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Purpose: To study survival outcomes and prognostic factors in patients undergoing whole brain radiation therapy (WBRT) for brain metastases in the contemporary setting. Methods: Patients undergoing WBRT from 2013–2021 were retrospectively included in an ethics-approved institutional database. Patient and treatment characteristics were assessed, including patient age, primary tumor histology, Karnofsky Performance Status (KPS), extracranial disease, as well as WBRT dose. Overall survival (OS) was calculated from onset of WBRT using the Kaplan-Meier method. Results: A total of 328 patients (median age 63 years) were included. Most patients (52%) had ≥ 10 brain metastases, and 17% had leptomeningeal disease. WBRT was delivered with 10 × 3 Gy (64%), 5 × 4 Gy (25%), or other regimens (11%). Median follow-up was 4.4 months (range, 0.1–154.3), and median OS was 4.7 months (95%CI, 3.8–6.0). OS differed between histologies (p = 0.01), with the longest survival seen in breast cancer (median 7.7 months). Patients with KPS of 90–100 survived for a median of 8.3 months, compared to 4.1 months with KPS 70–80, and 1.7 months with KPS < 70 (p < 0.01). Multivariate analyses revealed that KPS had the largest impact on survival. Patients who received a WBRT dose of ≥ 30 Gy also had a reduced risk of death (HR 0.45; p < 0.001). Survival differed between subgroups reclassified according to the Rades scoring system (p < 0.01). Conclusion: Survival outcomes of patients undergoing WBRT in the contemporary era appear comparable to historical cohorts, although individual patient factors need to be considered. Patients with otherwise favorable prognostic factors may benefit from longer-course WBRT. [ABSTRACT FROM AUTHOR]

Summary: Background: Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for brain metastasis (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. Our aim was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada. Methods: This population-based, retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 1, 2010, and March 31, 2018. Data were analysed between June 2, 2022, and December 20, 2023. Patients with second cancer diagnosis were excluded. Patients were identified and data retrieved from the Institute for Clinical Evaluative Sciences (ICES) databases. Kaplan–Meier and multivariable Cox regression analyses were performed to compare OS between patient cohorts stratified by disease stage, BM diagnosis, and intracranial treatment modality. Propensity score-matching based on age, disease stage, time to BM, and receipt of chemotherapy was performed to compare OS between intracranial treatment modalities. Findings: 8705 patients were included (male: 4433, female: 4272). Median age at diagnosis was 68 years (interquartile range, IQR, 61–75). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23–7.69). 32% (n = 2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) with median OS of 9.76 months (95% CI, 9.36–10.22). 102 (4%), 1654 (62%), and 930 (35%) patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS from time of BM diagnosis was non-inferior between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 0.68, 95% CI, 0.44–1.06, p = 0.091, n = 86) and in favour of SRS for those who received PCI prior to BM development (HR, 0.47, 95% CI, 0.31–0.72, p = 0.0042, n = 112). Interpretation: OS for patients with SCLC remains poor, and many patients present with BM. With careful selection, patients with SCLC and BM may benefit from SRS treatment. Future research should incorporate information on burden of intracranial disease and novel immunotherapies. Funding: None.

Background: Hippocampal-sparing whole brain irradiation with simultaneous integrated boost (HSIB-WBRT) emerges as a significant advancement in treating brain metastases, aiming to alleviate neurocognitive function (NCF) decline associated with traditional whole-brain radiotherapy (WBRT). This technique combines the advantages of WBRT and simultaneous integrated boost (SIB) through intensity-modulated radiation therapy (IMRT), offering enhanced tumor dosage while safeguarding hippocampal structures. Methods: This is a prospective, randomized, two-arm single institution study comparing the impact of hippocampal-sparing and integrated boost on NCF and local control after HSIB-VBRT versus WBRT in patients with multiple brain metastases. Radiation therapy consisted of intensity-modulated radiation therapy delivering 30 Gy in 10 fractions over 2 weeks to the whole brain with a simultaneous integrated boost of 40 Gy in 10 fractions to metastatic lesions. Hippocampal regions were limited to 16 Gy. Cognitive performance and cancer outcomes were evaluated. Results: In the HSIB-WBRT group, the most frequent localization of brain metastases were from the lung tumors, in 60% of patients while in the WBRT group, the most frequent localization were from the breast tumors, for 53.3% of patients. Although there was a trend in local control for patients with HSIB-WBRT, the statistical difference was not reached between the 2 groups at 6 months, progression was 26.4% for HSIB-WBRT group vs. 46.7% in the WBRT group (p = 0.253). The neurocognitive function was better in the HSIB-WBRT group, the mean Mini-Mental State Examination (MMSE) score at 6 months was 28.93 with a median of 29, whereas for the WBRT group, the mean was 24.6 with a median of 25, which proved to be statistically significant (p < 0.001). Conclusions: Despite limitations such as sample size constraints and compliance issues with neurocognitive testing, the study supports HSIB-WBRT as a safe and viable treatment option for brain metastases. Further research incorporating larger cohorts is warranted to validate these findings. The HSIB-WBRT group exhibited a favorable outcome in terms of maintenance of neurocognitive function in comparison to the WBRT group after 6 months despite not having superior local control. To amplify the statistical findings, more studies should be undertaken. The study is constrained by the small sample size of each study group, consisting of only 15 patients, which heightens the potential for type II error. In summary, HSIB-WBRT offers promising prospects for preserving neurocognition while potentially being effective regarding intracranial tumor control, emphasizing its potential as a standard therapeutic approach for patients with brain metastases. [ABSTRACT FROM AUTHOR]

Whole brain irradiation (WBI), also known as whole brain radiation therapy (WBRT), is a well-established treatment for multiple brain metastases and as a preventive measure to reduce the risk of recurrence after surgical removal of a cerebral metastasis. However, WBI has been found to lead to a gradual decline in neurocognitive function in approximately 50% of patients who survive the treatment, significantly impacting their overall quality of life. Recent preclinical investigations have shed light on the underlying mechanisms of this adverse effect, revealing a complex cerebrovascular injury that involves the induction of cellular senescence in various components of the neurovascular unit, including endothelial cells. The emergence of cellular senescence following WBI has been implicated in the disruption of the blood-brain barrier and impairment of neurovascular coupling responses following irradiation. Building upon these findings, the present study aims to test the hypothesis that WBI-induced endothelial injury promotes endothelial dysfunction, which mimics the aging phenotype. To investigate this hypothesis, we employed a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks) on young mice. Both the WBI-treated and control mice were fitted with a cranial window, enabling the assessment of microvascular endothelial function. In order to evaluate the endothelium-dependent, NO-mediated cerebral blood flow (CBF) responses, we topically administered acetylcholine and ATP, and measured the resulting changes using laser Doppler flowmetry. We found that the increases in regional CBF induced by acetylcholine and ATP were significantly diminished in mice subjected to WBI. These findings provide additional preclinical evidence supporting the notion that WBI induces dysfunction in cerebrovascular endothelial cells, which in turn likely contributes to the detrimental long-term effects of the treatment. This endothelial dysfunction resembles an accelerated aging phenotype in the cerebrovascular system and is likely causally linked to the development of cognitive impairment. By integrating these findings with our previous results, we have deepened our understanding of the lasting consequences of WBI. Moreover, our study underscores the critical role of cerebromicrovascular health in safeguarding cognitive function over the long term. This enhanced understanding highlights the importance of prioritizing cerebromicrovascular health in the context of preserving cognitive abilities. [ABSTRACT FROM AUTHOR]

Whole brain irradiation (WBI), a commonly employed therapy for multiple brain metastases and as a prophylactic measure after cerebral metastasis resection, is associated with a progressive decline in neurocognitive function, significantly impacting the quality of life for approximately half of the surviving patients. Recent preclinical investigations have shed light on the multifaceted cerebrovascular injury mechanisms underlying this side effect of WBI. In this study, we aimed to test the hypothesis that WBI induces endothelial senescence, contributing to chronic disruption of the blood-brain barrier (BBB) and microvascular rarefaction. To accomplish this, we utilized transgenic p16-3MR mice, which enable the identification and selective elimination of senescent cells. These mice were subjected to a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks), and cranial windows were applied to both WBI-treated and control mice. Quantitative assessment of BBB permeability and capillary density was performed using two-photon microscopy at the 6-month post-irradiation time point. The presence of senescent microvascular endothelial cells was assessed by imaging flow cytometry, immunolabeling, and single-cell RNA-sequencing (scRNA-seq). WBI induced endothelial senescence, which associated with chronic BBB disruption and a trend for decreased microvascular density in the mouse cortex. In order to investigate the cause-and-effect relationship between WBI-induced senescence and microvascular injury, senescent cells were selectively removed from animals subjected to WBI treatment using Navitoclax/ABT263, a well-known senolytic drug. This intervention was carried out at the 3-month post-WBI time point. In WBI-treated mice, Navitoclax/ABT263 effectively eliminated senescent endothelial cells, which was associated with decreased BBB permeability and a trend for increased cortical capillarization. Our findings provide additional preclinical evidence that senolytic treatment approaches may be developed for prevention of the side effects of WBI. [ABSTRACT FROM AUTHOR]

Patients with primary central nervous system lymphoma (PCNSL) typically present with non-focal neurological symptoms, including disorientation, poor balance and memory loss with unifocal or multifocal periventricular lesions seen on MRI. Deviations from these characteristic findings can delay diagnosis and lead to additional diagnostic tests being needed. The present study reports a 68-year-old man with a recent varicella zoster infection and history of acetylcholine receptor antibody-positive myasthenia gravis who received mycophenolate mofetil for 22 years. He presented with left eye vision changes and cognitive memory deficits. A brain MRI showed an enhancing lesion within his left medulla extending to the cerebellum. Cerebrospinal fluid analysis was positive for Epstein-Barr virus (EBV) and negative for malignancy. He was diagnosed with varicella zoster virus vasculopathy. At 3 months later, a repeat brain MRI showed multiple new enhancing lesions developing bilaterally along the periventricular white matter. Soon after, he presented to a local ER with acute left-sided blurry vision and worsening memory loss, and he began receiving steroids. Because of rapid symptom progression, he underwent resection of the left frontal lesion, which showed EBV-induced diffuse large B-cell lymphoma (DLBCL). Mycophenolate mofetil was discontinued, and within 24 h of one dose of intravenous 500 mg/m2 rituximab, he had a dramatic improvement in left eye vision and memory loss. He experienced mixed responses to rituximab after 3 cycles. Following one dose of high-dose methotrexate, he developed subsequent chronic kidney disease and required dialysis. He received whole-brain radiation therapy with craniospinal radiation and is currently in complete remission. An EBV-induced DLBCL diagnosis should be highly considered for patients with periventricular lesions and EBV-positive cerebrospinal fluid. Misdiagnosis or delay in PCNSL diagnosis because of atypical features in disease presentation and radiographic findings could lead to PCNSL progression and worsening neurological deficits. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastases are of increasing concern in the management of cancer patients. New systemic treatment options like specific targeting agents or immune checkpoint inhibitors allow for longer survival with a higher incidence of brain metastases over the course of the disease. Single or a few small, asymptomatic lesions are mainly treated with focal stereotactic radiotherapy. On the other hand, in many cases, large and, in particular, symptomatic metastases require microsurgical resection for immediate symptom relief. However, the indication for surgery can be challenging concerning the clinic, patient and tumor characteristics, and the availability of alternative conservative treatment options. Of note, with surgery alone, local recurrence rates are about 50%; therefore, additional RT is needed to improve outcomes. Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastases are the most frequent type of intracranial cancer. Although the prognosis has improved, the outcomes still vary widely, with a median survival of less than one year. The Recursive Partitioning Analysis (RPA) is one of the first proposed brain metastases prognostic tools. We hypothesized that an Updated RPA (U-RPA) prognostic index, which can easily be determined in the clinic, would be informative for both patients and clinicians to make decisions in the contemporary management of brain metastases. We report a retrospective analysis of all patients treated at three academic institutions, between 2017 and 2019, to compare outcomes based on the U-RPA and according to the type of treatment and primary cancer. Our results suggest that determination and documentation of the U-RPA at the time of diagnosis may assist patients and clinicians to make better-informed decisions based on the potential value of contemporary brain-directed treatment options. Patients with brain metastases (BMETS) need information about the prognosis and potential value of treatment options to make informed therapeutic decisions, but tools to predict survival in contemporary practice are scarce. We propose an Updated Recursive Partitioning Analysis (U-RPA) instrument to predict survival and benefit from brain-directed treatment (BDT) of contemporary patients. This was a retrospective analysis of patients with BMETS treated between 2017 and 2019. With survival as the primary endpoint, we calculated the U-RPA and generated estimates using Kaplan–Meier curves and hazard ratios. Of 862 eligible patients, 752 received BDT and 110 received best supportive care (BSC). Median overall survival with BDT and BSC was 9.3 and 1.3 months, respectively. Patients in RPA class 1, 2A, 2B and 3 who underwent BDT had median survival of 28.1, 14.7, 7.6 and 3.3 months, respectively. The median survival for patients in RPA 3 who received BDT (n = 147), WBRT (n = 79) and SRS (n = 54) was 3.3, 2.9 and 4.1 months, respectively. The U-RPA defines prognosis estimates, independent of tumor type and treatment modality, which can assist to make value-based care treatment decisions. The prognosis for patients in U-RPA class 2B and 3 remains poor, with consideration for early palliative care involvement in these cases. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a rare malignancy. Standard of care is upfront high-dose methotrexate (HD-MTX) chemotherapy, while cranial radiation is more commonly used in the salvage setting. In this retrospective study, we aimed to investigate the safety and efficacy of salvage cranial radiation in PCNSL. PCNSL patients who received upfront HD-MTX chemotherapy and salvage cranial radiation after treatment failure between 1995 and 2018 were selected. Radiological response to cranial radiation was assessed as per Response Assessment in Neuro-Oncology Criteria. Twenty one patients were selected (median age 59.9 years), with median follow-up of 19.9 months. Fourteen patients (66.7%) received a boost to the gross tumour volume (GTV). Four patients (19.0%) sustained grade ≥2 treatment-related neurotoxicity post-completion of cranial radiation. Of the 19 patients who had requisite MRI with gadolinium imaging available for Response Assessment in Neuro-Oncology (RANO) criteria assessment, 47.4% achieved complete response, 47.4% achieved partial response, and 5.3% of patients exhibited stable disease. Higher dose to the whole brain (>30 Gy) was associated with higher rate of complete response (63.6%) than lower dose (≤30 Gy, 37.5%), while boost dose to the gross disease was also associated with higher rate of complete response (61.5%) compared with no boost dose (33.3%). Median overall survival was 20.0 months. PCNSL patients who relapsed following upfront chemotherapy showed a high rate of response to salvage cranial radiation, especially in those receiving greater than 30 Gy to the whole brain and boost to gross disease.

Purpose: To evaluate the feasibility of using a simplified non-coplanar volumetric modulated arc therapy (NC-VMAT) and investigate its dosimetric advantages compared with intensity modulated radiation therapy (IMRT) and coplanar volumetric modulated arc therapy (C-VMAT) for hippocampal-avoidance whole brain radiation therapy (HA-WBRT). Methods: Ten patients with brain metastase (BM) were included for HA-WBRT. Three treatment plans were generated for each case using IMRT, C-VMAT, and NC-VMAT, respectively. Results: The dosimetric results of the three techniques complied roughly with the RTOG 0933 criteria. After dose normalization, the V30Gy of whole brain planned target volume (WB-PTV) in all the plans was controlled at 95%. Homogeneity index (HI) of WB-PTV was significantly reduced in NC-VMAT (0.249 ± 0.017) over IMRT (0.265 ± 0.020, p=0.005) and C-VMAT (0.261 ± 0.014, p=0.020). In terms of conformity index (CI), NC-VMAT could provide a value of 0.821 ± 0.010, which was significantly superior to IMRT (0.788 ± 0.019, p<0.001). According to D2% of WB-PTV, NC-VMAT could provide a value of 35.62 ± 0.37Gy, significantly superior to IMRT (36.43 ± 0.65Gy, p<0.001). According to D50% of WB-PTV, NC-VMAT can achieve the lowest value of 33.18 ± 0.29Gy, significantly different from IMRT (33.47 ± 0.43, p=0.034) and C-VMAT (33.58 ± 0.37, p=0.006). Regarding D2%, D98%, and Dmean of hippocampus, NC-VMAT could control them at 15.57 ± 0.18Gy, 8.37 ± 0.26Gy and 11.71 ± 0.48Gy, respectively. D2% and Dmean of hippocampus for NC-VMAT was significantly lower than IMRT (D2%: 16.07 ± 0.29Gy, p=0.001 Dmean: 12.18 ± 0.33Gy, p<0.001) and C-VMAT (D2%: 15.92 ± 0.37Gy, p=0.009 Dmean: 12.21 ± 0.54Gy, p<0.001). For other organs-at-risk (OARs), according to D2% of the right optic nerves and the right lenses, NC-VMAT had the lowest values of 31.86 ± 1.11Gy and 7.15 ± 0.31Gy, respectively, which were statistically different from the other two techniques. For other organs including eyes and optic chiasm, NC-VMAT could achieve the lowest doses, different from IMRT statistically. Conclusion: The dosimetry of the three techniques for HA-WBRT could roughly comply with the proposals from RTOG 0933. After dose normalization (D95%=30Gy), NC-VMAT could significantly improve dose homogeneity and reduce the D50% in the brain. Besides, it can reduce the D2% of the hippocampus, optic nerves, and lens. With this approach, an efficient and straightforward plan was accomplished. [ABSTRACT FROM AUTHOR]

Introduction: We aim to evaluate the use of different whole brain radiation therapy (WBRT) fractionation schedules for brain metastases (BM) in Victoria, and the factors associated with it. Methods: This is a population‐based cohort of patients who received radiation therapy for BM between 2012 and 2017, as captured in the Victorian Radiotherapy Minimum Dataset. We excluded patients with primary brain tumour and those who had 'prophylactic' intent treatment. The Cochran–Armitage test was used to evaluate changing trend in WBRT fractionation. Multivariate multinomial logistic regressions were used to evaluate factors associated with WBRT fractionation. Results: Of the 3111 patients who had WBRT, 1048 (45%), 1291 (42%) and 312 (13%) had ≤5, 6–10 and >10 fractions WBRT respectively. There was progressive increase in ≤5 fractions WBRT use over time, from 37% in 2012 to 50% in 2017 (P‐trend < 0.001). In multivariate analyses, increasing age, patients with gastrointestinal cancer, patients living in remote/regional areas and more recent treatment were associated with the use of shorter WBRT fractionation (≤5 fractions), while patients who had WBRT plus stereotactic radiosurgery, and those treated in private institutions were associated with the use of prolonged WBRT fractionation (≥6 fractions). Three hundred eighty‐nine (13%) patients died within 30 days of WBRT, of which 241 (64%), 119 (32%) and 17 (5%) had ≤5, 6–10 and > 10 fractions WBRT respectively. Conclusion: We observed large variations in WBRT fractionation that are associated with patient, tumour, treatment and institutional factors. It is important to continuously monitor and benchmark our practice in order to reduce potentially unwarranted variations. [ABSTRACT FROM AUTHOR]

Breast cancer, along with lung cancer and melanoma, is one of the most common origins of central nervous system metastases. Due to improvement of systemic therapy options for primary disease and consequential prolonged survival, treatment of brain metastasis (BM) is presenting an evolving challenge. While new systemic therapy approaches for breast cancer brain metastasis are focusing on overcoming the blood brain and blood tumor barrier, as well as targeted therapies, local therapy remains the primary line of treatment. The decision of which local therapies to use, depends upon the number and volume of BM, their localization, patient’s clinical status, previously used treatments, status of extracranial disease and patient’s prognosis. In cases when an active approach, including surgery and/or radiotherapy, does not bring benefit to the patient’s quality of life or overall survival, best supportive care is recommended.

Primary central nervous system lymphoma (PCNSL) is a rare malignancy. Standard of care is upfront high-dose methotrexate (HD-MTX) chemotherapy, while cranial radiation is more commonly used in the salvage setting. In this retrospective study, we aimed to investigate the safety and efficacy of salvage cranial radiation in PCNSL. PCNSL patients who received upfront HD-MTX chemotherapy and salvage cranial radiation after treatment failure between 1995 and 2018 were selected. Radiological response to cranial radiation was assessed as per Response Assessment in Neuro-Oncology Criteria. Twenty one patients were selected (median age 59.9 years), with median follow-up of 19.9 months. Fourteen patients (66.7%) received a boost to the gross tumour volume (GTV). Four patients (19.0%) sustained grade ≥2 treatment-related neurotoxicity post-completion of cranial radiation. Of the 19 patients who had requisite MRI with gadolinium imaging available for Response Assessment in Neuro-Oncology (RANO) criteria assessment, 47.4% achieved complete response, 47.4% achieved partial response, and 5.3% of patients exhibited stable disease. Higher dose to the whole brain (>30 Gy) was associated with higher rate of complete response (63.6%) than lower dose (≤30 Gy, 37.5%), while boost dose to the gross disease was also associated with higher rate of complete response (61.5%) compared with no boost dose (33.3%). Median overall survival was 20.0 months. PCNSL patients who relapsed following upfront chemotherapy showed a high rate of response to salvage cranial radiation, especially in those receiving greater than 30 Gy to the whole brain and boost to gross disease. [ABSTRACT FROM AUTHOR]

Brain radiation is a crucial tool in neuro-oncology for enhancing local tumor control, but it can lead to mild-to-profound and progressive impairments in cognitive function. Radiation-induced brain injury is a significant adverse effect of radiotherapy for cranioencephalic tumors, primarily caused by indirect cellular damage through the formation of free radicals. This results in late neurotoxicity manifesting as cognitive impairment due to free radical production. The aim of this review is to highlight the role of different substances, such as drugs used in the clinical setting and antioxidants such as ascorbate, in reducing the neurotoxicity associated with radiation-induced brain injury. Currently, there is mainly preclinical and clinical evidence supporting the benefit of these interventions, representing a cost-effective and straightforward neuroprotective strategy., Competing Interests: Conflicts of InterestThe authors declare that they have no competing interests., (© 2024 by the authors.)

Background: Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for brain metastasis (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. Our aim was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada., Methods: This population-based, retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 1, 2010, and March 31, 2018. Data were analysed between June 2, 2022, and December 20, 2023. Patients with second cancer diagnosis were excluded. Patients were identified and data retrieved from the Institute for Clinical Evaluative Sciences (ICES) databases. Kaplan-Meier and multivariable Cox regression analyses were performed to compare OS between patient cohorts stratified by disease stage, BM diagnosis, and intracranial treatment modality. Propensity score-matching based on age, disease stage, time to BM, and receipt of chemotherapy was performed to compare OS between intracranial treatment modalities., Findings: 8705 patients were included (male: 4433, female: 4272). Median age at diagnosis was 68 years (interquartile range, IQR, 61-75). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23-7.69). 32% (n = 2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) with median OS of 9.76 months (95% CI, 9.36-10.22). 102 (4%), 1654 (62%), and 930 (35%) patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS from time of BM diagnosis was non-inferior between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 0.68, 95% CI, 0.44-1.06, p = 0.091, n = 86) and in favour of SRS for those who received PCI prior to BM development (HR, 0.47, 95% CI, 0.31-0.72, p = 0.0042, n = 112)., Interpretation: OS for patients with SCLC remains poor, and many patients present with BM. With careful selection, patients with SCLC and BM may benefit from SRS treatment. Future research should incorporate information on burden of intracranial disease and novel immunotherapies., Funding: None., Competing Interests: IBM declares honoraria from Bristol-Myers Squibb, Agence Unik, AstraZeneca, and Merck. IBM is on the Advisory board for InSightec and received trainee funding from Takeda, AstraZeneca, and BMS as well as research funding from AstraZeneca. BHL declares institutional grants from AstraZeneca and Pfizer and honoraria and support for travel/attending meetings from AstraZeneca. AS received a research grant and acted as a consultant for Elekta/Elekta AB and BrainLab. AS received Honoraria for educational seminars from Elekta/Elekta AB, Varian, BrainLab, AstaZeneca, Seagen Inc, Cerapedics, and CarboFIX. AS was reimbursed for travel expenses by Elekta/Elekta AB, Varian, and BrainLab. AS received research grants from Seagen Inc and is Vice President for the International Stereotactic Radiosurgery Society. SD has received grant funding from the Canadian Institutes of Health Research, Gratitude 10, the Canadian Cancer Society, the Calum Macbeth fund and the Keenan Chair in Surgery. SD received royalties from Oxford University Press. SD reports support for travel and accommodation from the Congress of Neurological Surgeons and the American Association of Neurological Surgeons. SD participated on a data safety monitoring board or advisory board for the Subcortical Surgery Group and XPan Medical. SD is the Provincial Lead for CNS Cancers at Ontario Health, Cancer Care Ontario. SD receives research support from the Keenan Chair in Surgery. KG, AWE, SC, and KKWC declare no competing interests., (© 2024 The Author(s).)

Brain metastases are the most common intracranial neoplasm and are seen in upwards of 10-30% of patients with cancer. For decades, whole brain radiation therapy (WBRT) was the mainstay of treatment in these patients. While WBRT is associated with excellent rates of intracranial tumor control, studies have demonstrated a lack of survival benefit, and WBRT is associated with higher rates of cognitive deterioration and detrimental effects on quality of life. In recent years, strategies to mitigate this risk, such as the incorporation of memantine and hippocampal avoidance have been employed with improved results. Furthermore, stereotactic radiosurgery (SRS) has emerged as an appealing treatment option over the last decade in the management of brain metastases and is associated with superior cognitive preservation and quality of life when compared to WBRT. This review article evaluates the pathogenesis and impact of cranial irradiation on cognition in patients with brain metastases, as well as current and future risk mitigation techniques. [ABSTRACT FROM AUTHOR]

Abstract Objectives This study aimed to explore the spatial distribution of brain metastases (BMs) from small cell lung cancer (SCLC) a homogenous sample, and to identify the metastatic risk levels in brain regions. Methods T1-enhanced magnetic resonance imaging (MRI) from SCLC patients were retrospectively reviewed from three medical institutions in China. All images were registered to the standard brain template provided by the Montreal Neurological Institute (MNI) 152 database, followed by transformation of the location of all BMs to the space of standard brain. The MNI structural atlas and Anatomical Automatic Labeling (AAL) atlas were then used to identify the anatomical brain regions, and the observed and expected rates of BMs were compared using 2-tailed proportional hypothesis testing. The locations and sizes of brain lesions were analyzed after image standardization. Results A total of 215 eligible patients with 1033 lesions were screened by MRI, including 157 (73%) males and 58 (27%) females. The incidence of crucial structures were as follows: hippocampus 0.68%, parahippocampal 0.97%, brainstem 2.05%, cauate 0.68%, putamen 0.68%, pallidum 0.2%, thalamus 1.36%. No BMs were found in the amygdala, pituitary gland, or pineal gland. The cumulative frequency of the important structures was 6.62%. Based on the results of MNI structural atlas, the cerebellum, deep white matter and brainstem was identified as a higher risk region than expected for BMs (P = 9.80 ×10−15, 9.04 ×10−6), whereas temporal lobe were low-risk regions (P = 1.65 ×10−4). More detailed AAL atlas revealed that the low-risk regions for BMs was inferior frontal gyrus (P = 6.971 ×10−4), while the high-risk regions for BMs was cerebellar hemispheres (P = 1.177 ×10−9). Conclusion Many crucial structures including the hippocampus, parahippocampus, pituitary gland and thalamus etc. have low frequency of brain metastases in a population of SCLC patients. This study provides the help to investigate the clinical feasibility of HA-WBRT and non-uniform dose of PCI in a population of SCLC patients.

Brain metastases are the most common intracranial neoplasm and are seen in upwards of 10-30% of patients with cancer. For decades, whole brain radiation therapy (WBRT) was the mainstay of treatment in these patients. While WBRT is associated with excellent rates of intracranial tumor control, studies have demonstrated a lack of survival benefit, and WBRT is associated with higher rates of cognitive deterioration and detrimental effects on quality of life. In recent years, strategies to mitigate this risk, such as the incorporation of memantine and hippocampal avoidance have been employed with improved results. Furthermore, stereotactic radiosurgery (SRS) has emerged as an appealing treatment option over the last decade in the management of brain metastases and is associated with superior cognitive preservation and quality of life when compared to WBRT. This review article evaluates the pathogenesis and impact of cranial irradiation on cognition in patients with brain metastases, as well as current and future risk mitigation techniques.

Abstract Background Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models. Methods Patients received WBRT to 25–40 Gy in 10–20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0–100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman–Kutcher–Burman (LKB) and Relative Seriality (RS) NTCP models. Results Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V10Gy–V20Gy correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69–0.71 for bother score. The values for the D50, m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D50, γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V10Gy–V15Gy were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively. Conclusions Xerostomia was most associated with parotid V10Gy–V20Gy, and dry eye with lacrimal V10Gy–V15Gy. NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT.

• Trametinib is a MEK inhibitor with intracranial activity used for BRAF+ disease. • Even subtherapeutic trametinib doses are toxic with whole brain radiation therapy. • The overall response rate was 33% with a median survival of 2.2 months. Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1–3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. 10 patients were enrolled (median age-59 [47–64], BM-5 [1–10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3–4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study. [ABSTRACT FROM AUTHOR]

Abstract Background: This technical note aims to verify the hippocampus and adjacent organs at risk (OARs) sparing ability of an improved beam arrangement, namely hybrid split-arc partial-field volumetric modulated arc therapy (VMAT) (Hsapf-VMAT) during whole brain radiation therapy (WBRT). Materials and methods: Computed tomography simulation images of 22 patients with brain metastases were retrieved in this retrospective planning study. The hippocampus was manually delineated according to the criterion of RTOG 0933. Plans delivering 30 Gy in 10 fractions were generated for each patient using split-arc partial-field VMAT (sapf-VMAT) and Hsapf-VMAT. The sapf-VMAT plans consisted of 4 arc fields of 179.9° each with reduced field size. The Hsapf-VMAT consisted of 4 arc fields similar to sapf-VMAT in addition to 2 lateral opposing static fields. Statistical comparisons between treatment plans of both techniques were performed using the paired t-test at 5% level significance. Results: The results demonstrated that Hsapf-VMAT can achieve superior dose sparing in hippocampus which is comparable to sapf-VMAT (p > 0.05). In both eyes, Hsapf-VMAT had significantly lower Dmean and Dmax compared to sapf-VMAT (p < 0.005). Decrease in Dmax of both lenses using Hsapf-VMAT (p < 0.005) were statistically significant when compared to sapf-VMAT. Hsapf-VMAT demonstrated significant reduction of Dmean and Dmedian to the optic nerves (p < 0.05). Whole brain planning target volume (PTV) coverage was not compromised in both techniques. Conclusion: The present study adopts a hybrid technique, namely Hsapf-VMAT, for hippocampal sparing WBRT. Hsapf-VMAT can achieve promising dose reduction to the hippocampus, both eyes and lenses. Therefore, Hsapf-VMAT can be considered an improved version of sapf-VMAT. [ABSTRACT FROM AUTHOR]

Radiotherapy for brain metastases has evolved tremendously over the past four decades, allowing for improved intracranial control of disease with reduced neurotoxicity. The main technological advance was provided by volumetric modulated arc therapy (VMAT), a computer-controlled delivery method that has opened the door for single-isocenter multi-metastases stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Other notable advances have occurred in the combination of immune checkpoint inhibitors (ICI) and radiosurgery. When these two modalities are combined in the proper sequence (within 30 days from each other), it provides promising results in the treatment of intracranial metastases from melanoma. There is emerging evidence of a synergistic interaction between ICI and SRS, providing better intracranial tumor control and lengthening the survival of patients afflicted by this common complication of cancer. [ABSTRACT FROM AUTHOR]

Abstract 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).

Abstract Background Although whole brain radiation therapy (WBRT) provides palliation and prophylaxis, reduces local recurrence probability and improves overall survival, it is evident that WBRT is associated with neurocognitive deficits due to radiation induced damage of the hippocampus. Therefore, minimizing hippocampal dose to the least possible level is of high clinical relevance. In dual-arc conventional volumetric modulated arc therapy (dac-VMAT), the large irradiation field for whole brain planned target volume (PTV) requires a wide jaw opening in which substantial low dose volume to the hippocampus may be produced due to suboptimal multi-leaf collimator (MLC) movements. The present study investigates the potential of a radiation therapy technique with split-arc and reduced field size, namely split-arc partial-field volumetric modulated arc therapy (sapf-VMAT) to spare the hippocampus during WBRT. Methods Computed tomography and magnetic resonance images of 20 patients with brain metastases were retrieved in this retrospective planning study. The hippocampus was manually delineated by single radiation oncologist strictly following the RTOG 0933 atlas definition. Plans delivering 30 Gy in 10 fractions were generated for each patient using dac-VMAT and sapf-VMAT. Dosimetric parameters from both techniques were compared by paired t-test. Results The results demonstrated that radiation dose to the hippocampus was significantly reduced using sapf-VMAT relative to dac-VMAT plans. sapf-VMAT (7.86Gy, p = 0.001) had significantly lowered average D100% compared to dac-VMAT (9.23 Gy). Decrease in hippocampus Dmax using sapf-VMAT (13.23 Gy, p = 0.001) was statistically significant when compared to dac-VMAT (16.33 Gy). The resulting mean dose to the hippocampus was 9.16 Gy for the for sapf-VMAT. Mean dose of sapf-VMAT was significantly lower than dac-VMAT (10.85 Gy, p

Abstract Background We sought to construct the optimal neurocognitive function (NCF) change criteria sensitive to health-related quality of life (HR-QOL) in patients who have undergone whole-brain radiation therapy (WBRT) for brain metastasis. Methods We categorized the patients by the changes of NCF into groups of improvement versus deterioration if at least one domain showed changes that exceeded the cut-off while other domains remained stable. The remaining patients were categorized as stable, and the patients who showed both significant improvement and deterioration were categorized as ‘both.’ We examined the clinical meaning of NCF changes using the cut-off values 1.0, 1.5, and 2.0 SD based on the percentage of patients whose HR-QOL changes were ≥ 10 points. Results Baseline, 4-month and 8-month data were available in 78, 41 (compliance; 85%), and 29 (81%) patients, respectively. At 4 months, improvement/stable/deterioration/both was seen in 15%/12%/41%/32% of the patients when 1.0 SD was used; 19%/22%/37%/22% with 1.5 SD, and 17%/37%/37%/9% with 2.0 SD. The HR-QOL scores on the QLQ-C30 functional scale were significantly worse in the deterioration group versus the others with 1.0 SD (p = 0.013) and 1.5 SD (p = 0.015). With 1.5 SD, the HR-QOL scores on the QLQ-BN20 was significantly better in the improvement group versus the others (p = 0.033). However, when ‘both’ was included in ‘improvement’ or ‘deterioration,’ no significant difference in HR-QOL was detected. Conclusions The NCF cut-off of 1.5 SD and the exclusion of ‘both’ patients from the ‘deterioration’ and ‘improvement’ groups best reflects HR-QOL changes.

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p=0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p=0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p=0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p =0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p =0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p =0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p <0.001] significantly impacted survival after diagnosis of CNS metastases. In a subgroup analysis, superior survival was observed in patients with CNS involvement not in first tumor recurrence who underwent GKS-based combination therapeutic regimens. The survival benefit of GKS-based treatment was not significant in patients with CNS involvement in first disease relapse, but a trend for longer survival was still observed. In conclusion, GKS-based combination treatment can be considered for the treatment of EOC patients with CNS metastases. The patients with CNS involvement not in first disease relapse could significantly benefit from GKS-based combination strategies. [ABSTRACT FROM AUTHOR]

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Abstract Background Different management options exist for patients with brain metastases from non-small cell lung cancer (NSCLC), patients whose treatment with whole brain radiotherapy (WBRT) has become more controversial over the last decade. It is not trivial to find the optimal balance of over- versus undertreatment in these patients. Several recent trials, including the randomized QUARTZ trial now influence the decision to recommend or withhold WBRT for patients with unfavorable prognosis, and similarly, for favorable prognosis patients, the balance between radiosurgery alone or WBRT has become a nuanced decision. Additionally, the availability of intracranially active targeted agent for some subsets of these patients has added another layer of complexity to the decision-making. Methods A multinational consortium of expert radiation oncologists was established with the aim of compiling treatment recommendations for challenging scenarios, in this case the choice between optimal supportive care (SC), WBRT and other types of radiation therapy (RT). We distributed 17 cases to 7 radiation oncologists who were allowed to involve coworkers to provide their treatment recommendations. The cases differed in extra- and intracranial disease extent, histology, age and other prognostic factors. Expert recommendations were tabulated with the aim of providing guidance. Results Regarding willingness to include the 17 patients in the QUARTZ trial, the rates of trial inclusion were low (range 0/7 to 3/7). Experts not recommending trial inclusion provided their treatment recommendations. These suggestions differed widely for most of the patients. It was not uncommon to see 3 or 4 different recommendations. In general, few (0–2) recommended SC. Some kind of local treatment was suggested by the majority of experts for all 17 patients. Commonly, stereotactic single-fraction radiosurgery (SRS) or stereotactic fractionated radiotherapy (SFRT) were recommended by many experts, also for patients with 5–7 lesions. The highest proportion of recommendations towards WBRT in any patient was 3/7. It was also quite common for patients with multiple metastases of varying size that experts suggested combinations of resection, post-operative SRS/SFRT and SRS/SFRT to intact lesions. Despite recommending active treatment, experts were often willing to include the patients in a hypothetical protocol investigating radiotherapy utilization in the last 30 days of life (assessment of factors predicting early death). Conclusions WBRT was infrequently recommended. Even in patients with adverse prognostic features that raised the experts’ awareness of an increased risk for futile treatment near the end of life, SRS/SFRT were more often recommended than optimal supportive care, unless a patient decided to forego active treatment.

Abstract Background The role of the dose escalation strategy in brain radiotherapy for small cell lung cancer (SCLC) patients with brain metastases (BMs) has not been identified. This study aims to determine whether an additional radiation boost to whole brain radiation therapy (WBRT) has beneficial effects on overall survival (OS) compared with WBRT-alone. Methods A total of 82 SCLC patients who were found to have BMs treated with WBRT plus a radiation boost (n = 33) or WBRT-alone (n = 49) from January 2008 to December 2015 were retrospectively analyzed. All patients were limited-stage (LS) SCLC at the time of the initial diagnosis, and none of them had extracranial metastases prior to detection of BMs. The primary end point was OS. Results The median OS for all of the patients was 9.6 months and the 6-, 12- and 24-months OS rates were 69.1, 42.2 and 12.8%, respectively. At baseline, the proportion of more than 3 BMs was significantly higher in the WBRT group than in the WBRT plus boost group (p = 0.0001). WBRT plus a radiation boost was significantly associated with improved OS in these patients when compared with WBRT-alone (13.4 vs. 8.5 months; p = 0.004). Further, the survival benefit still remained significant in WBRT plus boost group among patients with 1 to 3 BMs (13.4 vs. 9.6 months; p = 0.022). Conclusion Compared with WBRT-alone, the use of WBRT plus a radiation boost may prolong survival in SCLC patients with BMs. The dose escalation strategy in brain radiotherapy for selected BMs patients with SCLC should be considered.

• ECOG performance status 0 or 1 is the best prognostic factor. • Single BM and less than 3 chemotherapy lines are also good prognostic factors. • GI-GPA and DS-GPA are relevant scores for brain metastases from colorectal cancer. Brain metastases (BMs) from colorectal cancer (CRC) are rare (≈2%) but are increasing with the improvement of CRC prognosis. The main objective of this study was to evaluate the prognostic factors of BM from CRC. This multicenter retrospective study included all consecutive patients with BM from CRC diagnosed between 2000 and 2017. Prognostic factors of OS were evaluated in univariate (log-rank test) and multivariate analyses (Cox regression model). These prognostic factors could help the management of patients with BM from CRC. A total of 358 patients were included with a median age of 65.5 years. Primary tumors were mostly located in the rectum (42.4%) or left colon (37.2%) and frequently KRAS -mutated (56.9%). The median time from metastatic CRC diagnosis to BM diagnosis was 18.5 ± 2.5 months. BMs were predominantly single (56.9%) and only supratentorial (54.4%). BM resection was performed in 33.0% of the cases and 73.2% of patients had brain radiotherapy alone or after surgery. Median OS was 5.1 ± 0.3 months. In multivariate analysis, age under 65 years, ECOG performance status 0–1, single BM and less than 3 chemotherapy lines before BM diagnosis were associated with better OS. Prognostic scores, i.e. recursive partitioning analysis (RPA), Graded Prognostic Assessment (GPA), Disease Specific-Graded Prognostic Assessment (DS-GPA), Gastro-Intestinal-Graded Prognostic Assessment (GI-GPA) and the nomogram were statistically significantly associated with OS but the most relevant prognosis criteria seemed the ECOG performance status 0–1. ECOG performance status, number of BM and number of chemotherapy lines are the most relevant factors in the management of patients with BM from CRC. [ABSTRACT FROM AUTHOR]

Background: Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models.Methods: Patients received WBRT to 25-40 Gy in 10-20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0-100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models.Results: Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V10Gy-V20Gy correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69-0.71 for bother score. The values for the D50, m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D50, γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V10Gy-V15Gy were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively.Conclusions: Xerostomia was most associated with parotid V10Gy-V20Gy, and dry eye with lacrimal V10Gy-V15Gy. NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT. [ABSTRACT FROM AUTHOR]

Whole brain irradiation (WBI) therapy is an important treatment for brain metastases and potential microscopic malignancies. WBI promotes progressive cognitive dysfunction in over half of surviving patients, yet, the underlying mechanisms remain obscure. Astrocytes play critical roles in the regulation of neuronal activity, brain metabolism, and cerebral blood flow, and while neurons are considered radioresistant, astrocytes are sensitive to γ-irradiation. Hallmarks of astrocyte function are the ability to generate stimulus-induced intercellular Ca2+ signals and to move metabolic substrates through the connected astrocyte network. We tested the hypothesis that WBI-induced cognitive impairment associates with persistent impairment of astrocytic Ca2+ signaling and/or gap junctional coupling. Mice were subjected to a clinically relevant protocol of fractionated WBI, and 12 to 15 months after irradiation, we confirmed persistent cognitive impairment compared to controls. To test the integrity of astrocyte-to-astrocyte gap junctional coupling postWBI, astrocytes were loaded with Alexa-488-hydrazide by patch-based dye infusion, and the increase of fluorescence signal in neighboring astrocyte cell bodies was assessed with 2-photon microscopy in acute slices of the sensory-motor cortex. We found that WBI did not affect astrocyte-to-astrocyte gap junctional coupling. Astrocytic Ca2+ responses induced by bath administration of phenylephrine (detected with Rhod-2/AM) were also unaltered by WBI. However, an electrical stimulation protocol used in long-term potentiation (theta burst), revealed attenuated astrocyte Ca2+ responses in the astrocyte arbor and soma in WBI. Our data show that WBI causes a long-lasting decrement in synaptic-evoked astrocyte Ca2+ signals 12–15 months postirradiation, which may be an important contributor to cognitive decline seen after WBI. [ABSTRACT FROM AUTHOR]

Background: Brain metastasis secondary to gynecologic malignancy is rare and has no definitive management guidelines. In this descriptive study, we aimed to identify prognostic factors and treatments that may be associated with longer overall survival. Methods: Patients with brain metastases from gynecologic malignancies were identified between 2004 and 2019 at two institutions. Descriptive statistics were performed using N (%) and median (interquartile range). Univariate cox proportional hazards regression was performed to evaluate the effect of different factors on overall survival. Results: 32 patients presented with brain metastasis from gynecologic primaries (ovarian/fallopian tube/primary peritoneal n = 14, uterine n = 11, cervical n = 7). Median age of initial cancer diagnosis was 61 (34–79). At initial cancer diagnosis 83% of patients were Stage III/IV and underwent surgery (66%), chemotherapy (100%), and/or pelvic radiation (33%). Median time from initial cancer diagnosis to brain metastasis was 18 months. Treatment of brain metastasis with surgery and radiation compared to stereotactic radiosurgery or whole brain radiation therapy alone revealed a trend toward longer overall survival (p = 0.07). Time from initial cancer diagnosis to brain metastasis was associated with longer overall survival with each one-month increase from initial cancer diagnosis associated with a 7% reduction in risk of death (HR 0.93, 95% CI = 0.89–0.97, p = 0.01). Initial cancer treatment, stage, histology, and number of brain lesions did not affect overall survival. Conclusions: Patients with brain metastasis secondary to gynecologic malignancies with the longest overall survival had the greatest lag time between initial cancer diagnosis and brain metastasis. Brain metastasis treated with surgery and radiation was associated with longer overall survival.

BackgroundOwing to improved systemic therapies, the survival of patients with non-small cell lung cancer (NSCLC) was prolonged, and the risk of brain metastases was consequently increased. This study aims to compare different radiotherapy for brain metastases in patients with NSCLC.Materials and methodsThe patients with NSCLC who were treated with whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases at three medical centers between January 2012 and December 2017 were retrospectively analyzed.ResultsOf the 684 eligible patients, 217 received WBRT plus focal radiation boost (WBRT+boost), 324 received WBRT, and 143 received SRS. Patients with WBRT+boost lived longer than those with WBRT (median overall survival (OS), 22.2 vs 13.7 months, P < 0.001) or SRS (22.2 vs 17.3 months, P = 0.011). In subgroup analyses, the survival advantage of WBRT+boost was more obvious among patients with 1 to 3 brain metastases or who received targeted therapy than did SRS. From pair-wise comparisons of intracranial progression-free survival (iPFS), WBRT+boost was also superior to WBRT (12.9 vs 10.6 months, P = 0.028) and SRS (12.9 vs 9.1 months, P = 0.001).ConclusionsPatients who were treated with WBRT+boost experienced significantly longer OS and iPFS than those with WBRT or SRS alone. WBRT+boost should be a preferred strategy for brain metastases in NSCLC patients.

Abstract Background Gamma Knife radiosurgery (GKRS) is increasingly applied in patients with multiple brain metastases and is expected to have less adverse effects in cognitive functioning than whole brain radiation therapy (WBRT). Effective treatment with the least negative cognitive side effects is increasingly becoming important, as more patients with brain metastases live longer due to more and better systemic treatment options. There are no published randomized trials yet directly comparing GKRS to WBRT in patients with multiple brain metastases that include objective neuropsychological testing. Methods CAR-Study B is a prospective randomised trial comparing cognitive outcome after GKRS or WBRT in adult patients with 11–20 newly diagnosed brain metastases on a contrast-enhanced MRI-scan, KPS ≥70 and life expectancy of at least 3 months. Randomisation by the method of minimization, is stratified by the cumulative tumour volume in the brain, systemic treatment, KPS, histology, baseline cognitive functioning and age. The primary endpoint is the between-group difference in the percentage of patients with significant memory decline at 3 months. Secondary endpoints include overall survival, local control, development of new brain metastases, cognitive functioning over time, quality of life, depression, anxiety and fatigue. Cognitive functioning is assessed by a standardised neuropsychological test battery. Assessments (cognitive testing, questionnaires and MRI-scans) are scheduled at baseline and at 3, 6, 9, 12 and 15 months after treatment. Discussion Knowledge gained from this trial may be used to inform individual patients with BM more precisely about the cognitive effects they can expect from treatment, and to assist both doctors and patients in making (shared) individual treatment decisions. This trial is currently recruiting. Target accrual: 23 patients at 3-months follow-up in both groups. Trial registration The Netherlands Trials Register number NTR5463. ClinicalTrials.gov registration number NCT02953717, first received October 27, 2016, 8 patients were enrolled in this study on 31 July 2017.

Target populationThis recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain.RecommendationShould patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.

Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). Recommendation Surgical resection plus WBRT versus WBRT alone Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases. If WBRT is used, is there an optimal dosing/fractionation schedule? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Level 1 Class I evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control or neurocognitive outcomes when compared with “standard” WBRT dose/fractionation. (i.e., 30 Gy in 10 fractions or a biologically effective dose (BED) of 39 Gy10). If WBRT is used, what impact does tumor histopathology have on treatment outcomes? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Given the extremely limited data available, there is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology.The following question is fully addressed in the surgery guideline paper within this series by Kalkanis et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of WBRT in the management of brain metastases, this recommendation has been included below. Does the addition of WBRT after surgical resection improve outcomes when compared with surgical resection alone? Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection. Recommendation Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone.