
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae137
vdae137
Review
AcademicSubjects/MED00300
AcademicSubjects/MED00310
Mitigating radiation-induced cognitive toxicity in brain metastases: More questions than answers
Simó Marta Cognition and Brain Plasticity Group, Bellvitge Biomedical Research Institute (IDIBELL); Department of Cognition, Development and Educational Science, Campus Bellvitge, University of Barcelona, Barcelona, Spain
Neuro-Oncology Unit, Bellvitge University Hospital - Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) Barcelona, Spain

Rodríguez-Fornells Antoni Catalan Institution for Research and Advanced Studies, ICREA, Barcelona, Spain
Cognition and Brain Plasticity Group, Bellvitge Biomedical Research Institute (IDIBELL); Department of Cognition, Development and Educational Science, Campus Bellvitge, University of Barcelona, Barcelona, Spain

Navarro Valentín Department of Medical Oncology, Catalan Institute of Oncology (ICO), Barcelona, Spain

Navarro-Martín Arturo Department of Radiation Oncology, Catalan Institute of Oncology (ICO), Barcelona, Spain

Nadal Ernest Preclinical and Experimental Research in Thoracic Tumors (PReTT), Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
Department of Medical Oncology, Catalan Institute of Oncology (ICO), Barcelona, Spain

https://orcid.org/0000-0001-6895-5047
Bruna Jordi Neuro-Oncology Unit, Bellvitge University Hospital - Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) Barcelona, Spain

Corresponding Author: Jordi Bruna, MD, PhD, Neuro-Oncology Unit, Bellvitge University Hospital, Gran Via de l’Hospitalet 199-203. 08908. L’Hospitalet de Llobregat (Barcelona), Spain (35078jbe@comb.cat).
Ernest Nadal and Jordi Bruna Co-senior authors.

Jan-Dec 2024
07 8 2024
07 8 2024
6 1 vdae13707 9 2024
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

Abstract

The emergence of advanced systemic therapies added to the use of cranial radiation techniques has significantly improved outcomes for cancer patients with multiple brain metastases (BM), leading to a considerable increase in long-term survivors. In this context, the rise of radiation-induced cognitive toxicity (RICT) has become increasingly relevant. In this critical narrative review, we address the controversies arising from clinical trials aimed at mitigating RICT. We thoroughly examine interventions such as memantine, hippocampal avoidance irradiation during BM treatment or in a prophylactic setting, and the assessment of cognitive safety in stereotactic radiosurgery (SRS). Our focus extends to recent neuroscience research findings, emphasizing the importance of preserving not only the hippocampal cortex but also other cortical regions involved in neural dynamic networks and their intricate role in encoding new memories. Despite treatment advancements, effectively managing patients with multiple BM and determining the optimal timing and integration of radiation and systemic treatments remain areas requiring further elucidation. Future trials are required to delineate optimal indications and ensure SRS safety. Additionally, the impact of new systemic therapies and the potential effects of delaying irradiation on cognitive functioning also need to be addressed. Inclusive trial designs, encompassing patients with multiple BM and accounting for diverse treatment scenarios, are essential for advancing effective strategies in managing RICT and the treatment of BM patients.

brain metastases
cognitive toxicity
hippocampal avoidance
memantine
stereotactic radiosurgery
==== Body
pmcKey Points

Although phase 3 trials suggest a favorable impact of memantine use and hippocampal avoidance irradiation in mitigating radiation-induced cognitive toxicity, these trials raise concerns that warrant thorough discussion before full acceptance.

Hippocampal sparing irradiation relies on a hypothesis that is increasingly controversial and likely insufficient to mitigate the extensive brain damage associated with radiation-induced cognitive toxicity.

Cognitive safety of stereotactic radiosurgery for multiple brain metastases, balancing efficacy and safety, is still not well defined.

Radiotherapy is a crucial part of cancer treatment, used alongside surgery, cytostatic drugs, and emerging strategies like targeted therapies and immunotherapy. However, when dealing with brain metastases (BM), radiotherapy, while effective for limited cerebral metastatic disease, can have medium- and long-term adverse effects impacting patients’ quality of life and cognitive abilities.1

Radiation-induced cognitive toxicity (RICT), although common, is not exclusively associated with whole-brain radiotherapy (WBRT). It primarily affects attention and short-term memory, leading to moderate to severe impairment in verbal memory and executive functions. While some patients show stability over time, others may progress to subcortical dementia characterized by gait alterations, apathy, and extrapyramidal symptoms.2 Advanced imaging techniques have revealed reductions in cortical thickness in key brain structures such as the hippocampus and basal ganglia.3–5 Additionally, more extensive white matter damage has been observed, particularly affecting the fornix, cingulate, and corpus callosum.5,6

Preclinical research has identified several mechanisms underlying radiation-induced cognitive decline. These include reduced proliferation and altered differentiation of neural precursors in the hippocampus, an inflammatory response triggered by oxidative damage, changes in microvasculature, alterations in dendritic morphology of mature neurons, impaired physiological function of mature hippocampal neurons, and persistent activation of microglia.1,7,8

Over the last decade, cognitive toxicity has become more relevant, driven by the emergence of novel and more effective systemic therapies that led to a considerable increase in long-term survivors. Despite these therapeutic advancements, effectively managing patients with multiple BM and determining the optimal timing and integration of radiation and systemic treatments remain complex issues. Nevertheless, recent clinical trials that focused on preventing RICT, through interventions such as memantine, hippocampal radiotherapy avoidance (HA), or stereotactic radiosurgery (SRS) instead of WBRT have reported promising results. The objective of this critical narrative review is to contextualize the significance and conceptualization of the results obtained from these seminal phase 3 studies. Additionally, we reviewed and referenced other studies to provide a comprehensive understanding of the context that led to the development of the analyzed phase 3 trials.

Memantine Neuroprotection

One of the proposed mechanisms underlying RICT involves an increase in glutamate levels and the overstimulation of n-methyl-d-aspartate receptors (NMDARs). NMDARs play a critical role in maintaining synaptic plasticity, a mechanism essential for memory and learning.9,10 This mechanism prompted interest in exploring memantine, an uncompetitive NMDAR antagonist, as a potential intervention to mitigate RICT. Notably, this investigation of memantine was based on the same pathophysiological mechanism that led to its approval for the treatment of moderate to severe Alzheimer’s disease.11

In the phase 3 RTOG 0614 study, 508 patients with solid tumors and BM undergoing WBRT were randomized to receive memantine or placebo.12 The authors observed a strong yet not statistically significant trend towards improvement in the primary endpoint (delayed recall verbal memory) among patients with WBRT who received memantine (P = .0587). There was significant improvement in the secondary endpoint, time to cognitive failure (TCF) at 6 months, favoring the memantine group (54% showed cognitive impairment compared with 65% in the placebo group). However, the substantial loss of patients during the trial (approximately 50%) may have impacted the internal validity of the study. Additional secondary cognitive endpoints, involving executive functions—often altered in the context of RICT—yielded inconsistent results.

While memantine is increasingly recognized as a standard treatment for patients receiving WBRT for BM, both in clinical practice and ongoing trials, discrepancies persist between American and European guidelines.13,14

There are questions and concerns regarding the interpretation of the results. Although patient groups were well-balanced at baseline in terms of variables potentially impacting cognition (excluding cardiovascular comorbidities that were not considered), the significant loss of patients prompts concerns about a potential bias of the evaluable cohort. Additionally, intracranial progression was not specifically considered in the assessment and interpretation of the primary cognitive outcome (delayed recall verbal memory); it was only included in the secondary endpoint (TCF). On the whole, while there is a correlation between cognitive decline and both quality of life and functional status, it is important to note that some contradictory results have emerged.15,16 Furthermore, the determination of the minimal clinically important difference, especially concerning a modest decrease in cognitive test scores, remains uncertain. This has been a persistent issue in cognitive research for decades, particularly when evaluating the efficacy of anticholinergic and other dementia drugs. The widely recognized limited outcomes underscore the genuine impact of these drugs in dementia management, despite mere regulatory approval Figure 1.

Figure 1. Controversies over prevention of radiation-induced cognitive toxicity (RICT).

Hippocampal Avoidance-Whole Brain Radiation Therapy (HA-WBRT) for Neurotoxicity Mitigation

Hippocampus-avoidance WBRT (HA-WBRT) selectively restricts the radiation dose in the hippocampal region with the intention of preserving cognitive functions. However, the clinical and neuroimaging evidence accumulated over the years reveals that RICT extends beyond hippocampal structures.5,17 The notion that the preservation of hippocampal and surrounding medial temporal cortex (MTL) stem cells is crucial in encoding new information and learning, comes from the original article by Gondi et al.18 This proposal also relies on the observation that radiation in the dentate gyrus reduces neurogenesis, resulting in a diminished population of granular cells. This decline could potentially impede their role in facilitating learning-dependent plasticity.19 Nevertheless, the existence and extent of adult neurogenesis in the hippocampal dentate gyrus have become increasingly controversial.20 Recently, single-cell RNA sequencing from 5 subregions of the entorhinal-hippocampal complex from human donors compared with other species, observed neural progenitors in other species but not in humans, suggesting the absence of significant neurogenesis as an endogenous process in adult humans.21

Furthermore, cognitive impairment following cancer therapies can arise from other neurobiological mechanisms, such as disruptions in myelin homeostasis and plasticity. This mechanism involves adaptive changes in myelin structure, driven by neuronal activity, which modulates circuit function and optimizes cognitive function.22 Moreover, microglia activation plays a significant role in regulating synaptic connectivity by removing synapses in an activity-dependent manner, thereby altering neural networks.7,8,23 The intricate relationship between microglia and neurons allows them to collaborate in modifying white matter structure and functional connectivity, both of which are essential for efficient information processing. Recent research in the emerging field of cancer neuroscience24 is reformulating our understanding of the complex interaction between neurons, glia cells, and cancer progression. This prompts consideration of how preserving the efficiency of existing neural networks and glia might affect the important crosstalk between the nervous and immune systems in brain cancer.

Additionally, recent research in neuroscience, emphasizing neural network dynamics,25,26 has identified complex interactions between the medial temporal lobe, cortical and subcortical networks in memory and specifically in controlled retrieval of information. For example, recent evidence shows the clear involvement of the default mode network in memory retrieval and autobiographical memory.27–29 This shift, from focusing on simple and localized regions to considering the role of parallel neural networks sustaining complex cognitive processes, has led to the proposal of a theory of multiple-memory systems.

This theory is supported by complex network interactions involving, among others, the bilateral prefrontal cortex, the default mode network, parietal lobe (including the posterior cingulate cortex), subcortical regions, and the medial temporal lobe.30–34 To preserve memory and learning as key outcomes for patients undergoing radiotherapy, it is essential to consider this emerging parallel memory systems framework, emphasizing the importance of preserving the structural and functional connectivity in these complex networks that participate in the storage and controlled retrieval of long-term knowledge. Preserving the hippocampal cortex is important for encoding new information. However, the impact of WBRT on other cortical regions and diffuse white matter, affecting structural connectivity, will probably impair the optimal performance of these networks. This could potentially affect memory and cognition, influencing the overall quality of life for patients.

Hippocampal Avoidance-Whole Brain Radiation Therapy (HA-WBRT) for the Treatment of Brain Metastases

Two small phase 2 trials, one randomized and the other contrasting with a historical cohort, compared HA-WBRT with conventional WBRT. These trials suggested that HA-WBRT might offer a slight advantage in preserving verbal memory function.35,36 Subsequently, to confirm HA-WBRT and memantine efficacy, the NRG CC001 trial, a phase 3 randomized clinical trial, randomized 518 patients to receive either conventional WBRT or HA-WBRT, both in combination with memantine.37 Interestingly, the number of patients randomized was higher than pre-specified in the sample size calculations. Moreover, the NRG CC001 trial faced challenges similar to the RTOG 0614 trial, with a significant loss of patients. The potential impact of brain metastasis progression was not considered when assessing cognition. Unlike the memantine RTOG 0614 trial and the previous phase 2 trials in HA-WBRT, the primary endpoint here was TCF, showing a significant 26% relative reduction in cognitive decline in favor of HA-WBRT plus memantine (59.5% vs 68.2% conventional WBRT plus memantine; HR 0.74).

Considering the heterogeneity in BM populations, patient dropout rates, variations in outcome assessment, and definition between the current HA-WBRT study (NRG CC001) and the RTOG 0614 trial, notable differences have emerged, particularly in the comparison of the TCF endpoint. Despite having similar BM populations in terms of age, performance status, and overall survival, these differences persist. Firstly, the TCF at 6 months for the WBRT plus memantine arms in the NRG CC001 and RTOG 0614 trials revealed noticeable differences (68% in NRG CC001 vs 54% in RTOG 0614), with the TCF for patients included in the NRG CC001 trial more closely resembling the placebo group (68% vs 65%) from the RTOG 0614 memantine trial. This suggests that patients with BM patients who underwent WBRT, with or without memantine, exhibited a comparable rate of cognitive impairment at 6 months. Additionally, there were inconsistencies in secondary endpoints, such as delayed recognition of verbal memory or executive functioning, and in terms of quality of life and patient-reported outcomes. Despite controversies over the study population definition, discussions about internal validity, effect size, and results interpretation, the findings establish the combination of HA-WBRT and memantine as the standard of care for patients with multiple BM who are not suitable for SRS Figure 1.

In light of these trials analyzed, a pivotal question emerges for designing cognitive neurotoxicity trials: What is the most suitable primary endpoint? Standardizing primary cognitive endpoints can enhance the comparability across studies and facilitate a more comprehensive evaluation of cognitive outcomes. For details, see Figure 2.

Figure 2. Proposed Framework for Assessing Radiation-Induced Cognitive Toxicity (RICT).

Another point to consider is that the feasibility of HA-WBRT is influenced by the distribution of BM and the margins used to define the HA region. Sparing the hippocampus can be challenging when metastases are nearby, although hippocampal involvement is relatively low (3%–8%),38 increasing in patients with multiple BM.38,39 Defining the HA region, typically with a 5 mm margin, requires advanced treatment planning techniques like intensity-modulated radiation therapy or volumetric modulated arc therapy to enhance feasibility.35 Other patient-specific factors such as prognosis, baseline cognitive impairment, or lung cancer histology also yield different cognitive sparing benefits from HA-WBRT, as demonstrated in a secondary analysis of the NRG CC001 trial.40 In summary, advanced planning techniques and careful consideration of patient-specific factors are essential for the feasibility of HA-WBRT.

Hippocampal Avoidance-Prophylactic Cranial Irradiation (HA-PCI) in Small-Cell Lung Cancer Population

To contribute further to this controversy, similar clinical trials have been conducted in patients with small-cell lung cancer (SCLC) who are undergoing prophylactic cranial irradiation (PCI). Two published randomized phase 3 trials comparing HA-PCI to standard PCI have shown conflicting results.41,42 The first phase 3 trial (n = 150) showed a significantly lower rate of cognitive decline (verbal memory) at 3 months associated with HA-PCI (5.8% vs 23.5%) compared with PCI alone42; while the second trial (n = 168) found higher rates of cognitive failure (verbal memory) at 4 months in patients treated with HA-PCI, that were similar to those treated with PCI alone (29% vs 28%).41

In 2023, preliminary results of a phase 3 trial (NRG CC003) comparing HA-PCI plus memantine with PCI plus memantine (n = 392) showed no differences between groups in the primary endpoint of the 6-month verbal memory score.43 However, HA-PCI plus memantine showed less cognitive failure, which was a secondary endpoint. In addition, a recent study reported a marginal decrease in hippocampal atrophy that did not correlate with differences in cognitive outcomes among patients who underwent HA-PCI compared with PCI. Both radiotherapy techniques were associated with declines in gray and white matter in other locations, irrespective of hippocampal sparing.17 This suggests that incorporating advanced imaging techniques can provide valuable insights into the neurocognitive effects of radiation therapy on brain structure and function. See Figure 2.

On the other hand, a recent systematic review and meta-analysis comprising 109 studies on PCI, found that the PCI survival benefit is evident primarily in those SCLC patients with asymptomatic BM diagnosed through MRI. This suggests that the previously reported survival benefit may be attributed to the therapeutic rather than prophylactic effect of cranial irradiation. In light of this evolving understanding, prospective trials are needed that examine the effect of PCI on survival in patients with SCLC.44 See Figure 1.

Cognitive Safety of Stereotactic Radiosurgery (SRS) for Multiple Brain Metastases

While WBRT has improved intracranial tumor control compared to SRS alone, it does not confer a survival benefit and is linked to increased cognitive decline and adverse effects on quality of life.45 Early randomized trials (NCCTG N0574) evaluating the effect of adding WBRT to SRS versus SRS alone in patients with 1 to 3 BMs (n = 213) demonstrated substantial cognitive decline at 3 months (91.7% for WRBT plus SRS vs 63.5% for SRS alone) that persisted at 6 and 12 months.46,47 In 2017, a phase 3 trial (NCCTG N107C; n = 194) demonstrated that adjuvant SRS, following brain metastasis resection, led to improved cognitive outcome (cognitive impairment rate at 6 months was 52% for SRS vs 85% for WBRT) with no compromise on survival but with lower intracranial brain control rates compared with WBRT.48 See Figure 1. 

However, SRS use carries an inherent risk of radionecrosis (4%–15%),47–49 a condition that challenges clinical response assessment and often requires prolonged steroid use, which may led to discontinuation of immunotherapy. Despite these challenges, SRS emerged as an attractive treatment option, demonstrating efficacy with a more favorable cognitive profile than WBRT.

Although strong evidence supports SRS in managing limited numbers of BM, its use remains controversial in cases with larger numbers of BM lesions. A large multi-institutional prospective non-randomized longitudinal study included 1194 patients with 1 to 10 BMs (with a maximum total cumulative volume ≤15 mL) who were treated with SRS and showed non-inferior overall survival between patients with 2 to 4 compared to 5 to 10 metastases.50 A subsequent secondary analysis, using Mini-Mental State Examination (MMSE), revealed 6%–9% of patients experiencing cognitive declines at 4 and 12 months, with no significant differences based on the number of BM.51 However, MMSE while effective for established dementia, is largely insensitive for detecting moderate cognitive impairment.52 This might explain differences in cognitive deterioration compared with seminal trials comparing SRS and WBRT.46–48 This underscores the significance of homogenizing study methods, particularly in defining cognitive impairment and standardizing cognitive tests.53,54 For further insights into our proposed framework for assessing RICT, see Figure 2. Fortunately, ongoing trials, like NCT04277403 or NCT03550391, specifically focusing on assessing cognitive outcomes in patients with BM treated with SRS, will provide valuable insights into the optimal treatment strategy for patients with multiple BM.

Concluding Remarks

The core question regarding research efforts to improve the tolerance of WBRT needs to be reexamined. The QUARTZ phase 3 trial, particularly in patients with poor prognosis, showed that WBRT does not confer significant survival or quality-of-life advantages over best palliative treatment. However, controversies exist, particularly surrounding its potential utility in patients with favorable prognostic factors, as suggested by secondary analyses.

While refined WBRT techniques hold theoretical neurocognitive benefits, their impact on RICT appears marginal. HA-WBRT relies on a hypothesis that is increasingly controversial and likely insufficient to mitigate the extensive brain damage associated with RICT. Despite phase 3 trials favoring the use of HA-WBRT plus memantine, the lack of consistency in clinical outcomes across these trials creates uncertainty about the efficacy of these preventive measures in mitigating the overall cognitive impact of RICT. On the other hand, SRS emerges as the most radical local treatment for patients with multiple metastases, yet its cognitive risks, especially in long-term survivors benefiting from immunotherapy or targeted therapies, warrant consideration.

While no standard of care has yet been established for managing RICT, non-pharmacological interventions such are exercise, as well as promising pharmacological approaches targeting neuroinflammation, have emerged from several preclinical studies. Consequently, several pivotal clinical trials (phase I/II) are currently underway to evaluate their effectiveness, including exercise (NCT03169075), lithium (NCT01486459), renin–angiotensin system blockage ramipril (NCT03475186), and peroxisomal proliferator-activated receptors agonist pioglitazone (NCT01151670).55

It is also crucial to establish a consensus regarding the optimal primary neurocognitive endpoint for assessing RICT in the setting of BM. This standardization is essential for harmonizing trial designs and elucidating the real impact of cognitive variations on activities of daily living. TCF appears to be a reasonable endpoint for cognitive assessment in BM.

Future trials must carefully define the suitable number and total volumes of lesions for SRS, balancing efficacy and safety. Moreover, trials exploring new drugs with potential high penetrance on the central nervous system should be more inclusive allowing participation of patients with multiple BM without prior local treatments, particularly in patients with asymptomatic or olygosymptomatic BM. This design would enable a proper assessment of the new drugs and their impact on survival without excluding common clinical scenarios. This approach would assist in planning and sequencing treatments for patients with multiple BM sparing extensive irradiation for very exceptional clinical situations.

Acknowledgments

The authors thank the CERCA Program/Generalitat de Catalunya for institutional support.

Conflict of Interest Statement

Marta Simó has participated in lectures from Pfizer. Ernest Nadal has participated in advisory board or lectures from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Amgen, Johnson and Johnson, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Pierre Fabre, Qiagen, Takeda, Sanofi, Regeneron and Genmab. Ernest Nadal received research funding from Pfizer, Roche, BMS, and Merck-Serono and has participated as a consultant advisor for Apollomics, MSD, Transgene and Roche.  Jordi Bruna has participated in advisory boards or lectures from Pfizer, Takeda, Boehringer-Ingelheim, and Novocure.
==== Refs
References

1. Wilke C , GrosshansD, DumanJ, BrownP, LiJ. Radiation-induced cognitive toxicity: Pathophysiology and interventions to reduce toxicity in adults. Neuro Oncol. 2018;20 (5 ):597–607.29045710
2. Roman DD , SperdutoPW. Neuropsychological effects of cranial radiation: Current knowledge and future directions. Int J Radiat Oncol Biol Phys. 1995;31 (4 ):983–998.7860415
3. Seibert TM , KarunamuniR, BartschH, et al . Radiation dose-dependent hippocampal atrophy detected with longitudinal volumetric magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 2017;97 (2 ):263–269.28068234
4. Seibert TM , KarunamuniR, KaifiS, et al . Cerebral cortex regions selectively vulnerable to radiation dose-dependent atrophy. Int J Radiat Oncol Biol Phys. 2017;97 (5 ):910–918.28333012
5. Simo M , VaqueroL, RipollesP, et al . Brain damage following prophylactic cranial irradiation in lung cancer survivors. Brain Imaging Behav. 2016;10 (1 ):283–295.26015269
6. Chapman CH , Nazem-ZadehM, LeeOE, et al . Regional variation in brain white matter diffusion index changes following chemoradiotherapy: A prospective study using tract-based spatial statistics. PLoS One. 2013;8 (3 ):e57768.23469234
7. Gibson EM , MonjeM. Microglia in cancer therapy-related cognitive impairment. Trends Neurosci. 2021;44 (6 ):441–451.33674135
8. Winkler F , VenkateshHS, AmitM, et al . Cancer neuroscience: State of the field, emerging directions. Cell. 2023;186 (8 ):1689–1707.37059069
9. Shi L , AdamsMM, LongA, et al . Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat Res. 2006;166 (6 ):892–899.17149974
10. Wu PH , CoultrapS, PinnixC, et al . Radiation induces acute alterations in neuronal function. PLoS One. 2012;7 (5 ):e37677.22662188
11. Reisberg B , DoodyR, StofflerA, et al . Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003;348 (14 ):1333–1341.12672860
12. Brown PD , PughS, LaackNN, et al ; Radiation Therapy Oncology Group (RTOG). Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: A randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15 (10 ):1429–1437.23956241
13. Le Rhun E , GuckenbergerM, SmitsM, et al ; EANO Executive Board and ESMO Guidelines Committee. Electronic Address: clinicalguidelines@esmo.org. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021;32 (11 ):1332–1347.34364998
14. Vogelbaum MA , BrownPD, MessersmithH, et al . Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol. 2022;40 (5 ):492–516.34932393
15. Li J , BentzenSM, LiJ, RenschlerM, MehtaMP. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys. 2008;71 (1 ):64–70.18406884
16. Laack NN , PughSL, BrownPD, et al . The association of health-related quality of life and cognitive function in patients receiving memantine for the prevention of cognitive dysfunction during whole-brain radiotherapy. Neurooncol Pract. 2019;6 (4 ):274–282.31386073
17. de Ruiter MB , GrootPFC, DeprezS, et al . Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) for small cell lung cancer reduces hippocampal atrophy compared to conventional PCI. Neuro Oncol. 2023;25 (1 ):167–176.35640975
18. Gondi V , TomeWA, MehtaMP. Why avoid the hippocampus? A comprehensive review. Radiother Oncol. 2010;97 (3 ):370–376.20970214
19. Monje ML , MizumatsuS, FikeJR, PalmerTD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8 (9 ):955–962.12161748
20. Sorrells SF , ParedesMF, Cebrian-SillaA, et al . Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555 (7696 ):377–381.29513649
21. Franjic D , SkaricaM, MaS, et al . Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron. 2022;110 (3 ):452–469.e14.34798047
22. Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008;31 (7 ):361–370.18538868
23. Fields RD , AraqueA, Johansen-BergH, et al . Glial biology in learning and cognition. Neuroscientist. 2014;20 (5 ):426–431.24122821
24. Mancusi R , MonjeM. The neuroscience of cancer. Nature. 2023;618 (7965 ):467–479.37316719
25. Avena-Koenigsberger A , MisicB, SpornsO. Communication dynamics in complex brain networks. Nat Rev Neurosci. 2017;19 (1 ):17–33.29238085
26. Bassett DS , SpornsO. Network neuroscience. Nat Neurosci. 2017;20 (3 ):353–364.28230844
27. Kaefer K , StellaF, McNaughtonBL, BattagliaFP. Replay, the default mode network and the cascaded memory systems model. Nat Rev Neurosci. 2022;23 (10 ):628–640.35970912
28. Smallwood J , BernhardtBC, LeechR, et al . The default mode network in cognition: A topographical perspective. Nat Rev Neurosci. 2021;22 (8 ):503–513.34226715
29. Buckner RL , DiNicolaLM. The brain’s default network: Updated anatomy, physiology and evolving insights. Nat Rev Neurosci. 2019;20 (10 ):593–608.31492945
30. Geib BR , StanleyML, DennisNA, WoldorffMG, CabezaR. From hippocampus to whole-brain: The role of integrative processing in episodic memory retrieval. Hum Brain Mapp. 2017;38 (4 ):2242–2259.28112460
31. Nyberg L , PerssonJ, HabibR, et al . Large scale neurocognitive networks underlying episodic memory. J Cogn Neurosci. 2000;12 (1 ):163–173.10769313
32. Moscovitch M , CabezaR, WinocurG, NadelL. Episodic memory and beyond: the hippocampus and neocortex in transformation. Annu Rev Psychol. 2016;67 :105–134.26726963
33. Dickerson BC , EichenbaumH. The episodic memory system: Neurocircuitry and disorders. Neuropsychopharmacology. 2010;35 (1 ):86–104.19776728
34. Squire LR , WixtedJT. The cognitive neuroscience of human memory since H.M. Annu Rev Neurosci. 2011;34 :259–288.21456960
35. Gondi V , PughSL, TomeWA, et al . Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): A phase II multi-institutional trial. J Clin Oncol. 2014;32 (34 ):3810–3816.25349290
36. Yang WC , ChenYF, YangCC, 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 (3 ):478–486.32789503
37. Brown PD , GondiV, PughS, et al ; for NRG Oncology. Hippocampal avoidance during whole-brain radiotherapy plus Memantine for patients with brain metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol. 2020;38 (10 ):1019–1029.32058845
38. Han YM , CaiG, ChaiWM, et al . Radiological distribution of brain metastases and its implication for the hippocampus avoidance in whole brain radiotherapy approach. Br J Radiol. 2017;90 (1079 ):20170099.28830202
39. Gondi V , TomeWA, MarshJ, et al . Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: Safety profile for RTOG 0933. Radiother Oncol. 2010;95 (3 ):327–331.20392503
40. Cherng HR , SunK, BentzenS, et al . Evaluating the heterogeneity of hippocampal avoidant whole brain radiotherapy treatment effect: A secondary analysis of NRG CC001. Neuro Oncol. 2024;26 (5 ):911–921.38069666
41. Belderbos JSA , De RuysscherDKM, De JaegerK, et al . Phase 3 randomized trial of prophylactic cranial irradiation with or without hippocampus avoidance in SCLC (NCT01780675). J Thorac Oncol. 2021;16 (5 ):840–849.33545387
42. Rodriguez de Dios N , CouñagoF, Murcia-MejiaM, et al . Randomized Phase III Trial of prophylactic cranial irradiation with or without hippocampal avoidance for small-cell lung cancer (PREMER): A GICOR-GOECP-SEOR Study. J Clin Oncol. 2021;39 (28 ):3118–3127.34379442
43. Gondi V , PughS, MehtaMP, et al . Primary endpoint results of NRG CC003: Phase IIR/III Trial of Prophylactic Cranial Irradiation (PCI) with or without Hippocampal Avoidance (HA) for Small Cell Lung Cancer (SCLC). Int J Radiat Oncol Biol Phys. 2023;117 (4 ):e3. LBA4.
44. Gaebe K , EricksonAW, LiAY, et al . Re-examining prophylactic cranial irradiation in small cell lung cancer: A systematic review and meta-analysis. EClinicalMedicine. 2024;67 :102396.38261885
45. Mulvenna P , NankivellM, BartonR, et al . Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): Results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388 (10055 ):2004–2014.27604504
46. Chang EL , WefelJS, HessKR, 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 (11 ):1037–1044.19801201
47. Brown PD , JaeckleK, BallmanKV, 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 (4 ):401–409.27458945
48. Brown PD , BallmanKV, CerhanJH, 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 (8 ):1049–1060.28687377
49. July J , PranataR. Hypofractionated versus single-fraction stereotactic radiosurgery for the treatment of brain metastases: A systematic review and meta-analysis. Clin Neurol Neurosurg. 2021;206 :106645.33984752
50. Yamamoto M , SerizawaT, ShutoT, et al . Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): A multi-institutional prospective observational study. Lancet Oncol. 2014;15 (4 ):387–395.24621620
51. Yamamoto M , SerizawaT, HiguchiY, et al . A multi-institutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901 Study Update): Irradiation-related complications and long-term maintenance of mini-mental state examination scores. Int J Radiat Oncol Biol Phys. 2017;99 (1 ):31–40.28816158
52. Meyers CA , WefelJS. 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 (19 ):3557–3558.12913103
53. Wefel JS , VardyJ, AhlesT, SchagenSB. International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol. 2011;12 (7 ):703–708.21354373
54. De Roeck L , GillebertCR, van AertRCM, et al . Cognitive outcomes after multimodal treatment in adult glioma patients: A meta-analysis. Neuro Oncol. 2023;25 (8 ):1395–1414.36809489
55. Turnquist C , HarrisBT, HarrisCC. Radiation-induced brain injury: Current concepts and therapeutic strategies targeting neuroinflammation. Neurooncol. Adv. 2020;2 (1 ):vdaa057.32642709
