Risk-reduction strategies for late complications arising from brain metastases treated with radiotherapy: a narrative review

Introduction

Brain metastases (BM) are the most common central nervous system malignancy, with up to 30% of cancer patients developing BM during the course of their disease (1). The prognosis of patients with BM used to be uniformly poor, with the median survival hovering around 6 months (2). As a result, the detection of BM had been the cue for many clinicians to assume a fatalistic approach, withholding aggressive treatment, as patients were believed to have a poor outcome despite treatment. Naturally, the potential of long-term complications from whole-brain radiotherapy (WBRT), which was then the mainstay, was mostly disregarded.

In the modern era, advances in neurosurgical techniques, neuro-imaging, systemic therapeutics and radiotherapy technology have conferred an improved survival for patients with BM. This is particularly so for patients with good performance status and solitary BM (3). As an example, Nieder reported the 1-year survival if patients treated between 1983–1989 to be 15%, comparatively patients treated between 2005–2009 achieved a 1-year survival of 34% (4). Due to the improved survival of patients, there is an increased concern (both by patients and oncologists) about the longer-term toxicities, in particular neuro-cognition.

In terms of treatment, radiotherapy (in various forms) continues to remain a cornerstone in the management of BM—spanning from palliative to “locally radical”. WBRT is still commonly used as a palliative treatment for patients with multiple BM and/or diffuse leptomeningeal disease. At the other end of the spectrum, stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (HSRT) allows for an ablative dose of radiation to be delivered to well-defined lesion (or lesions), in one or a few fractions, respectively, whilst sparing the uninvolved brain parenchyma. Recent trends demonstrate an increased use of SRS or HSRT for managing BM, even in the setting of multiple BM, compared to WBRT—particularly because of the lesser impact on neuro-cognition with SRS (5).

In general, toxicities of cranial radiotherapy can be divided into 3 main categories based on their timeline: acute, subacute, and late/delayed effects. Acute toxicities occur during RT or within days after RT, with symptoms ranging from headache, nausea and vomiting, drowsiness or worsening of focal neurological symptoms. Subacute toxicities occurs within 6 weeks and up to 6 months after completion of RT (6). Late/delayed toxicities occur more than 6 months after cranial irradiation and are irreversible. More often, late/delayed toxicities can be functionally debilitating and negatively affect quality of life, making it difficult for both patients and their families to cope. Moreover, many patients with metastatic cancer may be treated with systemic therapy (e.g., cytotoxic chemotherapy, targeted therapy, or immunotherapy) before, during and after cranial irradiation. The interaction of systemic therapy and radiotherapy remains unclear, and in certain cases may lead to a potentiation of toxicities, although this has never been proven in clinical trials.

In this narrative review, we will elaborate on the common late complications with cranial irradiation (e.g., WBRT, SRS) for BM. As there is a lack of effective treatment, we will summarise mitigation strategies which can be used to reduce the risk of these late complications. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-21-121/rc).

Search strategy and study selection

A search was conducted on MEDLINE, on 26^th July 2021, using MeSH Major topics “radiotherapy” AND “brain neoplasms/secondary”. The search results were limited to prospective clinical trials reported in the English language, from 2010. Studies reporting toxicity outcomes including neurocognitive decline and/or radiation necrosis were selected and presented in Table 1.

Whole-brain radiotherapy: neurocognitive decline

WBRT is typically delivered using parallel opposed photon beams, targeting the entire skull, meningeal reflections, and brain parenchyma. As with most palliative treatments, WBRT is hypo-fractionated with typical dose-fractionation regimens including 20 Gy in 5 fractions (over 1 week) or 30 Gy in 10 fractions (over 2 weeks). Indications of WBRT include multiple BM (such as patients with a poor prognosis who are deemed unsuitable for SRS), patients with diffuse classic leptomeningeal disease (e.g., sugar coating) or in prophylactic cranial irradiation. WBRT is generally well-tolerated in the short term, with patients experiencing minor acute toxicities (such as radiation dermatitis, alopecia, or xerostomia) (24). The most concerning toxicity from WBRT is that of radiation-related neurocognitive decline. Whilst it is possible that uncontrolled BM may also lead to neurocognitive declines, data from prophylactic cranial irradiation studies suggest that radiation exposure to the uninvolved brain parenchyma is a key causative factor (25). Case in point being the RTOG 0214 randomized controlled trial, which compared PCI (30 Gy in 15 fractions) versus observation in patients with locally advanced NSCLC (26,27). Secondary endpoints of the trial included neurocognitive function and quality-of-life (measured using HVLT, MMSE and activities of daily living). Although, the 1-year rates of BM were significantly better with PCI (7.7% vs. 18%, P=0.004), the PCI group reported a trend towards worse cognitive functioning and HVLT scores.

Radiation-induced neurocognitive decline occurs in a biphasic pattern (28,29). Following completion of WBRT, there is an initial subacute transient deterioration which peaks at 4 months post-treatment, in multiple domains of neurocognitive function, and after which there is a transient recovery over the first year (29). Neuroinflammation is suspected to contribute to the initial neurocognitive decline, in which there is an activation of astrocytes and microglia cells leading to an increase in pro-inflammatory cytokines. This may lead to ongoing tissue demyelination and remodeling and eventually resulting in altered neuronal function (30). In longer term, vascular changes in small and medium-sized vessels such as accelerated atherosclerosis and microangiopathy leads to vascular insufficiency and infarction of brain parenchyma, which in turns sets off a milieu of neuroinflammation and accelerated brain atrophy (29,30). The transient improvement in neurocognitive function, is then followed by the second phase of irreversible and progressive decline in memory function (29), which happens months to years after completion of WBRT. This is linked to radiation-induced damage to proliferating neuronal progenitor cells in hippocampus subgranular zone, which have been reported to be relatively radio-sensitive (31). New neurons generated in the hippocampus subgranular zone form an important part of memory function, and the radiation-induced damage to the hippocampus leads to disruption of neurogenesis, hence leading to memory decline after RT. As a summary, the neurocognitive outcomes from prospective clinical trials conducted in patients with BM treated with WBRT and/or focal RT are reported in Table 1.

Mitigation strategies

Maintaining neurocognitive function is prioritized by many patients and caregivers, and is intricately linked to quality of life. Mitigation strategies, and if possible, prevention, need to be instituted upfront. These may include use of focal RT (SRS/HSRT alone) in lieu of WBRT, or withholding RT entirely. In situations where WBRT is cleared indicated, then the use of pharmacological agents and/or hippocampal sparing techniques should be considered.

Focal RT alone

One of the main ways to avoid neurocognitive decline would be to consider the use of focal RT alone in patients with limited intracranial metastases. A phase III randomized trial comparing WBRT versus SRS with WBRT (32), demonstrated that cognitive deterioration was more likely in patients (91.7%) when combined with WBRT as compared to SRS alone (63.5%; 90% CI: −41.9% to – 14.4%; P<0.01). Furthermore, there was more reduction in verbal fluency, immediate and delayed recall in patients treated with both WBRT and SRS. The overall survival was not significantly better with the addition of WBRT to SRS (HR =1.02; 95% CI: 0.75–1.38; P=0.92). Hence in the absence of difference in overall survival and the increase in cognitive decline with WBRT, the preferred strategy for limited BM is SRS/focal radiotherapy (32) which can be considered to avoid neurocognitive decline. This is similarly illustrated in the individual patient data meta-analysis by Sahgal et al., looking at randomized controlled trials for patient with limited BM—where the addition of WBRT to SRS did not improve survival, despite distant brain failure being reduced with WBRT (33). Most of the Phase III randomized trials investigating focal RT alone only included patients with up to 3–4 BM. However, there has been a paradigm shift recently, and practice guidelines such as NCCN (34) have not placed a numerical upper limit when recommending focal RT alone. The evidence for this shift primarily stems from the large observational prospective study from Japan (35), where patients with up to 10 BM were treated with SRS alone. Based on their data, they did not find a survival difference between patients who had 2–4 and 5–10 BM.

Hippocampal avoidance

As mentioned earlier, the hippocampus is crucial for memory formation and learning. Radiation-induced injury to the hippocampal dentate gyrus has been proven to lead to loss in neurogenic capacity associated with memory formation and impaired recall (10). Advances in technology allowed for selective dose reduction to the hippocampi in patients with BM at least 5 mm away from them, through intensity modulated radiotherapy (IMRT), whilst still treating the remaining brain parenchyma and meninges to the required dose (29). This strategy was first evaluated in RTOG0933 (single arm Phase II), which utilized hippocampal-avoidance WBRT (HA-WBRT) 30 Gy in 10 fractions (10). The results were promising as there was a significantly lower neurocognitive decline at 4 months—mean decline in delayed recall of 7% as compared to 30% noted in the historical control group (P<0.001). Hippocampal avoidance was also evaluated, in the setting of prophylactic cranial irradiation for limited stage small cell lung cancer, in the PREMER Phase III trial, where patients received HA-PCI 25 Gy in 10 fractions versus standard PCI. Neurocognitive decline was less in the HA-PCI arm measured by delayed-free recall at 3 months (5.8% vs. 23.5%, OR 5, P<0.003) (36).

Pharmacological agents: memantine, donepezil

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist, which competes with glutamate to bring to NMDA receptor, hence reducing excessive NMDA activating and preventing excitotoxicity of the neuron (30). It is largely used in vascular and Alzheimer’s dementia and has been proven to improve cognitive performance. This led to a phase III randomized, double-blind, placebo-controlled trial (RTOG0614) of memantine in patients undergoing WBRT to 37.5 Gy in 15 fractions (37). Patients were assigned to receive either placebo or memantine (which was given in increasing dosage regimen to 20 mg/day) within 3 days of initiating radiotherapy for 24 weeks (37). Patients who received memantine showed significantly longer time to cognitive decline (HR =0.78; 95% CI: 0.62–0.99; P=0.01). Furthermore, the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm as compared to 64.9% in the placebo arm. Other results from this study which supports the use of memantine included better executive function at 8 and 16 weeks, processing speed and delayed recognition at 24 weeks. Although the RTOG0614 study primary endpoint did not reach statistical significance due to patient dropout, memantine should be considered in patients undergoing WBRT who have a prognosis of >6 months. In general, memantine is well tolerated. Based on a meta-analysis of RCTs (conducted in dementia patients) the likelihood of discontinuation due to intolerability was 11.5% with placebo and 10.1% with memantine (i.e., no significant difference). Common adverse reactions include dizziness (7% memantine, 5% placebo), headache (6% memantine, 3% placebo) and constipation (5% memantine, 3% placebo) (38).

Another pharmacological strategy available is the use of Donepezil, which is a reversible non-competitive inhibitor of acetylcholinesterase that enhances cholinergic-dependent neural communication (39). This has been studied in a phase III randomized, placebo-controlled clinical trial in which patients who were receiving partial- or whole-brain irradiation were randomly assigned to receive either placebo or daily donepezil. After 24 weeks of treatment, overall composite scores did not improve significantly, however there were improvements in several cognitive functions, especially among patients with greater pre-treatment impairment (40).

Hippocampal avoidance and memantine

Building upon the use of both memantine and HA-WBRT, a phase III trial (NRG CC001) evaluated the potential combined neuroprotective effects of hippocampal avoidance WBRT 30 Gy in 10 fractions with memantine (for 24 weeks), as compared to conventional WBRT with memantine. Results showed significantly lower risk of cognitive failure with HA-WBRT plus memantine as compared to WBRT plus memantine (adjusted HR =0.74; 95% CI: 0.58–0.95; P=0.02). The HA-WBRT plus memantine group showed less deterioration in executive function at 4 months, and learning and memory at 6 months. Overall at 6 months, HA-WBRT plus memantine group reported less fatigue, less difficulty with speech and memory, and less interference of neurological symptoms in daily activities (15). With these positive findings, HA-WBRT with memantine should be considered as standard of care for patient for patients requiring WBRT, especially if the expected prognosis is >6 months. Moving forward, there is a currently ongoing phase III randomized trial comparing SRS to HA-WBRT plus memantine for 5–15 BM (NCT03550391) (41). One area of investigation, which is currently unclear, is whether memantine should be continued as a maintenance strategy, for long term survivors.

Avoidance of RT by the use of upfront targeted therapy

There has been a recent trend to use targeted therapy alone for patients with known driver mutations. The advent of new small molecules with intracranial activity has made this possible, particularly in primary cancers such as EGFR-mutation positive lung cancer, Her2+ breast cancer, BRAF V600E mutation positive melanoma. However, this approach is not uniformly adopted by all, as it remains unclear how targeted therapy compares to RT. The retrospective multi-institutional cohort study by Magnusson et al suggested that the survival outcomes, in patients with BM from EGFR-mutation positive lung cancers, were inferior for patients treated with upfront tyrosine kinase inhibitors (TKI) (42). It has to be noted that this study was conducted prior to widespread availability of third generation TKI (e.g., osimiternib), which are known to have better intracranial activity. This topic has been comprehensively reviewed elsewhere (43,44).

Stereotactic radiosurgery (SRS)/hypofractionated stereotactic radiotherapy (HSRT)

Focal radiotherapy (e.g., SRS/HSRT) is increasingly the preferred management for BM, as it is highly effective and convenient. There is minimal disruption of systemic therapy, thereby allowing optimal control of extra-cranial disease. Although rare, late complications can be seen in up to 5% of patients, and may increase particularly in patients who survive more than 1 year. These include radiation necrosis, cranial nerve injury (particularly optic nerve) and brain stem injury. These will be elaborated on below, together with suggested mitigation strategies.

Radiation necrosis (RN)

RN is an inflammatory reaction, due to radiation-induced cell death, that occurs between 6–24 months after completion of SRS (45). Radiologically, RN is difficult to distinguish from intra-cranial disease progression/recurrence on conventional MRI (46) as it commonly occurs in close proximity to original tumour location or in-field. On conventional MRI, RN can appear as a contrast-enhancing lesion on T1 sequence, with peri-lesional vasogenic oedema. Due to the overlapping similarities between RN and tumour recurrences, more advanced imaging techniques are increasingly used to aid in the recognition and diagnosis of RN. Diffusion-weighted MRI imaging such as MR perfusion and MR spectroscopy, has increased sensitivity and specificity for radiation necrosis, hence allowing for accurate diagnosis of RN (47). As normal brain tissue has lower amino acid uptake as compared to tumour cells, specific amino acid tracers such as carbon-11 methionine (MET), fluoro-l-thymidine (FLT) and fluoroethyl tyrosine, are increasingly used in positron emission tomography (PET). These tracers have been reported to have a high sensitivity and specificity (47). However, these novel amino-acid tracers may not be widely available in clinical practice.

Histologically, radiation necrosis is found mainly in white matter with associated endothelial damage, perilesional oedema and gliosis (46). Histopathological findings include coagulation and liquefaction necrosis, with surrounding vessel thickening, hyalinization and thrombosis of blood vessels resulting in hypoxic injury to surrounding parenchyma (47,48). There are 2 main theories explaining the pathophysiology of radiation necrosis. The first theory postulates that necrosis arises due to damage to oligodendrocytes and glial cells, hence leading to demyelination in white matter. The second theory is that radiation leads to vascular injury around the irradiated tumor issues which leads to tissue ischemia. This is associated with increased release of pro-inflammatory factors such as TNF -alpha, VGEF, IL-1 and IL-6. These pro-inflammatory factors leads to increase in blood-brain barrier, increase in leukocyte adhesion and induce endothelial apoptosis (48).

The incidence of radiation necrosis post-SRS ranges between 5–25%. The large variation exists due to varying definitions of RN, and only some studies requiring histological confirmation and/or prolonged follow-up. In a large institutional series, consisting of 2,200 BM treated with SRS, investigators from UCSF reported the incidence of RN to be 5% at 1 year, with approximately half being symptomatic (49). Table 1 summaries the incidence of RN in prospective clinical trials which have utilized SRS for the management of BM.

Briefly, the usual management of symptomatic radiation necrosis includes a prolonged course of dexamethasone, which serves to reduce inflammation and oedema of necrotic tissue. Bevacizumab, an anti-VEGF antibody, can be used in the treatment of radiation necrosis, with reported 64% reduction in RN volume on radiographical imaging. Furthermore, there is a reduction in steroid requirement, with stability or improvement in RN-associated symptoms (50). MRI-guided laser-induced thermal therapy (LITT) is a minimally invasive ablative technique that generates high temperature with accurate delivery to target cells, resulting in tissue coagulation necrosis, angiogenesis eradication and cellular apoptosis (51). Other possible therapies include anti-coagulants and hyperbaric oxygen therapy, in which the benefits are limited and conservative. Alternatively, surgical resection of RN has to be considered for symptomatic patients who are refractory to medical treatment.

Clearly, there can be multiple contributory causes to RN, and ultimately the clinical manifestation may be due to a combination of these factors. Dose received by the uninvolved brain parenchyma plays a major role. The HyTEC group of investigators have recommended, tissue volumes (including target volume) receiving 12 Gy (single fraction) to be kept below 5 cm³ for the symptomatic RN risk to be kept below 10% (52). Similarly, for multi-fraction treatments, they have recommended 20 Gy (3 fractions) or 24 Gy (5 fractions) to be kept below 20 cm³ for the symptomatic RN risk to be below 10%. Prescription practices vary between SRS delivery platforms (e.g., Gamma Knife versus LINAC-based), however the risk of RN has not been shown to be different. For example, the 50% isodose line is typically selected for the Gamma Knife platform, whereas the 60–80% isodose line is selected for LINAC-based platforms. This typically results in higher maximum doses and steeper dose gradients for the Gamma Knife platform. Frameless radiosurgery platforms typically utilize a planning target volume (PTV) margin of 1 to 3 mm. Kirkpatrick et al. conducted a randomized controlled trial, and reported that the use of a 3 mm (vs. 1 mm) results in higher rates of RN (18). Dose heterogeneity has been suggested to contribute to RN, in particular if they occur within GTV-PTV margin where normal brain parenchyma is located (53). Table 2 outlines other contributory factors, and the suggested mitigation strategies (54).

Radiation-induced optic neuropathy

The optic nerve can be divided into 4 segments: intra-ocular, intra-orbital, intra-canalicular (within optic canal) and cisternal (within supra-sellar cistern) segments. The optic nerve is a special sensory nerve which transmits visual information regarding brightness, color and contrast. Radiation-induced optic neuropathy (RION) is a late complication which can present with painless visual impairment progressing rapidly over a few weeks. RION usually occurs months or years after radiation therapy, with average onset of approximately 18 months after treatment (78,79). Visual impairment may be bilateral for injuries located near the optic chiasm. Symptoms of RION may include impairment of colour vision, visual field deficit or worsening visual acuity. Clinical signs may include a relative afferent pupillary defect, optic disc pallor and/or swelling. Typically, contrast-enhancement (within the optic nerve) can be seen on T1 sequence, with a high signal on T2 (79).

Common management of RION includes the use of steroids, anti-coagulation, hyperbaric oxygen (78) and pentoxifylline. Hyperbaric oxygen therapy is believed to increase fibroblastic activity, collagen synthesis and neovascularization of irradiated tissues, and may help in RION if initiated within 72 h. However, it requires multiple sessions (over 6 weeks) which may be inconvenient for patients. Till date, the benefits and effectiveness of these management measures have shown limited results. Emerging evidence is suggestive that a course of bevacizumab can be helpful in RION, but more data is required (80). Clearly, as no effective treatment is available, more emphasis needs to be placed on prevention by proper patient selection and radiotherapy planning.

Contributing factors and mitigation strategies

The dose received by the optic nerve is the single most important factor for RION. Early reports have recommended the maximum point dose to the optic nerve is recommended to be kept to below 8 Gy (81). Data from Mayo Clinic has suggested that this may be overly conservative, and that the risk of RON is ~1% for patients receiving up to 12 Gy (82). Doses exceeding 12 Gy lead to a 10% risk (83). The recently published HyTEC data (52) offers guidance in terms of dose selection, to keep the risk of RION below 1%. The maximum dose should be kept to below 12 Gy (ideally 10 Gy) in a single fraction, 20 Gy in 3 fractions and 25 Gy in 5 fractions. It is not clear if a volume-effect exists for the optic nerve, but the general principles of ALARA should be adhered to. Data from Stanford has shown that the optic chiasm is subject to physiological motion, and thereby receiving up to 14% more dose that predicted. They have recommended to add a 0.5–0.75 mm planning at risk volume (PRV) margin to this structure during plan optimization (84). Whether underlying vasculopathic risk factors (such as diabetes mellitus, hypertension) contribute to RON remains controversial (79,85).

Appropriate contouring using high-resolution MR (e.g., ensuring no gaps between the optic nerve and chiasm), dose selection and rigorous radiotherapy planning should be used to reduce the risk of RION (86-88). In cases where the lesion is abutting the optic apparatus, single fraction SRS may not be considered appropriate if the maximum point dose to optic apparatus cannot be limited to 12 Gy or lower. In such situations, a 3 to 5 fractions approach should be considered to maximise the therapeutic window. In lesions where the optic nerve is compressed, decompressive surgery can be attempted prior to SRS, or a more conservative dose limit should be used.

Brain stem injury and mitigation strategies

Brainstem metastases only accounts for 5% of all BM. However, the consequences of brainstem injury can be devastating. The clinical manifestation depends on the location of the necrosis, as there are many cranial nerve nuclei and long tracts that pass through the brainstem. The diagnosis is made clinically, with correlative imaging findings. Enhancing foci may be seen on contrast enhanced MRI, similar to parenchymal RN, together with an abnormal T2 signal corresponding to the area of high dose. The overall incidence is low, as most practitioners will compromise tumor coverage instead of overdosing the brainstem. Similar to RION, mitigating brainstem injury is predicated on accurate contouring of the brainstem (using MRI) and adhering to known dose constraints (86,87). Based on studies in patients with brainstem metastases, doses of 15–20 Gy SRS have been used with relatively low complication rates (89,90). Data on brainstem tolerance from hypofractionated RT are obtained from treatment of skull base tumors, where early studies using a regimen of 42 Gy in 6 fractions reported a 5% complication rate (91). With modern planning and delivery, brainstem injuries have been very rare at doses of 20–21 Gy in 3 fractions, 22 Gy in 4 fractions and 25 Gy in 5 fractions (92-95). QUANTEC data recommends maximum point doses are 12.5 Gy in a single fraction, 21 Gy in 3 fractions or 25 Gy in 5 fractions (96). Fractionated schedules should be considered if constraints cannot be achieved with a single fraction SRS. Although not supported by strong clinical data, the periphery of the brainstem (especially if a small volume is exposed) has been suggested to be more tolerant (97).

Conclusions

Survival of patients with BM continues to improve. Although the focus is usually on intra-cranial control, serious treatment-related complications can occur impairing patient’s quality of life. Consequently, the use of WBRT is declining, and being substituted with focal RT, even in the setting of multiple BM. However, WBRT can still be used selectively, and may still have a role in patients with diffuse intracranial disease. Upfront mitigation strategies such as hippocampal avoidance and memantine should be instituted for these patients. With focal RT being performed for more patients, the risk of RN must be anticipated and counselled to patients. Fractionated focal RT (e.g., hypo fractionated stereotactic RT) is an attractive option which maximizes the therapeutic window. With an increase in awareness of these complications, more prospective trials are being conducted to investigate the effect of these mitigation strategies.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology, for the series “The Modern Approaches to the Management of Brain Metastases”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-21-121/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-21-121/coif). The series “The Modern Approaches to the Management of Brain Metastases” was commissioned by the editorial office without any funding or sponsorship. SL served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Chinese Clinical Oncology from May 2021 to April 2023. BV served as the unpaid Guest Editor of the series. SL reports leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Elekta AB, outside the submitted work. AS is an advisor/consultant with Abbvie, Merck, Roche, Varian (medical advisory group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (medical advisory board), a board member of International Steroeotactic radiosurgery (ISRS) and belongs to Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac based SRS consortia. AS also reports past educational seminars with Elekta AB, Accuray Inc, Varian (CNS teaching faculty), BrainLAB, Medtronic Kyphon, and travel accommodations/expenses from Elekta, Varian, BrainLAB. AS has a research grant with Elekta AB. The authors have no other 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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