Parsons, Michael

Abstract Background Multi-modality therapy has improved survival for many patients with brain metastases. However, neurocognitive sequelae remain a challenge. While advances in radiotherapy have reduced toxicity, the potential interaction with targeted therapy and immunotherapy and the consequent impact on neurocognitive outcomes remain poorly defined. We appraised the current evidence on neurocognitive outcomes in the era of modern combined-modality therapy. Methods This systematic review adhered to PRISMA guidelines and included clinical trials reporting neurocognitive outcomes in patients with brain metastases receiving radiotherapy ± concurrent systemic therapies. Studies published through December 31, 2024 were identified through PubMed/Medline, EMBASE, and Web of Science using pre-defined MeSH term-based search strings. Results 39 studies from 1997-2024 involving 6,617 patients met inclusion criteria (n = 27 whole-brain radiotherapy [WBRT]; n = 12 radiosurgery), including six studies evaluating combined-modality therapy in 1,161 patients. Baseline cognitive evaluation was performed inconsistently, but neurocognitive deficits were frequently observed prior to treatment. Most randomized trials reported improved cognitive outcomes and quality of life with advanced radiotherapy techniques (e.g., hippocampal avoidance, radiosurgery) vs WBRT. Among 20 randomized trials comparing radiotherapy with or without a concurrent investigational systemic therapy, only four included neurocognitive assessments. There was no evidence of cognitive sequelae with combined-modality therapy, though evaluable trials were limited due to inconsistent reporting of neurocognitive functioning. Conclusion As survival improves in patients with brain metastases, preserved cognition is an important outcome measure. The lack of neurocognitive endpoints in pivotal brain metastasis trials represents a critical evidence gap. The interaction between radiotherapy and novel systemic therapies, and their combined effects on neurocognition, remain unknown. To address this, we recommend 1) integrating sensitive, pragmatic, and tailored neurocognitive assessments into oncology trials to quantify additive toxicity, 2) early and systematically incorporating neuropsychology into care pathways, 3) expanding radiation dose-sparing and radioprotective strategies, and 4) evaluating the utility of cognitive rehabilitation programs.

Importance Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. Objective To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. Design, Setting, and Participants Phase 3, open-label, randomized clinical trial conducted at 4 United States–based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). Intervention Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. Main Outcomes and Measures Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory–Brain Tumor instrument (scale, 0-10; score change range, −10 to 10; −10 = best). A clinically meaningful Δ was defined as 0.98. Results Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory–Brain Tumor score from 2.69 to 2.37 (mean change, −0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, −1.06 [95% CI, −1.54 to −0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). Conclusions and Relevance In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT03075072

2011 Background: Radiation therapy forms the mainstay of management for patients with brain metastases. Published randomized trials have found improved quality of life with stereotactic radiation (SRS/SRT) over whole brain radiation (WBRT) in patients with ≤ 4 brain metastases; comparative trials in patients with >4 brain metastases are lacking. In addition, prior randomized trials have demonstrated the superiority of hippocampal avoidance WBRT (HA-WBRT) over traditional WBRT, but no study has compared SRS/SRT to HA-WBRT. Accordingly, we conducted a multicenter, phase 3 randomized trial comparing SRS/SRT to HA-WBRT in patients with 5-20 brain metastases. Methods: Eligible patients were age 18-80 with 5-20 brain metastases secondary to a solid primary other than small cell lung cancer, were naïve to prior brain-directed radiation, and lacked leptomeningeal disease. The primary endpoint was the average of patient-reported symptom severity and interference over the first six months post-baseline relative to baseline, using the MD Anderson Symptom Inventory–Brain Tumor (MDASI-BT) module, a validated instrument assessing 22 symptoms and 6 interference measures integral to quality of life, each scored 0-10 with higher scores indicating greater symptomatology/interference in function. The target effect size was a symptom severity of 0.70, corresponding to 50% of the observed difference between patients with a good (90-100) versus poor (≤80) Karnofsky performance status; with 80% power and a two-sided alpha of 0.05, 196 patients were required. Results: Between 4/2017-5/2024, 196 patients enrolled, 98 in each arm. The median number of brain metastases was 14 (IQR 11-18); 25% of patients underwent prior neurosurgical resection. Baseline mean MDASI-BT symptom severity scores were 2.2 (SRS/SRT arm) and 1.9 (HA-WBRT arm), p=0.20; respective interference scores were 3.5 and 3.2 (p=0.40). The average of weighted post-baseline severity and interference scores relative to baseline indicated lower symptomatology/inference in the SRS/SRT arm, meeting the primary endpoint of the study (difference between SRS/SRT and HA-WBRT: -1.06, p<0.001). Averaged post-baseline symptom severity scores minus baseline were -0.03 and 0.59 in the SRS/SRT and HA-WBRT arms, respectively (difference -0.62, with lower symptom severity in the SRS/SRT arm, p<0.001); respective interference estimates were -0.62 and 0.89 (difference -1.50, with lower interference in the SRS/SRT arm, p<0.001). Median survival was 8.3 and 8.5 months in the SRS/SRT and HA-WBRT arms, respectively (p=0.30). Conclusions: This phase 3 randomized trial indicates that patients with 5-20 brain metastases experience fewer symptoms and less interference in function after SRS/SRT as opposed to HA-WBRT, without compromise of survival, supporting SRS/SRT as the standard of care in this population. Clinical trial information: NCT03075072 .

Abstract Brain metastases occur commonly in patients with advanced solid malignancies. Yet, less is known about brain metastases than cancer-related entities of similar incidence. Advances in oncologic care have heightened the importance of intracranial management. Here, in this consensus review supported by the Society for Neuro-Oncology (SNO), we review the landscape of brain metastases with particular attention to management approaches and ongoing efforts with potential to shape future paradigms of care. Each coauthor carried an area of expertise within the field of brain metastases and initially composed, edited, or reviewed their specific subsection of interest. After each subsection was accordingly written, multiple drafts of the manuscript were circulated to the entire list of authors for group discussion and feedback. The hope is that the these consensus guidelines will accelerate progress in the understanding and management of patients with brain metastases, and highlight key areas in need of further exploration that will lead to dedicated trials and other research investigations designed to advance the field.

Abstract Neurocognitive function (NCF) deficits are common in patients with brain metastases, occurring in up to 90% of cases. NCF deficits may be caused by tumor-related factors and/or treatment for the metastasis, including surgery, radiation therapy, chemotherapy, and immunotherapy. In recent years, strategies to prevent negative impact of treatments and ameliorate cognitive deficits for patients with brain tumors have gained momentum. In this review, we report on research that has established the efficacy of preventative and rehabilitative therapies for NCF deficits in patients with brain metastases. Surgical strategies include the use of laser interstitial thermal therapy and intraoperative mapping. Radiotherapy approaches include focal treatments such as stereotactic radiosurgery and tailored approaches such as hippocampal avoidant whole-brain radiotherapy (WBRT). Pharmacologic options include use of the neuroprotectant memantine to reduce cognitive decline induced by WBRT and incorporation of medications traditionally used for attention and memory problems. Integration of neuropsychology into the care of patients with brain metastases helps characterize cognitive patterns, educate patients and families regarding their management, and guide rehabilitative therapies. These and other strategies will become even more important for long-term survivors of brain metastases as treatment options improve.

Following the identification of key molecular alterations that provided superior prognostication and led to the updated 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification, the understanding of glioma behavior has rapidly evolved. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are present in the majority of adult grade 2 and 3 gliomas, and when used in conjunction with 1p/19q codeletion for classification, the prognostic distinction between grade 2 versus grade 3 is diminished. As such, the previously often used term of “low-grade glioma,” which referred to grade 2 gliomas, has now been replaced by the phrase “lower-grade glioma” to encompass both grade 2 and 3 tumors. Additional molecular characterization is ongoing to even further classify this heterogeneous group of tumors. With such a colossal shift in the understanding of lower-grade gliomas, management of disease is being redefined in the setting of emerging molecular-genetic biomarkers. In this article, we review recent progress and future directions regarding the surgical, radiotherapeutic, chemotherapeutic, and long-term management of adult lower-grade gliomas.