Fia Cialdella

Background: Reirradiation is a widely accepted option for second-line treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. Hypofractionation is aimed at reducing patients’ burden while maintaining the survival benefit, but may increase the risk of radionecrosis. The primary objective of this study is to determine if reirradiation in just 4 fractions is non-inferior to 10 fractions, regarding survival after reirradiation. Methods: RISING trial A was an open label, randomized, non-inferiority, phase III trial with 1:1 allocation for 130 patients among all participating centers but failed to recruit according to planning. RISING trial B will be a phase II, multi-center, clinical trial with a historic control group. The experimental group receives 4 stereotactic fractions. The historic control group has received 10 fractions (standard-of-care) with a biologically equivalent dose on surrounding brain tissue. The primary endpoint is overall survival after reirradiation. The key secondary endpoint is progression-free survival. Other secondary endpoints are recurrence patterns, toxicity (specifically clinically relevant radionecrosis) and anti-edema treatment. We will collect and report on Health-Related Quality of Life (HRQoL) data in the experimental arm. Discussion: We expect to demonstrate the non-inferiority and safety of a 4-fraction hypofractionation schedule for reirradiation of gliomas. This schedule may then become a standard-of-care option with minimal burden for patients with recurrent glioma, and limited use of scarce healthcare resources. Trial registration: Registered at Netherlands Trial Register (NTR), Trial ID: NL72766.041.20, registered at 07-04-2020, https://www.onderzoekmetmensen.nl/en/trial/52643

Background: Brain metastases (BMs) are often treated with stereotactic radiosurgery (SRS). Even with the high dose fall-off at tumor borders, some dose is delivered outside the BMs to ensure adequate tumor coverage. This may include radiation to the neurogenic niches (ie, subventricular zones [SVZ] and hippocampi), which possibly play a role in neurocognitive functioning (NCF). In this study, we assessed the impact of radiotherapy dose on the SVZ and hippocampi compared with changes in NCF 3 months post-SRS, focusing on memory and information processing speed (IPS) in adult patients with BMs. Methods: Neurocognitive assessments were performed before and 3 months post-SRS, and reliable change indices were calculated to assess NCF changes. The SVZ and hippocampal regions were delineated on pre-SRS T1-weighted MRI images and median radiotherapy dose per region was calculated. Results: Multivariable linear regression analyses in 36 patients corrected for age, previous brain radiotherapy, number of BMs, and previous systemic therapy indicated a significant association between higher hippocampal radiotherapy dose and decline in memory, specifically in Hopkins Verbal Learning Test-Revised immediate recall, delayed recall, and Rey Osterieth Complex Figure Test delayed copy (all P < .05). Conversely, no significant association was found between dose to the SVZ and memory, nor between dose to either region and IPS. Conclusions: These results suggest potential benefits of minimizing radiation exposure to the hippocampi, even with SRS, to help preserve memory in patients with BMs. Further prospective evaluation is warranted to validate these findings and inform clinical decision-making regarding radiotherapy protocols for preserving NCF in this patient population.

BackgroundBrain metastases (BMs) affect >30% of patients with cancer. Beyond survival, quality of life (QoL), and disease progression are critical concerns for both patients and their caregivers. We present the design of COIMBRA (Cohort for patient-reported Outcomes, Imaging, and trial inclusion in Metastatic BRAin disease), clinical characteristics, and pre-radiotherapy QoL data for patients and caregivers. Methods: COIMBRA is an observational, prospective, single-center cohort at UMC Utrecht, the Netherlands, focusing on BMs patients planned for (fractionated) stereotactic radiosurgery (SRS) and their caregivers. We collected clinical characteristics, imaging, and QoL (patient and caregiver) data via patient-reported outcome (PRO) questionnaires. PROs include the EORTC QLQ-C30, BN20, EQ-5D-3L (including VAS), CFQ, HADS, MFI, and CSI. PROs were compared with reference values from the literature for healthy, cancer, and brain tumor populations. Results: From April 2019 to April 2023, 377 patients (50.4% male, median age 66 years) who received stereotactic radiosurgery, were included. Two hundred and seventy-six patients and 115 caregivers consented to PROs. Patients reported lower QoL compared to healthy individuals and primary brain tumor patients, with worse role- and cognitive functioning compared to patients with cancer. Pre-radiotherapy, 1/3 of the caregivers felt overwhelmed. Almost 40% of them report signs of anxiety, which is less than caregivers of cancer or primary brain tumor patients. Conclusions: These data from a large cohort of patients with BMs and their caregivers underscore the unique clinical profile of this vulnerable population. These findings highlight the urgent need for targeted support systems to address unmet needs of both patients and caregivers.

The increasing incidence of brain metastases (BMs) and improved survival rates underscore the necessity to investigate the effects of treatments on individuals. The aim of this study was to evaluate the individual trajectories of subjective and objective cognitive performance after radiotherapy in patients with BMs. The study population consisted of adult patients with BMs referred for radiotherapy. A semi-structured interview and comprehensive neurocognitive assessment (NCA) were used to assess both subjective and objective cognitive performance before, 3 months and ≥ 11 months after radiotherapy. Reliable change indices were used to identify individual, clinically meaningful changes. Thirty-six patients completed the 3-month follow-up, and 14 patients completed the ≥ 11-months follow-up. Depending on the domain, subjective cognitive decline was reported by 11–22% of patients. In total, 50% of patients reported subjective decline in at least one cognitive domain. Intracranial progression 3 months postradiotherapy was a risk-factor for self-reported deterioration (P = .031). Objective changes were observed across all domains, with a particular vulnerability for decline in memory at 3 months postradiotherapy. The majority of patients (81%) experienced both a deterioration as well as improvement (eg, mixed response) in objective cognitive functioning. Results were similar for the long-term follow-up (3 to ≥11 months). No risk factors for objective cognitive change 3 months postradiotherapy were identified. Our study revealed that the majority of patients with BMs will show a mixed cognitive response following radiotherapy, reflecting the complex impact. This underscores the importance of patient-tailored NCAs 3 months postradiotherapy to guide optimal rehabilitation strategies.

Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and this incidence is expected to rise due to advancements in primary tumor management. Besides improving survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions. DESIGN/ The prospective COIMBRA study is designed to monitor a cohort of patients with BMs and their caregivers who are referred to a tertiary academic radiation oncology department (ClinicalTrials.gov Identifier: NCT05267158). The study is designed according to the Trials within Cohorts (TwiCs) framework, an adaptive design that allows for the evaluation of multiple interventions over time. Patients receive state of the art treatment, which includes stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Clinical data, QoL and cognitive functioning are collected at baseline and at regular intervals post-treatment. Additionally, new MRI techniques can be evaluated for their feasibility and performance in patients with BMs. PRELIMINARY Since April 2019, 419 patients have been included of whom 51.2% were men and the majority of the patients had lung cancer (53.6%). SRS was administered in 92.4% and 68.1% received systemic therapy. Median overall survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before treatment (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patients’ diagnosis. Our study successfully collected in-depth clinical and QoL data from patients with BMs and their caregivers. The results suggest a modest improvement in anxiety and QoL after SRS. These findings highlight the need for ongoing evaluation of interventions in this patient population in order to ultimately guide personalized treatment strategies.

Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and the incidence is expected to rise due to advancements in primary tumor management. Besides survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions. COIMBRA is an observational, prospective cohort for patients with brain metastases and their caregivers that are referred to a tertiary academic radiation oncology department. The study is designed according to the Trials within Cohorts (TwiCs) framework. ClinicalTrials.gov Identifier: NCT05267158. Since April 2019, 419 patients have been included of which 51.2% were men and the majority of the patients had lung cancer (53.6%). Stereotactic radiosurgery (SRS) was administered in 92.4% and 68.1% received any systemic therapy. Median Overall Survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patient’s diagnosis. Our study successfully collected clinical and QoL data from a large cohort of patients and their caregivers. The results suggest a modest improvement in anxiety and QoL after radiotherapy.

Radiotherapy is the primary local intervention for cerebral metastases (BMs). Despite decades of advancements in this field, inadvertent collateral irradiation of adjacent healthy tissue in proximity to neoplastic site remains a persistent challenge. Neural stem cells (NSCs), crucial for the establishment and preservation of the nervous system, exhibit heightened sensitivity to radiation. Consequently, radiation-induced damage to NSCs may influence Overall Survival (OS) in patients with BMs. NSCs are primarily located in the subventricular zone (SVZ) and the subgranular zone (SGZ) within the hippocampus (HPC). In this study, our objective is to assess the influence of unintended radiotherapy dose on NSCs and its subsequent effect on OS. In this retrospective study, we incorporated data from 138 Non-Small Cell Lung Cancer (NSCLC) patients with BMs, from a single academic institution. NSC regions were projected on non-enhanced T1 MR images with Computational Anatomy Toolbox 12 and Statistical Parametric Mapping. The association between regional mean doses to the SVZ and HPC and OS was examined using a Cox regression model. Additionally, survival differences between lesion contact and no direct contact with SVZ and HPC were investigated with Kaplan-Meier (KM) analysis. Multivariable Cox regression analysis of the dose on the SVZ and HPC showed a significant negative correlation, with a hazard ratio (HR) of 1.366 (p = 0.041 [95% (CI) 1.013– 1.842]) and 1.194 (p = 0.037 [95% CI 1.010 – 1.411]), respectively. KM analysis did not identify a relationship between direct lesion contact with NSC-regions and OS. Any unintended dose on the neurogenic niches is correlated with poorer OS in patients with BMs from NSCLC. Interestingly, there was no association between direct contact or invasion of these regions and the OS. We recommend conducting further investigation into the impact on neurocognitive function within this specific group in a prospective study design.

INTRODUCTION: Brain metastases (BMs) occur in 10-30% of adult patients with cancer. The therapeutic approach for BMs depends on several factors including lesion number, location and size, primary cancer type, and the patient’s overall health. ASCO-SNO-ASTRO guidelines conditionally recommend stereotactic radiosurgery (SRS) for 1-10 BMs. The aim of this study was to investigate the outcomes of radiotherapy in patients with 5 or more BMs using SRS. METHODS: We implemented the prospective Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) to examine all patients with BM(s) who underwent radiotherapy. In this sub-study we investigated overall survival (OS) and health related quality of life (HRQoL) for 47 patients with 5 to 20 BMs. We evaluated patients’ HRQoL using the EQ5D-VAS, at baseline and at 3 monthly intervals after radiotherapy. RESULTS: Median OS was 21.3 months for patients with 5-10 BMs (n=38) and 12.5 months for patients with >10 BMs (n=9). Questionnaires at both baseline and 6 months after radiotherapy showed stability or improvement on the EQ5D-VAS after radiotherapy in 58.1%. Additionally, independence in self-care was not limited before or after SRS. Also, the proportion of patients (66.7%) reporting no limitation on their ability to do daily activities remained stable after radiotherapy. Fewer patients reported pain or other discomfort after SRS compared to before (25% vs 40%). CONCLUSION: Our findings suggest that radiotherapy may improve QoL in patients with 5-20 BMs. Furthermore, compared to the literature, we observed a prolonged OS in this prospective cohort, suggesting that SRS should be considered as the treatment option for these patients. These results highlight the need for further investigation of the role of SRS instead of Whole Brain Radiotherapy (WBRT) in the management of patients with multiple BMs.