The effects of radiation therapy on the brain: implications for management

Introduction

Radiation therapy (RT) has had a well-defined role in the management of central nervous system (CNS) malignancies for decades. For example, the BTSG 69-01 trial showed a significant increase in the survival of patients with malignant gliomas who had received RT (1). Patients who enrolled in BTSG 69-01 who received 60 Gray (Gy) lived longer than those who received 50 Gy and <45 Gy (1-5). In these early studies, there was no serious examination of the toxicities caused by RT, as it was assumed that the survival benefit outweighed the toxicity (1,4). Since then, brain RT has been used for many primary CNS neoplasms, including CNS lymphoma, medulloblastoma, ependymoma, and atypical teratoid rhabdoid tumor; metastatic brain tumors; and prophylactically for small cell lung cancer (6-9). As RT has become a common treatment option in the management of brain tumors, toxicities must be considered and addressed.

RT is perhaps most commonly utilized in the CNS for the treatment of CNS metastases, with decades of data supporting its efficacy, starting in the 1930s (10). Initial data supported the use of whole brain radiation therapy (WBRT) (11,12). However, concern regarding the neurocognitive toxicity of WBRT led to the development of new RT techniques. As a result, in recent decades, there has been a shift in practice, with evidence supporting the use of stereotactic radiosurgery (SRS) to safely deliver ablative doses of radiation to intracranial metastases while minimizing neurocognitive side effects (13-15).

While the goal of RT is to maximize dose to the tumor and minimize dose to the surrounding intact structures, it is impossible to completely spare healthy tissues. As such, like other tissues in the body, the brain can exhibit changes in function after receiving RT. Several studies have demonstrated that RT’s primary effect in inducing cellular damage comes from the creation of single- and double-stranded DNA breaks (16-20). Healthy neurons have limited DNA-repair capacity and they may accrue mutations both directly from the radiation administered and indirectly from RT-generated reactive oxygen species (ROS), leading ultimately to mitotic catastrophe and apoptosis (21). The process that results in apoptosis may occur over time, but also as quickly as four hours after radiation doses as low as 2 Gy (22). However, this may not completely explain the mechanism for damage in the CNS since neurons have a low potential for mitosis. Other possible mechanisms for CNS damage from RT include changes in blood vessel permeability, damage to the lipid bilayer, mitochondrial changes causing oxidative stress, and cell-cell junctional complex changes (23-25). The precise mechanism of neurotoxicity remains unclear (26).

In this review, we aim to provide clinicians with a comprehensive and practical framework for understanding and managing RT-induced toxicities in the brain. RT is an essential element in the treatment of intracranial malignancies, providing substantial therapeutic benefits. Understanding and addressing its side effects can help optimize its use across various clinical scenarios. In examining brain RT toxicities, we also address the challenge of isolating the toxicities of RT from the effects of the tumors themselves (27). We categorize RT toxicities into acute, early delayed, and late delayed phases, each defined by the timing of onset and specific cellular mechanisms that affect the reversibility of symptoms. Additionally, we discuss recent advances in RT that allow for highly precise targeting, significantly reducing the incidence of toxicities previously common in treatment, and we propose further strategies to mitigate these effects.

Acute toxicities

RT-induced toxicities are often described in three phases. The Radiation Therapy Oncology Group (RTOG) defines acute clinical CNS toxicity as symptoms attributable to RT and occurring during RT or within 90 days of its completion. Early-delayed effects occur one to six months after RT and late effects occur more than six months after RT.

In the acute setting, damage to the CNS may arise from cellular changes in the microenvironment, leading to oxidative stress and an upregulation of proinflammatory pathways (28). Furthermore, RT has been associated with changes in gray matter, white matter, and ventricles. Specifically, coagulation necrosis of white matter tracts is a feature of radiation-related injury. Finally, cellular death, particularly the death of endothelial cells, potentially leads to microvascular changes (28). Vascular changes lead to demyelination, neurodegeneration and/or neuroinflammation (26). Risk factors for radiation-related toxicity are primarily based on the radiation fraction size, the volume of tissue irradiated, the proximity of adjacent structures, the dose received by adjacent structures, and the individual patient and tumor characteristics, including age, comorbidities, genetic predisposition, and the other treatment modalities employed (such as chemotherapy and surgery) (26).

The most common acute CNS toxicity of RT is fatigue, which may be due to transient demyelination (29). Acute fatigue typically begins within two weeks of the start of RT, peaks four to eight weeks post-treatment, and resolves within eight to 12 weeks after RT. However, severe fatigue may occur and persist longer in some cases. Patients are high-risk for fatigue if they are younger, have preexisting fatigue, have baseline psychiatric comorbidities, or have received a higher RT dose to critical brain structures (30-33). Exercise programs, including aerobic and resistance training, may help reduce fatigue in these patients (34-36). Specifically, 150 minutes of aerobic activity and 2–3 resistance training sessions per week are recommended in patients with cancer who experience fatigue (34). Additionally, improvement in sleep through cognitive behavioral therapy or yoga has been shown to reduce fatigue (35,36).

Other acute CNS toxicities of RT, including headache, nausea, emesis, and an exacerbation of existing neurologic symptoms, are generally due to local edema. There is an increased risk of nausea and vomiting in patients who receive higher doses of RT, have larger irradiated volumes, or receive concurrent chemotherapy (31,32). Exacerbation of neurological symptoms is associated with tumor location, poor baseline neurological status, and higher RT dose to critical regions such as the thalamus and corticospinal tracts (32,37).

The acute toxicities caused by brain edema may be treated with corticosteroids. Corticosteroids are known for their anti-edema effects and have been used in conjunction with brain RT since the 1950s (38,39). Dexamethasone, in particular, is effective in reducing CNS edema due to its long half-life and potency with minimal mineralocorticoid side effects (40). Severe cerebral edema is treated with an initial 10 mg of dexamethasone delivered intravenously and 4 mg every 6 hours delivered either intravenously or orally until the resolution of symptoms, according to the Food and Drug Administration guidelines (41). A clinical response is normally observed within 24 hours and the steroids should subsequently be tapered. An acceptable tapering schedule will reduce the dose after 2–4 days with a taper over 5–7 days by decreasing the dose by around 4 mg per day every two days (41). Prophylactically, corticosteroids should be considered to manage cerebral edema in patients with significant peritumoral edema or with large tumor volumes before RT. The dose of prophylactic dexamethasone depends on the severity of the patient’s symptoms. Patients with moderate symptoms should receive 4–8 mg per day of dexamethasone according to the American College of Radiology (ACR) Appropriateness Criteria (AC) (42). The ACR AC recommends that patients with neurologic symptoms, more significant cerebral edema, or large cerebral metastases receive 16 mg per day of dexamethasone during definitive therapy, which may or may not include RT (43). However, the effects of corticosteroids are short-lived, and symptomatic cerebral edema may return. Prolonged use of corticosteroids is not recommended due to significant side effects including hyperglycemia, hypertension, osteoporosis, neurologic complications, increased risk of infection, and reduced tumor cell sensitivity to chemotherapy (40). Therefore, corticosteroids should be used as temporary treatment whenever possible.

Mannitol is another pharmacological intervention used to reduce cerebral edema. Mannitol can be used in the short term, before corticosteroids take effect (44-47). The initial recommended dose of mannitol is a 0.25–2 g/kg intravenous bolus, which may be repeated every 4–6 hours if needed as long as serum osmolality does not exceed 320 mOsm/L (44-47). However, mannitol is not recommended for long-term use due to its side effects of volume overload and hyperosmolarity (44-47). In addition, over-the-counter pain medications and prescription anti-nausea medications may be utilized to manage headaches, nausea and emesis, respectively.

Early delayed toxicities

Somnolence syndrome

Somnolence syndrome, first reported by Druckmann in 1929, may occur after brain RT (48). It occurs 4 to 6 weeks after intracranial RT and presents with non-specific symptoms, including drowsiness, fatigue, and decreased appetite (48,49). While the definitive pathophysiology of somnolence syndrome remains unclear, it has been proposed that RT-induced myelin dysfunction or vascular disruption may interrupt cell injury repair and precipitate symptoms (50). A grading system established by Littman evaluates the severity of somnolence syndrome from grade 1 (minimal disturbance to daily functioning) to grade 4 (severe disruption to daily functioning) (51,52).

There is relatively little data available on somnolence syndrome in adults, as the majority of studies focused on pediatric patient populations (50-53). As such, the exact patient risk factors remain unclear. However, somnolence syndrome has typically been described after WBRT, with some studies reporting a dose-effect relationship between RT and the resultant fatigue (49,54). Despite the relatively benign and self-limited nature of somnolence syndrome, the symptoms may induce anxiety among patients and their caretakers. As a result, anticipatory guidance and patient education have been recommended as important steps in management (53). Patients should be informed that fatigue and drowsiness may occur 4–6 weeks after treatment. It is critical to reassure them that these symptoms are temporary and typically resolve without the need for intervention. Additionally, steroids have historically been used to decrease the incidence of somnolence syndrome in children receiving prophylactic cranial RT (55). Studies have shown steroid therapy to be associated with decreased somnolence syndrome in both children and adults (53,55,56). However, steroids impose additional toxicity, especially to children, and patients with somnolence syndrome return to normal function within a few weeks with or without steroid treatment (49,56).

Peri-ictal pseudoprogression (PIPG)

For patients with cancer who have received cranial RT, follow-up imaging is a critical step in monitoring disease progression. One barrier to doing so is the possibility of PIPG, a rare, early-delayed sequela of cranial RT that may erroneously suggest disease progression (57). Patients with PIPG show transient neuroimaging abnormalities (for example, increased edema and/or contrast enhancement) following seizure activity, which may be interpreted and managed as tumor progression (58,59). In their analysis of ten patients with PIPG across six institutions, Rheims et al. identified focal cortical or leptomeningeal enhancement as common magnetic resonance imaging (MRI) features (58). They suggest that these features should raise suspicion of PIPG in the context of post-RT seizures (58). Due to the exceedingly rare nature of PIPG, the exact mechanisms that underlie this phenomenon remain undetermined and limited data exist on the specific features that distinguish PIPG from true tumor progression. For example, grade 2 gliomas may manifest with seizures and neuroimaging abnormalities that could be inappropriately designated as PIPG from RT. Conversely, it is important to identify when there is no true tumor progression and thus no additional treatment is necessary. Therefore, further research is necessary to guide clinicians in correctly identifying PIPG and preventing unnecessary therapeutic escalation in patients who do not have true disease progression.

Assessment of PIPG is recommended with MRI one to three months post-treatment (60). Elevated choline/N-acetyl aspartate and choline/creatine ratios on magnetic resonance (MR) spectroscopy can be used to diagnostically differentiate PIPG (characterized by lower ratios) from true progression (higher ratios) (60,61). Another diagnostic MRI method is perfusion imaging (62-64). Dynamic susceptibility contrast MRI will typically measure higher relative cerebral blood volume in true progression than in PIPG (63,64). Higher volume transfer constant and extravascular extracellular space per unit volume of tissue as measured by dynamic contrast-enhanced MRI are also associated with true progression (62).

Clinical management of patients with PIPG includes steroids and anticonvulsants, which have been shown to yield radiological resolution after one to three months (65). Levetiracetam specifically is recommended over phenytoin for the treatment of PIPG due to its safer side effect profile and absence of interactions with chemotherapeutic agents (66-68). The administered dose should be 500 mg per 12 hours (66). Levetiracetam is also recommended for prophylaxis for seizures in patients with large tumor volumes or significant peritumoral edema, according to the Society for Neuro-Oncology and the European Association of Neuro-Oncology (68-70). Finally, antiseizure medication should be gradually tapered only after a minimum of 12 months without seizures to lower the risk of recurrence (71).

Late toxicities

Radiation necrosis (RN)

Radiation-associated vascular injury may cause a cascade of events that result in demyelination, the release of inflammatory mediators, and the development of leaky blood vessels. These changes may lead to disruptions in the blood-brain barrier and RN (72). The development of RN depends on several treatment-related and tumor-associated risk factors. Treatment-related risk factors include the type of treatment, fraction size and total dose of RT administered, the location and volume of healthy brain tissue irradiated, any history of prior RT delivered to the same area, and the concurrent use of certain systemic therapies and/or radiation-sensitizing medications (73-75).

SRS poses a greater risk of RN than WBRT (76). Additionally, the incidence of RN after single-fraction SRS is higher in patients who have larger tumors (both by diameter and volume) (77-79). To lower the risk of symptomatic RN in such patients, fractionated SRS may be utilized. Prior work has shown a significantly decreased risk of RN with multifraction SRS as compared to single-session SRS (80).

There is an increased risk of RN with high RT doses and with reirradiation. In a first course of radiation, maximum point doses of <60 Gy and 72 Gy are associated with symptomatic RN risks of <3% and 5%, respectively. Over multiple courses, RN is associated with a cumulative equivalent dose in 2 Gy fractions (EQD2) of greater than 100 Gy (81,82). Decreased time to reirradiation also increases the risk of RN. Wong et al.’s study of the rat spinal cord demonstrated that the ability of the CNS to regenerate after RT depends on the initial dose and time between initial RT and reirradiation (83). Furthermore, regeneration rates vary by the type of CNS tissue affected. The hippocampus and dentate gyrus’ regenerative capacities are particularly blunted by RT. Hippocampal neurogenesis may decline to 5% of baseline levels and the dentate gyrus to 10–15% (84). Other tissues may recover more significantly. For example, the subventricular zone can retain 53% of actively proliferating cells compared to control levels (84). Oligodendrocyte precursor cells (OPCs) in white matter display increased rates of proliferation after RT (85). On the other hand, OPCs have a variable response in gray matter such as in the CA3 area of the hippocampus, where they are especially susceptible to RT-induced damage (85). Finally, CNS regeneration after RT is related to a patient’s age: older patients have less regenerative capacity than younger patients (81,84,85). Tumor-associated risk factors associated with RN include tumor location and biology, specifically a histology of lung adenocarcinoma or renal cell carcinoma and the presence of HER2, ALK, and BRAF mutations (86).

The symptomatology of RN varies according to its location and size. While some patients may have no or mild symptoms, others may experience headaches, drowsiness, cognitive dysfunction, memory difficulties, weakness, and seizures (74). Management depends on whether the patient is asymptomatic or symptomatic. Asymptomatic patients may be followed with serial brain MRI scans, including MR spectroscopy and MR perfusion, to differentiate RN from tumor recurrence (87).

Symptomatic patients may be managed with a combination of steroids, 5-Loxin (Boswellia serrata), bevacizumab, hyperbaric oxygen therapy (HBOT), and surgery (88-92). Corticosteroid treatment includes an initial dose of 8 mg per day of dexamethasone. Tapering should be individualized to the patient with a dose reduction of 2–4 mg every 3–7 days based on clinical improvement (41).

The supplement 5-Loxin (Boswellia serrata) has also been shown to decrease cerebral edema in patients who have undergone RT for brain tumors by inhibiting vascular endothelial growth factor expression (93). A recent study evaluated patients who received 4,050–4,500 mg daily of 5-Loxin for at least 2 months after developing RN following SRS for brain metastases (94). They demonstrated 5-Loxin’s safety and efficacy as measured by decreased cerebral edema present after treatment (94). As such, Boswellia is increasingly being utilized in clinical practice.

Bevacizumab is indicated for patients who are unresponsive to corticosteroids or who are dependent on high dose corticosteroids to manage RN symptoms (95-99). A bevacizumab regimen of 5–7.5 mg/kg every 2 weeks for 4–6 cycles has been shown to be effective in treating RN (97-99). HBOT can be considered for the treatment of RN for patients who are unable to tolerate or are unresponsive to corticosteroids and bevacizumab. A typical HBOT regimen, 20–40 sessions at 2.0–4.0 atmospheres absolute for 1.5–2 hours per session, may improve outcomes in patients with RN (88,100-102). However, availability, cost, side effects, and limited evidence limit the use of HBOT in clinical practice. HBOT requires expensive equipment and facilities which are not often accessible or covered by insurance. Although HBOT is generally well-tolerated, it may cause barotrauma, visual changes, or oxygen toxicity (88,103). Additional randomized controlled trials are necessary to definitively prove HBOT’s safety and efficacy (88,103).

Surgery is the last resort when RN is refractory to medical treatment (104-106). Surgery may also be considered when a large necrotic area causes mass effect that impairs other regions of the brain and leads to symptoms (107). Lastly, in cases where it is difficult to distinguish RN from tumor progression, surgical resection can be used as treatment and for definitive histological diagnosis (105). Surgery for RN is generally safe, but as an invasive procedure, it carries a higher risk of complications, including morbidity and mortality, and does not completely prevent RN from recurring (106,108).

Radiation-induced vascular disorders

RT can lead to the development of vasculopathy. In particular, tissue necrosis and inflammation may lead to the narrowing of blood vessels, which, in turn, results in diminished blood flow and disruptions to the blood-brain barrier (109,110). The spectrum of radiation-induced vascular disorders includes cerebrovascular accidents (CVAs), lacunar lesions, cerebral hemorrhages, and vascular malformations (such as aneurysms) (111).

RT can also cause vascular occlusive diseases, including radiation-induced Moyamoya syndrome (RIMS). Risk factors for RIMS are younger age during RT, higher dose of RT, and proximity of the RT field to the circle of Willis (112-114). RIMS presentation includes headache, seizure, stroke, motor weakness, cognitive impairment, speech difficulties, and other neurological deficits. The symptom onset varies from months to years after RT (112,113,115). RIMS is diagnosed by MR angiography. Regular surveillance is important for high-risk patients, including those with neurofibromatosis type 1 or optic pathway gliomas (112,113,116,117). Antiplatelet agents are used to reduce the risk of ischemia in RIMS, but are insufficient to halt progression (112,113). Instead, surgical revascularization is used to improve cerebral perfusion and promote angiogenesis (112,113,116).

For all RT-induced vasculopathies, risk factors include the concurrent use of chemotherapeutic agents, young age at the time of RT, a higher cumulative RT dose, a high dose delivered to the parasellar region, and pre-existing endocrine abnormalities (109-111). The symptomology and radiologic findings of radiation-induced vascular disorders are not pathognomonic; instead, they are similar to primary vascular disorders since they share pathophysiological processes (110). Thus, radiation-induced vascular disorders are mainly a diagnosis of exclusion based on clinicoradiological findings in patients with a history of prior RT to the region of the affected blood vessels (110). Clinical management is similar to that of primary vascular disorders and often involves stenting, angioplasty, surgery, and non-procedural approaches (111).

Cognitive impairment

Cognitive impairment is a common and well-defined late-delayed effect of brain RT. It is likely caused by a combination of demyelination, vascular changes, oxidative damage, and white matter necrosis leading to mitotic catastrophe, apoptosis and inflammation (118-120). Inflammation triggers endothelial cell dysfunction and microvascular changes that lead to the impairment of the blood brain barrier and development of neurodegenerative conditions (118). Specifically, neuroinflammation results in the secretion of proinflammatory cytokines and induction of inflammatory cascades, leading to RT-induced fibrosis approximately 4–12 months after RT (see Radiation necrosis section) (118,120).

Particular anatomic sites have been associated with RT-induced cognitive impairment. In a long-term study with a median follow-up time of 4.6 years after RT, the cognitive symptoms experienced by patients varied according to the area of the brain irradiated (121). When administered to either the left hippocampus, left temporal lobe, or left frontal lobe, high RT doses were associated with decreased verbal fluency; to the left temporal lobe, left frontal lobe, thalamus, or total brain, with impaired processing speed; and to the left frontal lobe and thalamus, with impaired executive functioning (121). Interestingly, no such associations between RT dose and cognition were found for the right and total hippocampus structures (121). Nonetheless, hippocampal radiation is a risk factor for cognitive decline as measured by a decreased Montreal Cognitive Assessment score (122). Genetic markers are also associated with decreased cognitive function after brain RT. The presence of the APOE genotype; low baseline levels of ApoJ, ApoE, or ApoA; or high amyloid beta proteins are associated with neurocognitive decline after SRS (123).

RT-induced cognitive decline can manifest as deficits in memory, learning, processing speed, and verbal fluency, and the symptoms may present and persist years after treatment. Learning and memory impairments are present in up to 50% of patients receiving WBRT (118). In one study, patients receiving either prophylactic or therapeutic WBRT experienced declining verbal memory function 6–8 weeks after treatment, although there were no visual memory or attention functional deficits associated with WBRT in this study (124). Impaired attentional functioning, executive functioning, and information processing speed may persist over the course of up to 12 years after WBRT, and notably, these deficiencies are independent of the RT dose (125). Cognitive decline, as measured by mini-mental status examination, is associated with poor survival outcomes, highlighting the importance of monitoring patients’ cognitive statuses and mediating the cognitive effects of RT (126).

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has shown potential in mitigating the vascular changes and cognitive decline associated with WBRT. In a key study, patients treated with memantine exhibited less white matter damage and better cognitive outcomes, particularly in verbal fluency, six months after WBRT compared to patients who received a placebo (127).

Hippocampal avoidance (HA) may also mitigate cognitive decline associated with brain RT, with further research currently underway to examine this benefit (13,128,129). RTOG 0933, a non-randomized phase II trial, compared patients receiving HA-WBRT to historical patients who had received WBRT and demonstrated fewer memory deficits and less decline in quality of life (128). Additionally, the results of a randomized controlled phase III 2020 trial by Brown et al. (NRG-CC001 protocol), showed a reduced risk of cognitive failure in patients in whom memantine was combined with HA-WBRT as compared to patients who received memantine and standard WBRT (13). Building off of this data, HIPPORAD, a phase II prospective randomized multicenter trial, will compare the impact of HA-WBRT on neurocognitive functioning for patients with multiple brain metastases (129). Taken together, these results establish HA-WBRT with memantine as a benchmark for future studies with the goal of delaying cognitive decline (13,107,130).

Implementing HA-WBRT with memantine requires planning using imaging and specific dose constraints. The recommended starting dose of memantine is 5 mg daily, increasing by 5 mg weekly to the target 10 mg twice daily at week 4 (131,132). Memantine administration should continue for six months following the initiation of WBRT (131-133). For HA-WBRT, a diagnostic MRI should be used to delineate an HA region consisting of the hippocampus with a 5-mm volumetric expansion contour (134-136). In treatment planning, an MRI-computed tomography fusion is used to align anatomic structures (134,135). The NRG-CC001 protocol recommends a maximum dose of ≤16 Gy, and a D100% ≤9 Gy (134,135). A typical whole brain dose of 30 Gy in 10 fractions will ensure adequate coverage with HA-WBRT (134,135).

In contrast to WBRT, targeted, partial brain treatments in the modern era have been shown to cause less cognitive impairment (137). For instance, patients receiving SRS for a single resected brain metastasis experienced less cognitive deterioration at three, six, and nine months post-treatment, with no differences in overall survival compared to patients receiving WBRT (138,139). Brown et al. also reported reduced cognitive decline in patients treated with SRS for one to three brain metastases compared to WBRT (140). Lastly, a 2023 study found no long-term neurocognitive deficits in patients with gliomas who were treated with focal brain RT at a median of 7 years of follow-up after treatment (141).

In addition to RT techniques and medical interventions, neuropsychological assessments, rehabilitation programs, and digital cognitive training platforms can be effective in monitoring and treating cognitive decline. Neuropsychological assessments, such as the Hopkins Verbal Learning Test-Revised, Trail Making Tests A and B, and Controlled Oral Word Association Test, can be used to identify cognitive decline and plan treatment strategies (142). Cognitive rehabilitation programs include Goal Management Training, which improves processing speed and executive function, and Cognitive Strategy Instruction, which helps to develop compensatory techniques (143,144). Finally, digital cognitive training platforms may provide cognitive problem solving and memory exercises to decrease impairment and improve cognitive function (144,145).

Neuropathies

Cranial nerve neuropathy is the primary RT-induced neuropathy specific to the treatment of intracranial malignancies. Patients undergoing head and neck RT are at risk of developing neuropathy due to the abundant nervous tissue in this region and the limited capacity of the CNS to regenerate and repair itself (120). It has been postulated that RT directly injures nerves via axonal damage and demyelination. Additionally, RT-induced fibrosis may trigger inflammation and sclerosis, which impair nerve function (146).

The most common neuropathy caused by RT to the brain is radiation-induced optic neuropathy (RION). In a systematic review of 70 studies on the effects of brain and head and neck RT, the prevalence of retinopathy or optic neuropathy was 3.8% (147). RION has been extensively described in the literature, although it is an uncommon effect of RT and its pathophysiology remains unclear. The proposed pathophysiology of RION includes ischemic demyelination secondary to damage to the capillary endothelium, injury to vascular endothelial cells leading to retinal occlusion, an induced hypoxic environment, generation of ROS, and/or direct optic nerve damage (120,148,149).

Evidence suggests that patient- and tumor-related risk factors play only a minor role in the development of neuropathy after CNS and head and neck RT and that radiation dosage constitutes the most significant determinant for the development of neuropathy (150). In a study examining optic toxicity from RT in the treatment of meningiomas, total dose and fraction size were both risk factors for optic nerve injury (151). Multiple systematic reviews have concluded that a total dose of <50 Gy is not associated with optic neuropathy or retinopathy, but higher doses are (147,152). However, there have been a few published cases of RION after WBRT of <50 Gy (153-156). These studies support conservative dosing of RT to the brain and optic nerves given the occurrence of RION even at lower doses. Other than dose, risk factors for RION may include hypertension, smoking, optic nerve compression, and concurrent chemotherapy (150,156,157).

Neuropathies other than RION are also associated with brain tumors, their symptoms and treatment, but their specific association with RT is unclear (158). These neuropathies include vagal, recurrent laryngeal, hypoglossal, or sympathetic neuropathies (158). Presenting symptoms of cranial neuropathy include acute loss in visual acuity, hypoglossal palsy, swallowing impairment, or facial paralysis, among others [depending on the particular nerve(s) involved] (146,159). Symptoms of optic toxicity after brain RT include headaches, visual acuity defects, dizziness, and diplopia (151). RION presents as rapid and irreversible vision loss with an onset months to years after the completion of RT (147,149,151,160).

Current management recommendations for cranial neuropathies following RT mainly focus on prevention or symptom relief since a curative strategy has yet to be determined (120). The incidence of neuropathies such as RION may be reduced by limiting the dosage of RT to susceptible structures (147,152). The American Association of Physicists in Medicine recommends a maximum dose of at most 54–60 Gy in conventional fractionation to the optic nerves and other cranial nerves to reduce the risk of RION and other cranial neuropathies (152,161-163). If delivering SRS, the maximum dose to the optic nerves and other cranial nerves should be <10–12 Gy (163,164). Unfortunately, in some cases, decreased doses may result in lower rates of local control.

HBOT may be used as an adjunctive treatment for RT-induced cranial neuropathies. HBOT enhances oxygen delivery to hypoxic tissues to facilitate cellular repair by promoting angiogenesis and reducing inflammation, but the evidence supporting its use in cranial neuropathies varies (88,100,103,165,166). The inconclusive proof of utility combined with the side effects of HBOT (see section Radiation necrosis) suggests that more research is necessary to establish HBOT as a treatment for cranial neuropathies.

Pentoxifylline, a methylxanthine derivative, and vitamin E have been explored as pharmacological options for the treatment RION through their anti-inflammatory and anti-fibrotic properties. Otluoglu et al. demonstrated the effectiveness of pentoxifylline and vitamin E, alone and in combination, in reducing RN in an animal model (167). In clinical practice, pentoxifylline 200 mg twice daily and vitamin E 1,000 IU daily are used for RT-related complications and may be used in RION management (168). However, the evidence in favor of these interventions derives from studies that did not specifically examine RION and other neuropathies. Therefore, further investigation into the optimal management of RT-induced cranial neuropathy is needed.

Aside from pharmacological interventions, it is crucial to involve neurologists and ophthalmologists in the care of patients presenting with cranial neuropathies post-RT. These specialists can help assess, diagnose, manage symptoms, and coordinate multidisciplinary care which may improve outcomes for patients.

Endocrine dysfunction

Endocrine dysfunction is a common late effect of cranial RT. Pituitary atrophy following cranial RT is caused by hypothalamic damage, impaired secretion of hormones, or direct pituitary damage (169-171). The hypothalamus is more sensitive to RT than the parenchymal cells of the pituitary. This is evident as lower doses of RT can lead to isolated growth hormone (GH) deficiency, while higher doses may result in deficiencies in multiple pituitary hormones (170,171). The etiology of hypothalamic damage is poorly understood, but it may result from direct neuronal injury to the hypothalamus or to its vasculature (170,171). In the pituitary, higher doses of RT (>50 Gy) lead to histologic changes such as fibrosis, squamous metaplasia, and mitochondrial damage (171).

High RT dose is a risk factor for the development of endocrinopathies and the RT doses associated with deficiencies in GH, luteinizing hormone/follicle stimulating hormone (LH/FSH), and thyroid stimulating hormone (TSH) are significantly different from one another (172-174). The location of the cranial RT is also significant. The development of endocrinopathies appears to be more likely in patients receiving RT to the posterior fossa, supratentorial, or suprasellar regions (175).

Hypothalamic-pituitary (HP) dysfunction, most commonly GH deficiency, occurs years after RT (173-178). In a meta-analysis of the long-term pituitary effects of patients who had received cranial RT, 86.9% developed GH deficiency, 34.6% had HP-gonadal axis symptoms, and 23.5% had HP-adrenal axis involvement, although most cases of adrenocorticotropic hormone (ACTH) deficiency were not clinically significant (178). Most (94.4%) patients in this study received fractionated photon RT with a median dose of 54 Gy (178). Similarly, in a study of 58 patients with adult-onset gliomas, the prevalence of RT-induced hypopituitarism was 84.5%, with GH deficiency the most common (82.8%) (172). Another study of endocrinopathies in patients who had received RT for the treatment of childhood tumors found that endocrinopathies occurred around six years after diagnosis and consisted of central hypothyroidism (53%), GH deficiency (39%), precocious puberty (31%), gonadotropin releasing hormone (GnRH) deficiency (27%), primary hypothyroidism (21%), diabetes insipidus (19%), ACTH deficiency (14%), and hyperprolactinemia (6%) (175).

Different RT dose thresholds are associated with an increased risk of endocrine dysfunction for each specific hormone. In general, endocrine surveillance should be performed when the dose to the HP axis exceeds 30 Gy. There is a 20% risk of GH deficiency in children receiving a mean dose of 21 Gy (in 2 Gy fractions) to the HP axis or 10 Gy for adults (172,179). There is a 20% risk of central hypothyroidism in children receiving a mean dose of 22 Gy (in 2 Gy fractions) to the HP or a 13% risk for adults receiving a mean dose of 30 Gy (179,180). A 20% risk of ACTH insufficiency is associated with a mean dose of 34 Gy in children or 32 Gy in adults (172,179). There is a significant risk of hypogonadism in adults who received RT doses greater than 30 Gy to the HP as children (172,181).

Since these deficiencies occur years after RT, regular screening is essential. We suggest conducting hormonal evaluations every 6–12 months post-RT for the first 5 years after RT and every 2–3 years thereafter. In the first five years, GH deficiency, hypothyroidism, ACTH deficiency, and gonadotropin deficiencies should be evaluated due to their high incidence (179,182-184). Long-term follow-up of these deficiencies is also recommended since they may present later.

There are several tests indicated to evaluate hormone deficiencies post-RT. Insulin-like growth factor 1 (IGF-1) levels are used to screen for GH deficiency (185,186). Low IGF-1 levels are associated with GH deficiency, but dynamic testing, such as the insulin tolerance test or GH-releasing hormone plus GH-releasing peptide-6 test, is necessary for confirmation (185,186). TSH and free thyroxine (fT4) are used to identify central hypothyroidism. A low fT4 combined with abnormally low or normal TSH indicates central hypothyroidism (187). ACTH deficiency is determined by the ACTH stimulation test using a standard dose (250 µg) of corticotropin. A peak cortisol level under 18 µg/dL at 30–60 minutes suggests adrenal insufficiency (188). Finally, low levels of LH and FSH in the absence of increased sex hormones suggest hypogonadotropic hypogonadism (189).

Hormone replacement is the treatment of choice for endocrine dysfunction. Recombinant human GH is used to treat GH deficiency. The recommended starting dose is 0.3 mg/day and it can be adjusted based on IGF-1 levels and clinical response (183). In hypothyroidism, treatment with levothyroxine is indicated when TSH is greater than 10 mIU/L or fT4 is less than 0.8 ng/dL (187). Adrenal insufficiency should be treated with hydrocortisone with a starting dose of 15–25 mg/day divided into 2–3 doses, with the morning dose higher than the other doses (187). Gonadotropin deficiency is treated with testosterone replacement therapy for males and estrogen and progesterone replacement therapy for females with hypogonadism. Progesterone must be added to protect against endometrial hyperplasia in women with an intact uterus (181).

Secondary malignancy

RT causes direct and indirect damage to the DNA of both cancer and healthy cells, which increases the long-term risk of secondary malignancies (21,118,120). Risk factors for the development of secondary malignancies after cranial RT are RT dose, younger age at the time of RT, and the time elapsed since the completion of RT (190,191). In a study of patients with histories of pediatric CNS neoplasms, cranial doses of 50 Gy or more were associated with a 7.1% incidence of new CNS neoplasms within 25 years of RT as compared to 5.2% for those who received less than 50 Gy and 1% for patients who did not receive RT (190).

Secondary malignancies present many years after the completion of RT. A meta-analysis reported a mean time to diagnosis of secondary glioma after RT of 9 years (192). Cranial RT for pituitary adenomas is associated with a 10.5-fold increase in the risk of a secondary brain tumor after 20 years (193). Among children who had acute lymphoblastic leukemia, the risk of secondary neoplasms was 3.5% in those who received cranial RT, compared to 1.2% in those who did not (194). Similarly, another study showed that the risk of secondary brain tumors after the initiation of RT was 2% at 10 years and 2.4% at 20 years (193). A study of childhood survivors of CNS malignancies, with nearly half having received RT, indicated that the risk of secondary malignancies could increase to 6.4% over 30 years (195). The most common secondary malignancies following cranial RT are meningiomas and gliomas (196,197).

Long-term follow up is crucial for survivors of childhood CNS malignancy. A study using patient data from 1970–1986 found that there was a 25% mortality rate in this population, which is 13 times higher than that of the general population (190). Secondary malignant neoplasms may account for up to 10% of these deaths (195). Continued surveillance and follow-up are essential for early detection, management of asymptomatic lesions, and improving overall survival. MRI screening for secondary brain tumors is recommended every two to five years starting 10 years after brain RT (198,199). For patients with a history of medulloblastoma treated with brain RT, the American Association for Cancer Research recommends starting MRI screening 30 years after treatment with repeat MRIs every three to five years (200).

Imaging biomarkers and circulating tumor DNA (ctDNA) may also provide a method of early detection of secondary malignancies. Currently, these are used to predict tumor progression and recurrence, but they have the potential to be used in the detection of secondary malignancies as well. For example, ctDNA monitoring can identify patients at risk of non-small cell lung cancer or esophageal cancer progression before it is apparent clinically or radiographically (201-203). Imaging biomarkers, such as MRI tumor regression grade, can be used in addition to ctDNA analysis to predict tumor recurrence (204). ctDNA and imaging biomarkers may also be able to detect new malignancies using the same methods.

Secondary malignancies may be mitigated by using more advanced RT techniques. Proton beam therapy (PBT) is a form of external beam RT characterized by a rapid dose fall-off beyond the Bragg peak (205). This property enables the sparing of adjacent healthy tissues. Previous studies have demonstrated that PBT can lower the brain integral dose, potentially mitigating RT-induced neurocognitive impairment and secondary cancer (205-207). To date, there has been no reported outcome of a prospective, phase III clinical trial comparing PBT with photon therapy for patients with cancers of the CNS. However, Brown et al. reported a prospective, phase II clinical trial that assessed PBT versus photon therapy for patients with newly diagnosed glioblastoma (207). They found that the PBT arm was associated with reduced toxicity and patient-reported fatigue though a comparable time to cognitive failure compared to the photon therapy arm (207). There is also emerging data on the benefit of PBT in the setting of re-irradiation. Scartoni et al. reported the outcome of a small cohort of patients with recurrent glioblastoma undergoing re-irradiation with PBT, noting that the patients experienced stable, if not improving, health-related quality of life (208). Currently, PBT has been increasingly utilized for cancer treatment across various disease sites, including the CNS and cases of re-irradiation for both CNS and non-CNS disease (209-211). However, larger randomized trials are warranted to quantify the exact benefit of PBT.

Lifestyle interventions may also help prevent additional malignancies post-RT. Smoking cessation, weight management, and moderate intensity exercise for at least 150 minutes a week is recommended to reduce the risk of secondary malignancies (212,213). A diet consisting of whole grains, lean proteins, fruits, and vegetables and which limits processed foods, red meat, and refined sugar is also encouraged (213).

Stroke-like migraine attacks after radiation therapy (SMART) syndrome

SMART syndrome has been reported in multiple case reports and series but remains poorly understood (214-217). Symptoms of SMART syndrome include migraine-like headaches with focal neurological deficits, often suspected to represent a CVA. In 2013, Black et al. reported the largest case series of 11 patients with SMART syndrome and noted that patients may present with seizure activity (82%), headaches (73%), speech disturbances (64%), visual field defects (64%), hemiparesis (45%), and altered mentation (45%) (217). The authors also found that brain MRI typically demonstrated thick gyriform cortical enhancement, which they suspected was located in the regions that received prior RT (217). SMART syndrome and PIPG display similar MRI findings. However, SMART syndrome can be differentiated from PIPG by symptoms of headache, significant neurological impairment, and quick recovery (217). Biopsies of several patients with SMART syndrome demonstrated no pathologic etiology (217).

The exact pathophysiological mechanism of SMART syndrome remains unknown, but RT-induced endothelial damage is the suspected first step (218). In 2023, Ota et al. proposed the most recent diagnostic criteria for SMART syndrome, including a history of cranial irradiation, signs and symptoms traceable to a unilateral cortical region, unilateral gyriform enhancement, and exclusion of other disorders, including residual or recurrent intracranial tumor (219). SMART syndrome remains a diagnosis of exclusion based on clinicoradiological findings, not pathologic findings. There is no standard management guideline for patients with SMART syndrome (219). Management is mainly aimed at addressing symptoms, such as the use of anticonvulsants, antimigraine agents, and corticosteroids for headaches and neurologic deficits thought to be secondary to focal cerebral edema (214,216,219).

Acute late-onset encephalopathy after radiation therapy (ALERT) syndrome

First described by Di Stefano et al. in 2013, ALERT syndrome is a poorly understood disease process that may occur following brain RT (220). In Di Stefano et al.’s case series, five patients presented with an acute onset of altered consciousness, which progressed to diffuse cerebral dysfunction or coma (220). Other symptoms such as headaches, seizures, focal sensory or motor deficits, visual disturbances, dysphagia, aphasia, and stroke-like symptoms have also been described in the literature (219-221).

The pathophysiology of the condition remains an area of ongoing investigation. Di Stefano et al. proposed endothelial or mitochondrial damage as possible underlying mechanisms for the development of this condition, but no definitive conclusions can be drawn from the limited data available (221). Electroencephalogram recordings of patients suffering from ALERT syndrome generally display diffuse slowing abnormalities, usually bilaterally (220). Epileptiform discharges have also been documented in some patients (221). MRI findings typically include bilateral patchy subcortical or leptomeningeal enhancement, ring enhancing lesions, leukoencephalopathy, and T2/FLAIR hyperintensity (219-221). However, some patients may have no acute findings visible on MRI (221).

The primary risk factor for the development of ALERT syndrome appears to be a history of WBRT, as all patients observed by Di Stefano et al. received a course of WBRT to either 30 or 60 Gy for the management of metastatic disease or primary brain tumors (220,221). Symptom onset ranged from 9 months to 17 years following treatment. All patients described in the original study by Di Stefano et al. received treatment in young to middle age, although not enough information is available to draw conclusions for age being a significant risk factor. These patients were managed with anticonvulsants and high-dose steroids. Three of the five patients in the initial report demonstrated a rapid response to medical therapy and resolution of their symptoms (220). The remaining two patients did not show signs of improvement and later succumbed to pneumonia.

Strengths and limitations

Early data on the impact of ionizing radiation on the CNS originated from catastrophic, whole-body exposures, which are far removed from clinical radiation use. These included rare accidental exposures, such as the 1964 uranium-235 incident, in which an employee at a private nuclear mining and applications company added the wrong bottle during a routine solvent washing procedure and caused a nuclear fission reaction. In the process he received a whole-body dose of at least 70 Gy, and experienced vomiting and bleeding, which was ultimately fatal less than three days later (222). Although the field of radiation biology was nascent at that time, early observations highlighted the diverse histologic impacts of RT on the CNS, including papilledema, hypotension, and altered cognition.

Throughout this review, we have highlighted data limitations. These include difficulties in differentiating RT-induced toxicities from other pathologic processes, a lack of diagnostic criteria for radiation-induced vascular disorders, and the incomplete understanding of SMART syndrome. For conditions like somnolence syndrome and neuropraxia, pathophysiology remains speculative and not reliably detected by brain imaging, despite its critical role in monitoring demyelination diseases. In cases of PIPG, we discussed the challenge of differentiating pseudoprogression from true progression according to symptoms and based on imaging. Evaluation of late effects, such as endocrinopathies or secondary malignancies, depends on fraction size, RT delivery method, and time since RT. As expected, dose constraints and radiation techniques have evolved over the decades. Other limitations stem from the inherent difficulty in meaningfully measuring subtle changes in cognition in a way that is generalizable. Ongoing efforts are needed to better prevent, diagnose, and treat the range of complications arising from brain RT.

Conclusions

Our current understanding of CNS radiotoxicity is derived from the extensive clinical use of ionizing radiation to treat intracranial targets. This review aims to provide clinicians with a nuanced and practical understanding of these toxicities. We propose several frameworks for understanding and managing toxicities. First, toxicities are categorized into acute, early delayed, and late delayed groups based on their timing and underlying cell type involvement, influencing the reversibility of effects. Acute and early effects are mainly due to myelin damage, while late effects often involve interactions between CNS tissues and supporting vessels. The modern era in radiation oncology, in which RT can be delivered precisely, has enhanced our understanding of the focal effects of RT on cranial substructures, including cranial nerves, endocrine tissues, and the hippocampus. Modern treatment planning, such as the use of SRS, aims to minimize toxicities that were once unavoidable with WBRT. Other mitigation strategies, such as early screening for secondary malignancies and the use of memantine and HA-WBRT to minimize cognitive decline, should be used to limit the toxicity caused by RT. Carefully evaluating RT location and dose can help clinicians identify which of the toxicities we describe pose the greatest risk to their patients, enabling early detection and prompt treatment. Future research on RT-related toxicities should explore the role of biomarkers in treatment efficacy and adverse outcomes, as well as long-term data on newer RT techniques such as SRS, HA-WBRT, and PBT.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-125/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-125/coif). K.H. is supported by the 2023 ASTRO-AstraZeneca Radiation Oncology Research Training Fellowship Program. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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