BACKGROUND: The landscape of brain metastases radiotherapy is evolving, with a shift away from whole-brain radiotherapy (WBRT) toward targeted stereotactic approaches aimed at preserving neurocognitive functions and maintaining overall quality of life. For patients with multiple metastases, especially in cases where targeted radiotherapy is no longer feasible due to widespread dissemination, the concept of hippocampal sparing radiotherapy (HA_WBRT) gains prominence. METHODS: In this narrative review we explore the role of the hippocampi in memory formation and the implications of their postradiotherapy lateral damage. We also consider the potential advantages of selectively sparing one hippocampus during whole-brain radiotherapy (WBRT). Additionally, by systematic evaluation of relevant papers published on PubMed database over last 20 years, we provide a comprehensive overview of the various changes that can occur in the left or right hippocampus as a consequence of radiotherapy. RESULTS: While it is important to note that various neurocognitive functions are interconnected throughout the brain, we can discern certain specialized roles of the hippocampi. The left hippocampus appears to play a predominant role in verbal memory, whereas the right hippocampus is associated more with visuospatial memory. Additionally, the anterior part of the hippocampus is more involved in episodic memory and emotional processing, while the posterior part is primarily responsible for spatial memory and pattern separation. Notably, a substantial body of evidence demonstrates a significant correlation between post-radiotherapy changes in the left hippocampus and subsequent cognitive decline in patients. CONCLUSION: In the context of individualized palliative radiotherapy, sparing the unilateral (specifically, the left, which is dominant in most individuals) hippocampus could expand the repertoire of strategies available for adapted WBRT in cases involving multiple brain metastases where stereotactic radiotherapy is not a viable option. Prospective ongoing studies assessing various memory-sparing radiotherapy techniques will define new standard of radiotherapy care of patients with multiple brain metastases.

• Keywords
• brain metastases, hippocampus, neurocognitive function, unilateral, whole brain radiotherapy,
• Publication type
• Journal Article MeSH
• Review MeSH

Cancer therapy for both central nervous system (CNS) and non-CNS tumors has been previously associated with transient and long-term cognitive deterioration, commonly referred to as 'chemo fog'. This therapy-related damage to otherwise normal-appearing brain tissue is reported using post-mortem neuropathological analysis. Although the literature on monitoring therapy effects on structural magnetic resonance imaging (MRI) is well established, such macroscopic structural changes appear relatively late and irreversible. Early quantitative MRI biomarkers of therapy-induced damage would potentially permit taking these treatment side effects into account, paving the way towards a more personalized treatment planning.This systematic review (PROSPERO number 224196) provides an overview of quantitative tomographic imaging methods, potentially identifying the adverse side effects of cancer therapy in normal-appearing brain tissue. Seventy studies were obtained from the MEDLINE and Web of Science databases. Studies reporting changes in normal-appearing brain tissue using MRI, PET, or SPECT quantitative biomarkers, related to radio-, chemo-, immuno-, or hormone therapy for any kind of solid, cystic, or liquid tumor were included. The main findings of the reviewed studies were summarized, providing also the risk of bias of each study assessed using a modified QUADAS-2 tool. For each imaging method, this review provides the methodological background, and the benefits and shortcomings of each method from the imaging perspective. Finally, a set of recommendations is proposed to support future research.

• Keywords
• Chemotherapy, Cognitive decline, Long-term adverse effects, Neuroimaging, Radiotherapy,
• MeSH
• Cognition Disorders * MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Brain diagnostic imaging   pathology   MeSH
• Neoplasms * diagnostic imaging   drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH

INTRODUCTION: Hippocampi sparing whole brain radiotherapy (WBRT) is an evolving approach in the treatment of patients with multiple brain metastases, pursuing mitigation of verbal memory decline as a consequence of hippocampal radiation injury. Accumulating data are showing different postradiotherapy changes in the left and right hippocampus with a theoretical proposal of only unilateral (dominant, left) hippocampal sparing during WBRT. METHOD: The aim of this retrospective study is to describe spatial distribution of brain metastases on MRI in a cohort of 260 patients (2595 metastases) and to evaluate distribution separately in the left and right hippocampus and in respective hippocampal avoiding zones (HAZ, region with subtherapeutic radiation dose), including evaluation of location of metastatic mass centre. RESULTS: The median number of brain metastases was three, with lung cancer being the most common type of primary tumour; 36% had single metastasis. Almost 8% of patients had metastasis within hippocampus (1.1% of all metastases) and 18.1% of patients within HAZ (3.3% of all metastases). No statistically significant difference was observed in the laterality of hippocampal involvement, also when the location of centre of metastases was analyzed. There were more patients presenting the centre of metastasis within left (15) versus right (6) HAZ approaching the borderline of statistical significance. CONCLUSION: No significant difference in the laterality of BM seeding within hippocampal structures was observed. The hypothesized unilateral sparing WBRT would have theoretical advantage in about 50% reduction in the risk of subsequent recurrence within spared regions.

• MeSH
• Hippocampus diagnostic imaging   MeSH
• Organ Sparing Treatments * MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Brain Neoplasms diagnostic imaging   pathology   radiotherapy   MeSH
• Retrospective Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH