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Abstract BACKGROUND Guidelines regarding stereotactic radiosurgery (SRS) for brain metastases are missing recently published evidence. OBJECTIVE To conduct a systematic review and provide an objective summary of publications regarding SRS in managing patients with 1 to 4 brain metastases. METHODS Using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using PubMed and Medline up to November 2016. A separate search was conducted for SRS for larger brain metastases. RESULTS Twenty-seven prospective studies, critical reviews, meta-analyses, and published consensus guidelines were reviewed. Four key points came from these studies. First, there is no detriment to survival by withholding whole brain radiation (WBRT) in the upfront management of brain metastases with SRS. Second, while SRS on its own provides a high rate of local control (LC), WBRT may provide further increase in LC. Next, WBRT does provide distant brain control with less need for salvage therapy. Finally, the addition of WBRT does affect neurocognitive function and quality of life more than SRS alone. For larger brain metastases, surgical resection should be considered, especially when factoring lower LC with single-session radiosurgery. There is emerging data showing good LC and/or decreased toxicity with multisession radiosurgery. CONCLUSION A number of well-conducted prospective and meta-analyses studies demonstrate good LC, without compromising survival, using SRS alone for patients with a limited number of brain metastases. Some also demonstrated less impact on neurocognitive function with SRS alone. Practice guidelines were developed using these data with International Stereotactic Radiosurgery Society consensus.

Abstract Please see the full-text version of this guideline https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2) for the target population of each recommendation listed below.  SURGERY FOR METASTATIC BRAIN TUMORS AT NEW DIAGNOSIS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT)? RECOMMENDATIONS: Level 1: Surgery + WBRT is recommended as first-line treatment in patients with single brain metastases with favorable performance status and limited extracranial disease to extend overall survival, median survival, and local control. Level 3: Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors Level 3: Multimodal treatments including either surgery + WBRT + SRS boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits.  SURGERY AND RADIATION FOR METASTATIC BRAIN TUMORS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgical resection followed by WBRT, SRS, or another combination of these modalities? RECOMMENDATIONS: Level 1: Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases. Level 3: Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival. Level 3: It is recommended that SRS alone be considered equivalent to surgery + WBRT.  SURGERY FOR RECURRENT METASTATIC BRAIN TUMORS QUESTION: Should patients with recurrent metastatic brain tumors undergo surgical resection? RECOMMENDATIONS: Level 3: Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS.  SURGICAL TECHNIQUE AND RECURRENCE QUESTION A: Does the surgical technique (en bloc resection or piecemeal resection) affect recurrence? RECOMMENDATION: Level 3: En bloc tumor resection, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases. QUESTION B: Does the extent of surgical resection (gross total resection or subtotal resection) affect recurrence? RECOMMENDATION: Level 3: Gross total resection is recommended over subtotal resection in recursive partitioning analysis class I patients to improve overall survival and prolong time to recurrence. The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2.

Proton minibeam radiation therapy (pMBRT) is a novel strategy for minimizing normal tissue damage resulting from radiotherapy treatments. This strategy partners the inherent advantages of protons for radiotherapy with the gain in normal tissue preservation observed upon irradiation with narrow, spatially fractionated beams. In this study, whole brains (excluding the olfactory bulb) of Fischer 344 rats (n = 16) were irradiated at the Orsay Proton Therapy Center. Half of the animals received standard proton irradiation, while the other half were irradiated with pMBRT at the same average dose (25 Gy in one fraction). The animals were followed-up for 6 months. A magnetic resonance imaging (MRI) study using a 7-T small-animal MRI scanner was performed along with a histological analysis. Rats treated with conventional proton irradiation exhibited severe moist desquamation, permanent epilation and substantial brain damage. In contrast, rats in the pMBRT group exhibited no skin damage, reversible epilation and significantly reduced brain damage; some brain damage was observed in only one out of the eight irradiated rats. These results demonstrate that pMBRT leads to an increase in normal tissue resistance. This net gain in normal tissue sparing can lead to the efficient treatment of very radio-resistant tumours, which are currently mostly treated palliatively.

Key Points An increased understanding of the molecular biology of metastatic processes, including cell migration, blood–brain barrier penetration, angiogenesis and tumour proliferation, is providing new opportunities for the development of targeted therapies Advances in MRI, incorporating spectroscopy and perfusion techniques, and tracers unique to metastases, provide additional information on responses to treatment and enable the earlier detection of new tumours Improvements in intraoperative tumour identification using MRI and fluorescent agents maximize the likelihood of complete tumour resection and minimize injury to normal tissue Reduction of radiation-induced cerebral injury and cognitive decline through repeated use of stereotactic radiosurgery or hippocampal-avoidance whole-brain radiotherapy provide useful options for individuals with advanced cerebral metastatic disease Targeted therapy is beneficial in molecularly-selected tumours, including erlotinib in EGFR -mutant lung tumours, crizotinib in lung carcinomas with EML4 – ALK translocations, trastuzumab in HER2 + breast cancer and dabrafenib in BRAF -mutant melanoma Brain metastasis is an important complication associated with a number of common primary cancers, including lung and breast cancers, and melanoma, and has major effects on patient morbidity and mortality. This Review discusses the advances in our understanding of the molecular biology of brain metastases, and how this knowledge has influenced the imaging, surgical, radiological and pharmaceutical approaches involved in the management of brain metastasis. Metastatic tumours involving the brain overshadow primary brain neoplasms in frequency and are an important complication in the overall management of many cancers. Importantly, advances are being made in understanding the molecular biology underlying the initial development and eventual proliferation of brain metastases. Surgery and radiation remain the cornerstones of the therapy for symptomatic lesions; however, image-based guidance is improving surgical technique to maximize the preservation of normal tissue, while more sophisticated approaches to radiation therapy are being used to minimize the long-standing concerns over the toxicity of whole-brain radiation protocols used in the past. Furthermore, the burgeoning knowledge of tumour biology has facilitated the entry of systemically administered therapies into the clinic. Responses to these targeted interventions have ranged from substantial toxicity with no control of disease to periods of useful tumour control with no decrement in performance status of the treated individual. This experience enables recognition of the limits of targeted therapy, but has also informed methods to optimize this approach. This Review focuses on the clinically relevant molecular biology of brain metastases, and summarizes the current applications of these data to imaging, surgery, radiation therapy, cytotoxic chemotherapy and targeted therapy.

Whole-brain radiotherapy (WBRT) remains a standard treatment for extensive brain metastases, providing symptom relief and improved progression-free survival (PFS). Re-irradiation is often necessary for recurrent disease, particularly in the cerebellum, which accounts for 10–20% of cases. Cerebellar metastases are associated with distinct symptoms and poorer prognoses compared to supratentorial lesions. This study evaluates the outcomes of cerebellar-only re-irradiation for brain metastases, with or without stereotactic radiosurgery (SRS) for supratentorial lesions. A retrospective analysis of 56 patients treated between 2017 and 2023 was conducted. Patients received cerebellar-only re-irradiation after WBRT. Symptom improvement was assessed three months post-treatment. Statistical analyses included t-tests, Mann-Whitney U tests, and multivariable logistic regression. The cohort’s median age was 53 years, with breast cancer being the most prevalent histology (71%). Symptom improvement occurred in 75% of patients, with relief rates of 84.6% for nausea, 80% for headache, and 58.3% for dizziness. Dexamethasone use decreased in 76.3% of cases. Median PFS was 39.2%, with a six-month overall survival of 50%. Only 1.7% of patients developed symptomatic radiation necrosis. Factors associated with symptom improvement included younger age, extended intervals between WBRT and re-irradiation, and higher equivalent dose in 2 Gy fractions (EQD2). Cerebellar-only re-irradiation is an effective, low-toxicity option for recurrent cerebellar metastases. This approach warrants further validation in prospective studies, particularly in comparison to SRS.

The dosimetry of scalp dose was prospectively studied and correlated with alopecia following conventional cranial irradiation in primary brain tumors patients. Patients with primary brain tumors who required conventional radiotherapy were enrolled. A hairline marker was applied to the patient's scalp to identify the entire scalp region. The maximal dose to 2% volume of interest (D2) for the entire scalp region were obtained. The radiation dosages at the localized hair-loss areas were evaluated during the final week of RT (transient alopecia) and six months after completing RT (permanent alopecia). Kruskal-Wallis tests were used to compare the dosimetric parameter values with statistical significance set as p < 0.05. Forty-eight patients were included in the analysis. The prescribed radiation doses ranged from 50.4 to 60.0 Gy. Thirty-two patients experienced alopecia (27 transient and 5 permanent). The median D2 values adjusted for the entire scalp were higher in the alopecia group (38.40 Gy for transient alopecia and 47.84 Gy for permanent alopecia vs 11.90 Gy for no alopecia, p < 0.001). The D2 value was determined as a predictive parameter for alopecia. The threshold values for transient and permanent alopecia over the entire scalp were 22.15 Gy and 36.81 Gy, respectively. At the localized hair-loss areas, the D2 values for transient and permanent alopecia were higher at 44.82 Gy and 50.00 Gy, respectively. The radiation intensity at the localized hair-loss areas was also related to the severity of alopecia, with D2 values of 35.14 Gy and 46.39 Gy for clinically assigned grade 1 and grade 2 transient alopecia, respectively, with the D2 value being even higher for permanent alopecia. The D2 parameter value could be used to predict the type and severity of alopecia.

Abstract TARGET POPULATION Adult patients (older than 18 yr of age) with newly diagnosed brain metastases. QUESTION If whole brain radiation therapy (WBRT) is used, is there an optimal dose/fractionation schedule? RECOMMENDATIONS Level 1:  A standard WBRT dose/fractionation schedule (ie, 30 Gy in 10 fractions or a biological equivalent dose [BED] of 39 Gy10) is recommended as altered dose/fractionation schedules do not result in significant differences in median survival or local control. Level 3: Due to concerns regarding neurocognitive effects, higher dose per fraction schedules (such as 20 Gy in 5 fractions) are recommended only for patients with poor performance status or short predicted survival. Level 3: WBRT can be recommended to improve progression-free survival for patients with more than 4 brain metastases. QUESTION What impact does tumor histopathology or molecular status have on the decision to use WBRT, the dose fractionation scheme to be utilized, and its outcomes? RECOMMENDATIONS There is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology. Molecular status may have an impact on the decision to delay WBRT in subgroups of patients, but there is not sufficient data to make a more definitive recommendation. QUESTION Separate from survival outcomes, what are the neurocognitive consequences of WBRT, and what steps can be taken to minimize them? RECOMMENDATIONS Level 2: Due to neurocognitive toxicity, local therapy (surgery or SRS) without WBRT is recommended for patients with ≤4 brain metastases amenable to local therapy in terms of size and location. Level 2:  Given the association of neurocognitive toxicity with increasing total dose and dose per fraction of WBRT, WBRT doses exceeding 30 Gy given in 10 fractions, or similar biologically equivalent doses, are not recommended, except in patients with poor performance status or short predicted survival. Level 2: If prophylactic cranial irradiation (PCI) is given to prevent brain metastases for small cell lung cancer, the recommended WBRT dose/fractionation regimen is 25 Gy in 10 fractions, and because this can be associated with neurocognitive decline, patients should be told of this risk at the same time they are counseled about the possible survival benefits. Level 3: Patients having WBRT (given for either existing brain metastases or as PCI) should be offered 6 mo of memantine to potentially delay, lessen, or prevent the associated neurocognitive toxicity. QUESTION Does the addition of WBRT after surgical resection or radiosurgery improve progression-free or overall survival outcomes when compared to surgical resection or radiosurgery alone? RECOMMENDATIONS Level 2: WBRT is not recommended in WHO performance status 0 to 2 patients with up to 4 brain metastases because, compared to surgical resection or radiosurgery alone, the addition of WBRT improves intracranial progression-free survival but not overall survival. Level 2: In WHO performance status 0 to 2 patients with up to 4 brain metastases where the goal is minimizing neurocognitive toxicity, as opposed to maximizing progression-free survival and overall survival, local therapy (surgery or radiosurgery) without WBRT is recommended. Level 3: Compared to surgical resection or radiosurgery alone, the addition of WBRT is not recommended for patients with more than 4 brain metastases unless the metastases’ volume exceeds 7 cc, or there are more than 15 metastases, or the size or location of the metastases are not amenable to surgical resection or radiosurgery. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_3.

Background Whole-brain radiotherapy (WBRT) is an important way to treat multiple metastases. Ultra-high dose rate (FLASH) can avoid neurotoxicity caused by conventional irradiation, it has attracted much attention. This study aims to study the difference of irradiation-induced intestinal flora between conventional dose rate and FLASH WBRT. Methods WBRT with 10 Gy was performed with electron-beam conventional irradiation (2 Gy/s) and electron-beam FLASH (eFLASH) irradiation (230 Gy/s). The intestinal feces and whole brain of mice were isolated after behavioral evaluation at 1st, 3rd and 10th weeks post-irradiation. HE staining and immunofluorescence were used to access the level of brain damage. The differences in intestinal microbes and transcription levels were detected by 16S rRNA gene sequencing and transcriptome sequencing, respectively. Results eFLASH irradiation significantly reduced radiation neurotoxicity and had a long-term protective effect on cognitive function and learning and memory ability. Compared with conventional irradiation, eFLASH irradiation not only up-regulated the expression of genes related to neuronal regeneration and digestive system, but also induced more abundant intestinal microflora, especially the “probiotics” such as Lachnospiraceae and others, which were proved to play a role in radiation protection, increased significantly after eFLASH irradiation. The up-regulated microbiota after eFLASH irradiation was significantly positively correlated with genes related to neuronal development and regeneration, while significantly negatively correlated with genes related to inhibitory synapses. Additionally, conventional irradiation down-regulated microbial metabolism-related pathways, while FLASH did not. Conclusions In summary, we explored the unique gut microbiota changes induced by eFLASH WBRT for the first time, providing a theoretical basis for exploring the mechanism of action of FLASH.

Background Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB). Methods This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter. Discussion This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases. Trial registration The HIPPORAD trial is registered with the German Clinical Trials Registry ( DRKS00004598 , registered 2 June 2016).

Dose verification in preclinical CyberKnife-based stereotactic radiosurgery (CK-SRS) of intracranial tumors is complicated by the unique characteristics of the system, including its highly conformal, non-coplanar radiation delivery and small-field irradiation. This raises concerns about the reliability of dosimetric measurements in CK-SRS radiobiological studies, emphasizing the need for standardized dosimetry protocols to improve dose accuracy and reproducibility. This study aims to evaluate a fully 3D-printed mouse phantom as a tool for preclinical intracranial CK-SRS dose verification. A 3D-printed mouse phantom was fabricated using clear resin and glass-filled polyamide (PA3200 GF) for tissue-bone-equivalent structures and modified to accommodate both EBT3 film and thermoluminescent dosimeters (TLD). Two treatment configurations were employed using CyberKnife M6 system, including two simple static field plans and two complex non-planar plans. The dosimetric evaluation of the mouse phantom involved comparing the mean dose and dose discrepancies between film profile measurements, TLD-derived point-dose readings, and the corresponding doses calculated by the treatment plan system (TPS) for each configuration. Across all measurements for single-beam and non-planer stereotactic treatment configuration, dose values exhibited a deviation of no more than 4.20% from the corresponding TPS calculated data. The 2D dose distributions obtained from the film measurements and those calculated by the TPS were successfully registered. The mean dose differences for lateral profiles showed a high level of agreement, with discrepancies of only 2.23%. Similarly, the agreement was similarly excellent with a mean dose difference of 2.31% along the anteroposterior axes. TLD measurements also displayed comparable agreement with TPS-calculated results, with the maximum dose difference recorded at 2.20% for the single-beam and 4.12% for the non-planar treatment configuration. This study demonstrates the utility of 3D-printed mouse phantom for accurate dose assessment in preclinical intracranial CK-SRS. The phantom serves as an effective tool for pre-treatment dose verification, improving dosimetric precision while offering a cost-efficient solution for radiobiological research.