dose using techniques such as proton therapy. (See 'Secondary tumor formation' above.)

  1. Belka C, Budach W, Kortmann RD, Bamberg M. Radiation induced CNS toxicity--molecular and cellular mechanisms. Br J Cancer 2001; 85:1233.
  2. Rola R, Raber J, Rizk A, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 2004; 188:316.
  3. Nordal RA, Wong CS. Molecular targets in radiation-induced blood-brain barrier disruption. Int J Radiat Oncol Biol Phys 2005; 62:279.
  4. Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene 2003; 22:5897.
  5. Roongpiboonsopit D, Kuijf HJ, Charidimou A, et al. Evolution of cerebral microbleeds after cranial irradiation in medulloblastoma patients. Neurology 2017; 88:789.
  6. Burger P, Boyko OB. The pathology of central nervous system radiation injury. In: Radiation injury to the nervous system, Raven Press, New York 1991. p.191.
  7. Burger PC, Mahley MS Jr, Dudka L, Vogel FS. The morphologic effects of radiation administered therapeutically for intracranial gliomas: a postmortem study of 25 cases. Cancer 1979; 44:1256.
  8. Brown PD, Gondi V, Pugh S, et al. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol 2020; 38:1019.
  9. Monje M, Dietrich J. Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis. Behav Brain Res 2012; 227:376.
  10. Bovi JA, Pugh SL, Sabsevitz D, et al. Pretreatment Volume of MRI-Determined White Matter Injury Predicts Neurocognitive Decline After Hippocampal Avoidant Whole-Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology Radiation Therapy Oncology Group 0933. Adv Radiat Oncol 2019; 4:579.
  11. Dietrich J, Monje M, Wefel J, Meyers C. Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist 2008; 13:1285.
  12. Jalali R, Gupta T, Goda JS, et al. Efficacy of Stereotactic Conformal Radiotherapy vs Conventional Radiotherapy on Benign and Low-Grade Brain Tumors: A Randomized Clinical Trial. JAMA Oncol 2017; 3:1368.
  13. Gross JP, Powell S, Zelko F, et al. Improved neuropsychological outcomes following proton therapy relative to X-ray therapy for pediatric brain tumor patients. Neuro Oncol 2019; 21:934.
  14. Crossen JR, Garwood D, Glatstein E, Neuwelt EA. Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 1994; 12:627.
  15. Lai R, Abrey LE, Rosenblum MK, DeAngelis LM. Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study. Neurology 2004; 62:451.
  16. Kim PH, Suh CH, Kim HS, et al. Immune checkpoint inhibitor therapy may increase the incidence of treatment-related necrosis after stereotactic radiosurgery for brain metastases: a systematic review and meta-analysis. Eur Radiol 2021; 31:4114.
  17. Andreassen CN, Alsner J. Genetic variants and normal tissue toxicity after radiotherapy: a systematic review. Radiother Oncol 2009; 92:299.
  18. Hosking FJ, Feldman D, Bruchim R, et al. Search for inherited susceptibility to radiation-associated meningioma by genomewide SNP linkage disequilibrium mapping. Br J Cancer 2011; 104:1049.
  19. West CM, Barnett GC. Genetics and genomics of radiotherapy toxicity: towards prediction. Genome Med 2011; 3:52.
  20. Barnett GC, West CM, Dunning AM, et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer 2009; 9:134.
  21. Rosenstein BS. Identification of SNPs associated with susceptibility for development of adverse reactions to radiotherapy. Pharmacogenomics 2011; 12:267.
  22. Wefel JS, Deshmukh S, Brown PD, et al. Impact of Apolipoprotein E (APOE) genotype on neurocognitive function (NCF) in patients with brain metastasis (BM): An analysis of NRG Oncology’s RTOG 0614. Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, 2018.
  23. Miller RC, Lachance DH, Lucchinetti CF, et al. Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: the Mayo Clinic experience. Int J Radiat Oncol Biol Phys 2006; 66:1178.
  24. Strenger V, Lackner H, Mayer R, et al. Incidence and clinical course of radionecrosis in children with brain tumors. A 20-year longitudinal observational study. Strahlenther Onkol 2013; 189:759.
  25. Leibel S, Sheline G. Tolerance of the brain and spinal cord to conventional therapeutic irradiation. In: Radiation Injury to the Nervous System, Gutin P, Leibel S, Sheline G (Eds), Raven Press, New York 1991. p.239.
  26. Ruben JD, Dally M, Bailey M, et al. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys 2006; 65:499.
  27. Blonigen BJ, Steinmetz RD, Levin L, et al. Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2010; 77:996.
  28. Suh JH. Stereotactic radiosurgery for the management of brain metastases. N Engl J Med 2010; 362:1119.
  29. Chao ST, Ahluwalia MS, Barnett GH, et al. Challenges with the diagnosis and treatment of cerebral radiation necrosis. Int J Radiat Oncol Biol Phys 2013; 87:449.
  30. Winter SF, Vaios EJ, Muzikansky A, et al. Defining Treatment-Related Adverse Effects in Patients with Glioma: Distinctive Features of Pseudoprogression and Treatment-Induced Necrosis. Oncologist 2020; 25:e1221.
  31. Chen J, Dassarath M, Yin Z, et al. Radiation induced temporal lobe necrosis in patients with nasopharyngeal carcinoma: a review of new avenues in its management. Radiat Oncol 2011; 6:128.
  32. Dietrich J. Neurotoxicity of Cancer Therapies. Continuum (Minneap Minn) 2020; 26:1646.
  33. Huang X, Zhang X, Wang X, et al. A nomogram to predict symptomatic epilepsy in patients with radiation-induced brain necrosis. Neurology 2020; 95:e1392.
  34. Winter SF, Loebel F, Loeffler J, et al. Treatment-induced brain tissue necrosis: a clinical challenge in neuro-oncology. Neuro Oncol 2019; 21:1118.
  35. Kano H, Kondziolka D, Lobato-Polo J, et al. T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 2010; 66:486.
  36. Leeman JE, Clump DA, Flickinger JC, et al. Extent of perilesional edema differentiates radionecrosis from tumor recurrence following stereotactic radiosurgery for brain metastases. Neuro Oncol 2013; 15:1732.
  37. Sugahara T, Korogi Y, Tomiguchi S, et al. Posttherapeutic intraaxial brain tumor: the value of perfusion-sensitive contrast-enhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast-enhancing tissue. AJNR Am J Neuroradiol 2000; 21:901.
  38. Mitsuya K, Nakasu Y, Horiguchi S, et al. Perfusion weighted magnetic resonance imaging to distinguish the recurrence of metastatic brain tumors from radiation necrosis after stereotactic radiosurgery. J Neurooncol 2010; 99:81.
  39. 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 2005; 26:1455.
  40. Rock JP, Scarpace L, Hearshen D, et al. Associations among magnetic resonance spectroscopy, apparent diffusion coefficients, and image-guided histopathology with special attention to radiation necrosis. Neurosurgery 2004; 54:1111.
  41. Quan D, Hackney DB, Pruitt AA, et al. Transient MRI enhancement in a patient with seizures and previously resected glioma: use of MRS. Neurology 1999; 53:211.
  42. Davidson A, Tait DM, Payne GS, et al. Magnetic resonance spectroscopy in the evaluation of neurotoxicity following cranial irradiation for childhood cancer. Br J Radiol 2000; 73:421.
  43. Henry RG, Vigneron DB, Fischbein NJ, et al. Comparison of relative cerebral blood volume and proton spectroscopy in patients with treated gliomas. AJNR Am J Neuroradiol 2000; 21:357.
  44. Lin A, Bluml S, Mamelak AN. Efficacy of proton magnetic resonance spectroscopy in clinical decision making for patients with suspected malignant brain tumors. J Neurooncol 1999; 45:69.
  45. Kimura T, Sako K, Tanaka K, et al. Evaluation of the response of metastatic brain tumors to stereotactic radiosurgery by proton magnetic resonance spectroscopy, 201TlCl single-photon emission computerized tomography, and gadolinium-enhanced magnetic resonance imaging. J Neurosurg 2004; 100:835.
  46. Valk PE, Budinger TF, Levin VA, et al. PET of malignant cerebral tumors after interstitial brachytherapy. Demonstration of metabolic activity and correlation with clinical outcome. J Neurosurg 1988; 69:830.
  47. Thiel A, Pietrzyk U, Sturm V, et al. Enhanced accuracy in differential diagnosis of radiation necrosis by positron emission tomography-magnetic resonance imaging coregistration: technical case report. Neurosurgery 2000; 46:232.
  48. Barker FG 2nd, Chang SM, Valk PE, et al. 18-Fluorodeoxyglucose uptake and survival of patients with suspected recurrent malignant glioma. Cancer 1997; 79:115.
  49. Doyle WK, Budinger TF, Valk PE, et al. Differentiation of cerebral radiation necrosis from tumor recurrence by [18F]FDG and 82Rb positron emission tomography. J Comput Assist Tomogr 1987; 11:563.
  50. Janus TJ, Kim EE, Tilbury R, et al. Use of [18F]fluorodeoxyglucose positron emission tomography in patients with primary malignant brain tumors. Ann Neurol 1993; 33:540.
  51. Glantz MJ, Hoffman JM, Coleman RE, et al. Identification of early recurrence of primary central nervous system tumors by [18F]fluorodeoxyglucose positron emission tomography. Ann Neurol 1991; 29:347.
  52. Ross DA, Sandler HM, Balter JM, et al. Imaging changes after stereotactic radiosurgery of primary and secondary malignant brain tumors. J Neurooncol 2002; 56:175.
  53. Schwartz RB, Holman BL, Polak JF, et al. Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy. J Neurosurg 1998; 89:60.
  54. Eisele SC, Dietrich J. Cerebral radiation necrosis: diagnostic challenge and clinical management. Rev Neurol 2015; 61:225.
  55. Palmisciano P, Haider AS, Nwagwu CD, et al. Bevacizumab vs laser interstitial thermal therapy in cerebral radiation necrosis from brain metastases: a systematic review and meta-analysis. J Neurooncol 2021; 154:13.
  56. Vellayappan B, Lim-Fat MJ, Kotecha R, et al. A Systematic Review Informing the Management of Symptomatic Brain Radiation Necrosis After Stereotactic Radiosurgery and International Stereotactic Radiosurgery Society Recommendations. Int J Radiat Oncol Biol Phys 2024; 118:14.
  57. Gonzalez J, Kumar AJ, Conrad CA, Levin VA. Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys 2007; 67:323.
  58. Torcuator R, Zuniga R, Mohan YS, et al. Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis. J Neurooncol 2009; 94:63.
  59. Liu AK, Macy ME, Foreman NK. Bevacizumab as therapy for radiation necrosis in four children with pontine gliomas. Int J Radiat Oncol Biol Phys 2009; 75:1148.
  60. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 2011; 79:1487.
  61. Deibert CP, Ahluwalia MS, Sheehan JP, et al. Bevacizumab for refractory adverse radiation effects after stereotactic radiosurgery. J Neurooncol 2013; 115:217.
  62. Boothe D, Young R, Yamada Y, et al. Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. Neuro Oncol 2013; 15:1257.
  63. Sadraei NH, Dahiya S, Chao ST, et al. Treatment of cerebral radiation necrosis with bevacizumab: the Cleveland clinic experience. Am J Clin Oncol 2015; 38:304.
  64. Glitza IC, Guha-Thakurta N, D'Souza NM, et al. Bevacizumab as an effective treatment for radiation necrosis after radiotherapy for melanoma brain metastases. Melanoma Res 2017; 27:580.
  65. Xu Y, Rong X, Hu W, et al. Bevacizumab Monotherapy Reduces Radiation-induced Brain Necrosis in Nasopharyngeal Carcinoma Patients: A Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 2018; 101:1087.
  66. Furuse M, Kawabata S, Kuroiwa T, Miyatake S. Repeated treatments with bevacizumab for recurrent radiation necrosis in patients with malignant brain tumors: a report of 2 cases. J Neurooncol 2011; 102:471.
  67. Jeyaretna DS, Curry WT Jr, Batchelor TT, et al. Exacerbation of cerebral radiation necrosis by bevacizumab. J Clin Oncol 2011; 29:e159.
  68. McPherson CM, Warnick RE. Results of contemporary surgical management of radiation necrosis using frameless stereotaxis and intraoperative magnetic resonance imaging. J Neurooncol 2004; 68:41.
  69. Newman WC, Goldberg J, Guadix SW, et al. The effect of surgery on radiation necrosis in irradiated brain metastases: extent of resection and long-term clinical and radiographic outcomes. J Neurooncol 2021; 153:507.
  70. Ahluwalia M, Barnett GH, Deng D, et al. Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis. J Neurosurg 2018; 130:804.
  71. Rao MS, Hargreaves EL, Khan AJ, et al. Magnetic resonance-guided laser ablation improves local control for postradiosurgery recurrence and/or radiation necrosis. Neurosurgery 2014; 74:658.
  72. Rammo R, Asmaro K, Schultz L, et al. The safety of magnetic resonance imaging-guided laser interstitial thermal therapy for cerebral radiation necrosis. J Neurooncol 2018; 138:609.
  73. Hong CS, Deng D, Vera A, Chiang VL. Laser-interstitial thermal therapy compared to craniotomy for treatment of radiation necrosis or recurrent tumor in brain metastases failing radiosurgery. J Neurooncol 2019; 142:309.
  74. Glantz MJ, Burger PC, Friedman AH, et al. Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 1994; 44:2020.
  75. Chuba PJ, Aronin P, Bhambhani K, et al. Hyperbaric oxygen therapy for radiation-induced brain injury in children. Cancer 1997; 80:2005.
  76. Cihan YB, Uzun G, Yildiz S, Dönmez H. Hyperbaric oxygen therapy for radiation-induced brain necrosis in a patient with primary central nervous system lymphoma. J Surg Oncol 2009; 100:732.
  77. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009; 10:1037.
  78. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011; 29:279.
  79. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 2007; 25:1260.
  80. Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 2016; 316:401.
  81. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2017; 18:1049.
  82. Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol 2013; 31:65.
  83. Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys 2013; 86:656.
  84. Monaco EA 3rd, Faraji AH, Berkowitz O, et al. Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer. Cancer 2013; 119:226.
  85. Wara WM, Bauman GS, Sneed PK, et al. Brain, brain stem and cerebellum. In: Principles and Practice of Radiation Oncology, 3rd ed, Perez E, Brady LW (Eds), Lippincott-Raven, Philadelphia 1997. p.799.
  86. Sabsevitz DS, Bovi JA, Leo PD, et al. The role of pre-treatment white matter abnormalities in developing white matter changes following whole brain radiation: a volumetric study. J Neurooncol 2013; 114:291.
  87. Constine LS, Konski A, Ekholm S, et al. Adverse effects of brain irradiation correlated with MR and CT imaging. Int J Radiat Oncol Biol Phys 1988; 15:319.
  88. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology 1989; 39:789.
  89. Tekkök IH, Carter DA, Robinson MG, Brinker R. Reversal of CNS-prophylaxis-related leukoencephalopathy after CSF shunting: case histories of identical twins. Childs Nerv Syst 1996; 12:309.
  90. Perrini P, Scollato A, Cioffi F, et al. Radiation leukoencephalopathy associated with moderate hydrocephalus: intracranial pressure monitoring and results of ventriculoperitoneal shunting. Neurol Sci 2002; 23:237.
  91. Dietrich J, Klein JP. Imaging of cancer therapy-induced central nervous system toxicity. Neurol Clin 2014; 32:147.
  92. Correa DD, DeAngelis LM, Shi W, et al. Cognitive functions in low-grade gliomas: disease and treatment effects. J Neurooncol 2007; 81:175.
  93. Kiehna EN, Mulhern RK, Li C, et al. Changes in attentional performance of children and young adults with localized primary brain tumors after conformal radiation therapy. J Clin Oncol 2006; 24:5283.
  94. Prust MJ, Jafari-Khouzani K, Kalpathy-Cramer J, et al. Standard chemoradiation for glioblastoma results in progressive brain volume loss. Neurology 2015; 85:683.
  95. Karunamuni R, Bartsch H, White NS, et al. Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma. Int J Radiat Oncol Biol Phys 2016; 94:297.
  96. Prust ML, Jafari-Khouzani K, Kalpathy-Cramer J, et al. Standard chemoradiation in combination with VEGF targeted therapy for glioblastoma results in progressive gray and white matter volume loss. Neuro Oncol 2018; 20:289.
  97. Klein M, Heimans JJ, Aaronson NK, et al. Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet 2002; 360:1361.
  98. Douw L, Klein M, Fagel SS, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol 2009; 8:810.
  99. Brown PD, Buckner JC, O'Fallon JR, et al. Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination. J Clin Oncol 2003; 21:2519.
  100. Meyers CA, Wefel JS. The use of the mini-mental state examination to assess cognitive functioning in cancer trials: no ifs, ands, buts, or sensitivity. J Clin Oncol 2003; 21:3557.
  101. Prabhu RS, Won M, Shaw EG, et al. Effect of the addition of chemotherapy to radiotherapy on cognitive function in patients with low-grade glioma: secondary analysis of RTOG 98-02. J Clin Oncol 2014; 32:535.
  102. Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol 2022; 40:492.
  103. Gondi V, Bauman G, Bradfield L, et al. Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol 2022; 12:265.
  104. Leskinen S, Shah HA, Yaffe B, et al. Hippocampal avoidance in whole brain radiotherapy and prophylactic cranial irradiation: a systematic review and meta-analysis. J Neurooncol 2023; 163:515.
  105. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 2013; 15:1429.
  106. Gondi V, Deshmukh S, Brown PD, et al. Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001. Int J Radiat Oncol Biol Phys 2023; 117:571.
  107. Yang WC, Chen YF, Yang CC, et al. Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial. Neuro Oncol 2021; 23:478.
  108. Pulsifer MB, Sethi RV, Kuhlthau KA, et al. Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors. Int J Radiat Oncol Biol Phys 2015; 93:400.
  109. Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys 2014; 89:1060.
  110. Yock TI, Yeap BY, Ebb DH, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: A phase 2 single-arm study. Lancet Oncol 2016; 17:287.
  111. Tabrizi S, Yeap BY, Sherman JC, et al. Long-term outcomes and late adverse effects of a prospective study on proton radiotherapy for patients with low-grade glioma. Radiother Oncol 2019; 137:95.
  112. https://www.clinicaltrials.gov/ct2/show/NCT03180502?term=NRG+BN005&draw=2&rank=1.
  113. Karschnia P, Parsons MW, Dietrich J. Pharmacologic management of cognitive impairment induced by cancer therapy. Lancet Oncol 2019; 20:e92.
  114. Richard NM, Bernstein LJ, Mason WP, et al. Cognitive rehabilitation for executive dysfunction in brain tumor patients: a pilot randomized controlled trial. J Neurooncol 2019; 142:565.
  115. Meyers CA, Weitzner MA, Valentine AD, Levin VA. Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 1998; 16:2522.
  116. Mulhern RK, Khan RB, Kaplan S, et al. Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer. J Clin Oncol 2004; 22:4795.
  117. Butler JM Jr, Case LD, Atkins J, et al. A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy. Int J Radiat Oncol Biol Phys 2007; 69:1496.
  118. Gehring K, Patwardhan SY, Collins R, et al. A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor. J Neurooncol 2012; 107:165.
  119. Day J, Yust-Katz S, Cachia D, et al. Interventions for the management of fatigue in adults with a primary brain tumour. Cochrane Database Syst Rev 2022; 9:CD011376.
  120. Kirkman MA, Day J, Gehring K, et al. Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation. Cochrane Database Syst Rev 2022; 11:CD011335.
  121. Page BR, Shaw EG, Lu L, et al. Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue. Neuro Oncol 2015; 17:1393.
  122. Porter AB, Liu H, Kohli S, et al. Efficacy of Treatment With Armodafinil for Cancer-Related Fatigue in Patients With High-grade Glioma: A Phase 3 Randomized Clinical Trial. JAMA Oncol 2022; 8:259.
  123. Shaw EG, Rosdhal R, D'Agostino RB Jr, et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol 2006; 24:1415.
  124. Rapp SR, Case LD, Peiffer A, et al. Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial. J Clin Oncol 2015; 33:1653.
  125. Campen CJ, Kranick SM, Kasner SE, et al. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors. Stroke 2012; 43:3035.
  126. Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2006; 24:5277.
  127. Murphy ES, Xie H, Merchant TE, et al. Review of cranial radiotherapy-induced vasculopathy. J Neurooncol 2015; 122:421.
  128. Nordstrom M, Felton E, Sear K, et al. Large Vessel Arteriopathy After Cranial Radiation Therapy in Pediatric Brain Tumor Survivors. J Child Neurol 2018; 33:359.
  129. Kenney LB, Ames BL, Huang MS, et al. Consensus Recommendations for Managing Childhood Cancer Survivors at Risk for Stroke After Cranial Irradiation: A Delphi Study. Neurology 2022; 99:e1755.
  130. Desai SS, Paulino AC, Mai WY, Teh BS. Radiation-induced moyamoya syndrome. Int J Radiat Oncol Biol Phys 2006; 65:1222.
  131. Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 2007; 68:932.
  132. Aizer AA, Du R, Wen PY, Arvold ND. Radiotherapy and death from cerebrovascular disease in patients with primary brain tumors. J Neurooncol 2015; 124:291.
  133. El-Fayech C, Haddy N, Allodji RS, et al. Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries. Int J Radiat Oncol Biol Phys 2017; 97:278.
  134. Kranick SM, Campen CJ, Kasner SE, et al. Headache as a risk factor for neurovascular events in pediatric brain tumor patients. Neurology 2013; 80:1452.
  135. Haddy N, Mousannif A, Tukenova M, et al. Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality. Brain 2011; 134:1362.
  136. Hooning MJ, Dorresteijn LD, Aleman BM, et al. Decreased risk of stroke among 10-year survivors of breast cancer. J Clin Oncol 2006; 24:5388.
  137. Bates A, Gonzalez-Viana E, Cruickshank G, et al. Primary and metastatic brain tumours in adults: summary of NICE guidance. BMJ 2018; 362:k2924.
  138. Strenger V, Sovinz P, Lackner H, et al. Intracerebral cavernous hemangioma after cranial irradiation in childhood. Incidence and risk factors. Strahlenther Onkol 2008; 184:276.
  139. Burn S, Gunny R, Phipps K, et al. Incidence of cavernoma development in children after radiotherapy for brain tumors. J Neurosurg 2007; 106:379.
  140. Lew SM, Morgan JN, Psaty E, et al. Cumulative incidence of radiation-induced cavernomas in long-term survivors of medulloblastoma. J Neurosurg 2006; 104:103.
  141. Kralik SF, Mereniuk TR, Grignon L, et al. Radiation-Induced Cerebral Microbleeds in Pediatric Patients With Brain Tumors Treated With Proton Radiation Therapy. Int J Radiat Oncol Biol Phys 2018; 102:1465.
  142. Wahl M, Anwar M, Hess CP, et al. Relationship between radiation dose and microbleed formation in patients with malignant glioma. Radiat Oncol 2017; 12:126.
  143. Neu MA, Tanyildizi Y, Wingerter A, et al. Susceptibility-weighted magnetic resonance imaging of cerebrovascular sequelae after radiotherapy for pediatric brain tumors. Radiother Oncol 2018; 127:280.
  144. Heckl S, Aschoff A, Kunze S. Radiation-induced cavernous hemangiomas of the brain: a late effect predominantly in children. Cancer 2002; 94:3285.
  145. Winter SF, Klein JP, Vaios EJ, et al. Clinical Presentation and Management of SMART Syndrome. Neurology 2021; 97:118.
  146. Kerklaan JP, Lycklama á Nijeholt GJ, Wiggenraad RG, et al. SMART syndrome: a late reversible complication after radiation therapy for brain tumours. J Neurol 2011; 258:1098.
  147. Fan EP, Heiber G, Gerard EE, Schuele S. Stroke-like migraine attacks after radiation therapy: A misnomer? Epilepsia 2018; 59:259.
  148. Farid K, Meissner WG, Samier-Foubert A, et al. Normal cerebrovascular reactivity in Stroke-like Migraine Attacks after Radiation Therapy syndrome. Clin Nucl Med 2010; 35:583.
  149. Olsen AL, Miller JJ, Bhattacharyya S, et al. Cerebral perfusion in stroke-like migraine attacks after radiation therapy syndrome. Neurology 2016; 86:787.
  150. Armstrong AE, Gillan E, DiMario FJ Jr. SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients. J Child Neurol 2014; 29:336.
  151. van Kempen-Harteveld ML, Struikmans H, Kal HB, et al. Cataract after total body irradiation and bone marrow transplantation: degree of visual impairment. Int J Radiat Oncol Biol Phys 2002; 52:1375.
  152. Mayo C, Martel MK, Marks LB, et al. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 2010; 76:S28.
  153. Brecht S, Boda-Heggemann J, Budjan J, et al. Radiation-induced optic neuropathy after stereotactic and image guided intensity-modulated radiation therapy (IMRT). Radiother Oncol 2019; 134:166.
  154. Harris JR, Levene MB. Visual complications following irradiation for pituitary adenomas and craniopharyngiomas. Radiology 1976; 120:167.
  155. Borruat FX, Schatz NJ, Glaser JS, et al. Visual recovery from radiation-induced optic neuropathy. The role of hyperbaric oxygen therapy. J Clin Neuroophthalmol 1993; 13:98.
  156. Kelly PJ, Dinkin MJ, Drappatz J, et al. Unexpected late radiation neurotoxicity following bevacizumab use: a case series. J Neurooncol 2011; 102:485.
  157. Fishman ML, Bean SC, Cogan DG. Optic atrophy following prophylactic chemotherapy and cranial radiation for acute lymphocytic leukemia. Am J Ophthalmol 1976; 82:571.
  158. De Cicco L, Cella L, Liuzzi R, et al. Radiation therapy in primary orbital lymphoma: a single institution retrospective analysis. Radiat Oncol 2009; 4:60.
  159. Kennerdell JS, Flores NE, Hartsock RJ. Low-dose radiotherapy for lymphoid lesions of the orbit and ocular adnexa. Ophthal Plast Reconstr Surg 1999; 15:129.
  160. Bessell EM, Henk JM, Wright JE, Whitelocke RA. Orbital and conjunctival lymphoma treatment and prognosis. Radiother Oncol 1988; 13:237.
  161. Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation retinopathy after external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys 1994; 30:765.
  162. Jereczek-Fossa BA, Zarowski A, Milani F, Orecchia R. Radiotherapy-induced ear toxicity. Cancer Treat Rev 2003; 29:417.
  163. Bhandare N, Antonelli PJ, Morris CG, et al. Ototoxicity after radiotherapy for head and neck tumors. Int J Radiat Oncol Biol Phys 2007; 67:469.
  164. Ho WK, Wei WI, Kwong DL, et al. Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: A prospective study. Head Neck 1999; 21:547.
  165. Herrmann F, Dörr W, Müller R, Herrmann T. A prospective study on radiation-induced changes in hearing function. Int J Radiat Oncol Biol Phys 2006; 65:1338.
  166. Pan CC, Eisbruch A, Lee JS, et al. Prospective study of inner ear radiation dose and hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 2005; 61:1393.
  167. Hua C, Bass JK, Khan R, et al. Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose. Int J Radiat Oncol Biol Phys 2008; 72:892.
  168. Paulino AC, Lobo M, Teh BS, et al. Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol Phys 2010; 78:1445.
  169. Kretschmar CS, Warren MP, Lavally BL, et al. Ototoxicity of preradiation cisplatin for children with central nervous system tumors. J Clin Oncol 1990; 8:1191.
  170. Low WK, Toh ST, Wee J, et al. Sensorineural hearing loss after radiotherapy and chemoradiotherapy: a single, blinded, randomized study. J Clin Oncol 2006; 24:1904.
  171. Huang E, Teh BS, Strother DR, et al. Intensity-modulated radiation therapy for pediatric medulloblastoma: Early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 2002; 52:599.
  172. Formanek M, Czerny C, Gstoettner W, Kornfehl J. Cochlear implantation as a successful rehabilitation for radiation-induced deafness. Eur Arch Otorhinolaryngol 1998; 255:175.
  173. Zuur CL, Simis YJ, Lansdaal PE, et al. Ototoxicity in a randomized phase III trial of intra-arterial compared with intravenous cisplatin chemoradiation in patients with locally advanced head and neck cancer. J Clin Oncol 2007; 25:3759.
  174. Zuur CL, Simis YJ, Lansdaal PE, et al. Risk factors of ototoxicity after cisplatin-based chemo-irradiation in patients with locally advanced head-and-neck cancer: a multivariate analysis. Int J Radiat Oncol Biol Phys 2007; 68:1320.
  175. Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 1993; 328:87.
  176. Taphoorn MJ, Heimans JJ, van der Veen EA, Karim AB. Endocrine functions in long-term survivors of low-grade supratentorial glioma treated with radiation therapy. J Neurooncol 1995; 25:97.
  177. Collet-Solberg PF, Sernyak H, Satin-Smith M, et al. Endocrine outcome in long-term survivors of low-grade hypothalamic/chiasmatic glioma. Clin Endocrinol (Oxf) 1997; 47:79.
  178. Arlt W, Hove U, Müller B, et al. Frequent and frequently overlooked: treatment-induced endocrine dysfunction in adult long-term survivors of primary brain tumors. Neurology 1997; 49:498.
  179. Lam KS, Tse VK, Wang C, et al. Effects of cranial irradiation on hypothalamic-pituitary function--a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med 1991; 78:165.
  180. Pai HH, Thornton A, Katznelson L, et al. Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: demonstration of a dose-effect relationship using dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2001; 49:1079.
  181. Minniti G, Jaffrain-Rea ML, Osti M, et al. The long-term efficacy of conventional radiotherapy in patients with GH-secreting pituitary adenomas. Clin Endocrinol (Oxf) 2005; 62:210.
  182. Appelman-Dijkstra NM, Kokshoorn NE, Dekkers OM, et al. Pituitary dysfunction in adult patients after cranial radiotherapy: systematic review and meta-analysis. J Clin Endocrinol Metab 2011; 96:2330.
  183. Wara W, Bauman G, Sneed P. Brain, brain stem, and cerebellum. In: Principles and Practice of Radiation Oncology, Perez C, Brady L (Eds), Lippincott-Raven, Philadelphia 1998. p.777.
  184. Balasubramaniam A, Shannon P, Hodaie M, et al. Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: case report and review of the literature. Neuro Oncol 2007; 9:447.
  185. Sheehan J, Yen CP, Steiner L. Gamma knife surgery-induced meningioma. Report of two cases and review of the literature. J Neurosurg 2006; 105:325.
  186. Chung CS, Yock TI, Nelson K, et al. Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys 2013; 87:46.
Topic 91670 Version 44.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟