Management Of Brain Metastases Research Articles

Navigating the Complexities of Brain Metastases Management.

The management of brain metastases, a potentially devastating complication of advanced cancers, has become increasingly complex with advancements in local and systemic therapies. Improved outcomes and extended survival for patients with metastatic solid tumors have led to a surge in the prevalence and possibly incidence of brain metastases, affecting up to 40% of individuals with solid tumors. Enhanced imaging technologies contribute to more accurate and early detection, shaping the understanding of the intricate landscape of this condition. Traditionally, surgery and radiation stood as the mainstays of treatment because of the limited efficacy of systemic therapies within the brain. However, emerging clinical data, particularly in melanoma, lung, and breast cancers, reveal promising results with novel systemic treatments such as immunotherapy and targeted therapies. Despite the historical exclusion of patients with active brain metastases from clinical trials, a shift is occurring toward a more inclusive approach. This chapter delves into the multifaceted challenges associated with managing brain metastases, with a focus on the evolving landscape of systemic approaches as well as the intricacies of shared decision making, providing a comprehensive overview of the current state and future directions in navigating the complexities of brain metastases management.

Navigating breast cancer brain metastasis: Risk factors, prognostic indicators, and treatment perspectives

In this editorial, we comment on the article by Chen et al . We specifically focus on the risk factors, prognostic factors, and management of brain metastasis (BM) in breast cancer (BC). BC is the second most common cancer to have BM after lung cancer. Independent risk factors for BM in BC are: HER-2 positive BC, triple-negative BC, and germline BRCA mutation. Other factors associated with BM are lung metastasis, age less than 40 years, and African and American ancestry. Even though risk factors associated with BM in BC are elucidated, there is a lack of data on predictive models for BM in BC. Few studies have been made to formulate predictive models or nomograms to address this issue, where age, grade of tumor, HER-2 receptor status, and number of metastatic sites (1 vs > 1) were predictive of BM in metastatic BC. However, none have been used in clinical practice. National Comprehensive Cancer Network recommends screening of BM in advanced BC only when the patient is symptomatic or suspicious of central nervous system symptoms; routine screening for BM in BC is not recommended in the guidelines. BM decreases the quality of life and will have a significant psychological impact. Further studies are required for designing validated nomograms or predictive models for BM in BC; these models can be used in the future to develop treatment approaches to prevent BM, which improves the quality of life and overall survival.

Abstract PO1-05-01: Cyclin-dependent Kinase 4/6 Inhibitors Combined with Radiotherapy in the Management of Brain Metastases in HR-positive/HER2-negative Breast Cancer Patients

Abstract Purpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy demonstrated overall survival benefits in advanced breast cancer patients (ABC), hormone receptor-positive, HER2-negative (HR+/HER2-) and remains the mainstay in the first and second-line treatment. Brain metastases are rare at the beginning of treatment in this group of patients and are found more often during subsequent lines of treatment and other subtypes of breast cancer. However, there is a paucity of data on the safety and efficacy of multimodality CDK4/6i and radiotherapy treatment in the management of brain metastases. Thus, we performed a retrospective analysis of ABC patients (pts) treated at our institution with radiation therapy to the brain and CDK4/6i. Pts who received radiotherapy before CDK4/6i initiation or concurrently with CDK4/6i (group 1) were compared to the patients who progressed in the brain during CDK4/6i treatment and then received radiotherapy (group 2). The primary endpoint was progression-free survival (PFS) in group 1 vs. group 2; the secondary endpoints were local control (LC) within the brain in group 1 vs. group 2 and severe toxicity. Materials/Methods: Among 379 pts who received CDK4/6i, 26 pts (6.9%) received radiotherapy to the brain. 17 pts received radiotherapy before or concurrent with CDK4/6i and were included in group 1. Nine pts received radiotherapy after CDK4/6i discontinuation due to disease progression and comprised group 2. Results: The median age was 51.5 years (IQR range 41-62). Six pts had de novo metastatic disease. The majority of patients were treated in the first-line setting (15 pts, 58%). 17 pts received ribociclib, 7 palbociclib, and 2 abemaciclib. 15 pts received letrozole as an endocrine compound and 11 pts fulvestrant. 19 pts (73%) received previous chemotherapy. Six pts had an ECOG performance status of 0, 15 pts ECOG 1, and 5 pts ECOG 2. The most common local treatment was whole-brain radiotherapy with a total dose of 20 Gy delivered in 5 fractions (fr) (11 pts: 4 pts VMAT, 2 pts IMRT, 3 pts 3D, and 2 pts 2D). Eight pts received stereotactic radiation therapy (6 pts with Linac: 2 pts 24 Gy/2 fr, 2 pts 24 Gy/3 fr, 2 pts 25 Gy/5 fr; 1 pt GammKnife 20 Gy/1 fr, 1 pt Cyberknife 15 Gy/3 fr). Six- and 12-month PFS in group 1 was 88.2% (95% CI74.1-100) and 58.8% (95% CI: 37.7- 91.8), respectively, whereas in group 2, six- and 12-month PFS was 55.6% (95%CI: 31- 99.7) and 44.4% (95% CI: 21- 92.2), respectively. Six- and 12-month LC in group 1 was 92.3% (95%CI: 78.9-100) and 83.9% (65.7-100), respectively. LC in group 2 was poor: 3-month LC was only 66.7 (30-100). At a median follow-up of 8.8 months, no unanticipated toxicity was reported. Conclusion: Multimodality treatment with CDK4/6i and radiotherapy to the brain is safe and effective. Patients who developed metastases during CDK4/6i treatment tend to have a worse prognosis in comparison to those who received prior radiotherapy. CDK4/6i following radiotherapy seems to be an effective and valuable treatment option in this particular metastatic breast cancer population. Citation Format: Marcin Kubeczko, Dorota Gabryś, Anna Polakiewicz-Gilowska, Aleksandra Krzywon, Donata Gräupner, Barbara Łanoszka, Marta Mianowska-Malec, Aleksandra Leśniak, Katarzyna Świderska, Konstanty Chomik, Barbara Grandys, Michał Jarząb. Cyclin-dependent Kinase 4/6 Inhibitors Combined with Radiotherapy in the Management of Brain Metastases in HR-positive/HER2-negative Breast Cancer Patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-01.

Surgical Management of Brain Metastasis from Esophageal Cancer: A Systematic Review and Single-Center Experience

Brain metastases from esophageal cancer (BMEC) are rare and aggressive, with limited literature on optimal treatment modalities and a standard of care yet to be established. The objective of this study was to systematically review existing literature and perform a retrospective analysis of our institution's patients to evaluate the influence of different treatment modalities on patient outcomes. A systematic review of the literature following PRISMA guidelines and a retrospective review of our institutional experience with BMEC were both conducted. Data based on mean survival based on histology, metastasis location, and treatment modality were abstracted. A total of 48 studies representing 136 patients with BMEC were identified, in addition to the 11 patients treated at our institution. There were a total of 100 males (12 unreported), with a median age of 62.2 at diagnosis in our systematic review, along with 8 males with a median age of 62 in our institutional review. Collectively, survival rates observed based on histology were not similar (squamous cell carcinoma: 9.2 months, adenocarcinoma: 13.4 months), however, based on treatment modalities (surgery: 11.6 months, radiation: 10.4 months, chemotherapy: 12.3 months), and metastasis location (supratentorial: 10.5 months, infratentorial: 9.9 months), the survival times were comparable. Our review suggests that causes of death were often independent of brain metastases highlighting the need for further studies on early detection and prevention of primary esophageal cancer, as well as improved treatment modalities for BMECs.

Efficacy and Safety of Stereotactic Radiosurgery Versus Whole Brain Radiotherapy for the Management of Brain Metastasis: A Systematic Review and Meta-analysis (P4-5.011)

Efficacy and Safety of Stereotactic Radiosurgery Versus Whole Brain Radiotherapy for the Management of Brain Metastasis: A Systematic Review and Meta-analysis (P4-5.011)

Hypofractionated Stereotactic Radiosurgery in the Management of Brain Metastases.

Stereotactic radiosurgery (SRS) is an important weapon in the management of brain metastases. Single-fraction SRS is associated with local control rates ranging from approximately 70% to 100%, which are largely dependent on lesion and postoperative cavity size. The rates of local control and improved neurocognitive outcomes compared with conventional whole-brain radiation therapy have led to increased adoption of SRS in these settings. However, when treating larger targets and/or targets located in eloquent locations, the risk of normal tissue toxicity and adverse radiation effects within healthy brain tissue becomes significantly higher. Thus, hypofractionated SRS has become a widely adopted approach, which allows for the delivery of ablative doses of radiation while also minimizing the risk of toxicity. This approach has been studied in multiple retrospective reports in both the postoperative and intact settings. While there are no reported randomized data to date, there are trials underway evaluating this paradigm. In this article, we review the role of hypofractionated SRS in the management of brain metastases and emerging data that will serve to validate this treatment approach. Pertinent articles and references were obtained from a comprehensive search of PubMed/MEDLINE and clinicaltrials.gov.

Stereotactic Radiosurgery and Stereotactic Fractionated Radiotherapy in the Management of Brain Metastases.

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM patients have changed. Considering and addressing the fact that patients with BM are living longer, the need to provide effective local control while preserving quality of life and neurocognition is fundamental. Over the past decade, SRS and SRT have become a more commonly chosen treatment option for BM. Despite significant advances in the treatment of BM, numerous questions remain regarding patient selection and optimal treatment sequencing. Clinical trials are critical to advancing our understanding of BM, especially as more therapeutic alternatives become available. Therefore, it is imperative for interdisciplinary teams to improve their understanding of the latest advances in SRS-SRT. This review aims to comprehensively explore SRS and SRT as treatments for BM, covering clinical considerations in their application (e.g., patient selection and eligibility), managing limited and multiple intact BM, addressing brainstem metastases, exploring combination therapies with systemic treatments, and considering the health economic perspective.

From pre-clinical to translational brain metastasis research: current challenges and emerging opportunities.

Brain metastasis, characterized by poor clinical outcomes, is a devastating disease. Despite significant mechanistic and therapeutic advances in recent years, pivotal improvements in clinical interventions have remained elusive. The heterogeneous nature of the primary tumor of origin, complications in drug delivery across the blood-brain barrier, and the distinct microenvironment collectively pose formidable clinical challenges in developing new treatments for patients with brain metastasis. Although current preclinical models have deepened our basic understanding of the disease, much of the existing research on brain metastasis has employed a reductionist approach. This approach, which often relies on either in vitro systems or in vivo injection models in young and treatment-naive mouse models, does not give sufficient consideration to the clinical context. Given the translational importance of brain metastasis research, we advocate for the design of preclinical experimental models that take into account these unique clinical challenges and align more closely with current clinical practices. We anticipate that aligning and simulating real-world patient conditions will facilitate the development of more translatable treatment regimens. This brief review outlines the most pressing clinical challenges, the current state of research in addressing them, and offers perspectives on innovative metastasis models and tools aimed at identifying novel strategies for more effective management of clinical brain metastasis.

Is two-staged gamma knife surgery a reasonable management option for very large cerebellar metastases? A case series of three patients.

Two-staged gamma knife surgery (GKS) is a method that may extend the upper tumor volume limit for using GKS in the management of brain metastases. However, the safety of treating very large posterior fossa lesions with this technique has not been well demonstrated. Therefore, we analyzed our experience in treating cerebellar metastases larger than 12 cm3 with two-staged GKS. Four consecutive patients harboring 12 to 30 cm3 cerebellar metastases scheduled two-staged GKS were included in the study, and all but one patient completed the treatment. The treatment doses were 10-13Gy. All patients were followed with regular MR imaging and clinical assessments, and the tumor volumes were measured on all treatment and follow-up images. Tumor progression was not demonstrated in any of the patients. Tumor volumes decreased by, on average, more than half between the two stages. The median survival was 22months, and no patient died due to intracranial tumor progression. Peritumoral edema at the first GKS resolved in all patients, replaced by asymptomatic mild T2 changes in two of them not requiring any treatment. No radiation-induced complication has developed thus far. Staged GKS seems to be a feasible management option for very large cerebellar metastases.

Coordination of anti-CTLA-4 with whole-brain radiation therapy decreases tumor burden during treatment in a novel syngeneic model of lung cancer brain metastasis

Lung cancer is the most common primary tumor to metastasize to the brain. Although advances in lung cancer therapy have increased rates of survival over the past few decades, control and treatment of lung cancer brain metastasis remains an urgent clinical need. Herein, we examine the temporal coordination of α-CTLA-4 administration in combination with whole-brain radiation therapy in a syngeneic preclinical model of lung cancer brain metastasis in both C57Bl/6 and athymic nude mice. Brain tumor burden, survival, and weight loss were monitored. Immunotherapy administration 24 h prior to irradiation resulted in increased brain tumor burden, while administration of immunotherapy 12 h after radiation decreased tumor burden. Neither of the treatments affected survival outcomes or weight loss due to brain tumor recurrence. These findings suggest that the coordination of α-CTLA-4 administration in addition to whole-brain radiation therapy may be a viable strategy for reduction of tumor burden for the management of lung cancer brain metastasis.

Evolution of the Management of Brain Metastases: A Bibliometric Analysis

A systematic review of the published literature was conducted to analyze the management evolution of brain metastases from different cancers. Using the keywords “brain metastasis”, “brain metastases”, “CNS metastasis”, “CNS metastases”, “phase III” AND/OR “Randomized Controlled Trial” (RCT), relevant articles were searched for on the SCOPUS database. A total of 1986 articles were retrieved, published over a 45-year period (1977–2022). Relevant articles were defined as clinical studies describing the treatment or prevention of brain metastases from any cancer. Articles on imaging, quality of life, cognitive impairment after treatment, or primary brain tumors were excluded. After a secondary analysis, reviewing the abstracts and/or full texts, 724 articles were found to be relevant. Publications significantly increased in the last 10 years. A total of 252 articles (34.8%) were published in 12 core journals, receiving 50% of the citations. The number of publications in Frontiers in Oncology, BMC Cancer, and Radiotherapy and Oncology have increased considerably over the last few years. There were 111 randomized controlled trials, 128 review articles, and 63 meta-analyses. Most randomized trials reported on brain metastases management from unselected tumors (49), lung cancer (47), or breast cancer (11). In the last 5 years (2017 to 2022), management of brain metastasis has moved on from WBRT, the use of chemotherapy, and radio-sensitization to three directions. First, Radiosurgery or Radiotherapy (SRS/SRT), or hippocampal-sparing WBRT is employed to reduce radiation toxicity. Second, it has moved to the use of novel agents, such as tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) and third, to the use of molecularly directed therapy such as TKIs, in asymptomatic low volume metastasis, obviating the need for WBRT.

Immunotherapy as a promising treatment strategy for dmmr colorectal cancer with brain metastasis: a case report

Brain metastasis in colorectal cancer is a rare occurrence with poor prognosis and limited treatment options. This case report presents a unique and previously unreported case of brain metastasis in a patient with dMMR (DNA mismatch repair-deficient) colorectal cancer. The patient, a 70-year-old male, initially presented with abdominal pain and was diagnosed with moderately differentiated adenocarcinoma of the right colon. Following surgical resection and adjuvant chemotherapy, the patient developed cognitive decline and was found to have a metastatic lesion in the left temporal lobe. Immunohistochemical analysis revealed MSH2 positivity and MSH6, MLH1, and PMS2 negativity, indicating dMMR status. Further genetic testing showed wild-type Kras, Nras, and Braf, and high tumor mutational burden (TMB). The patient was subsequently treated with pembrolizumab immunotherapy, resulting in a significant improvement of symptoms and a reduction in the size of brain metastasis. This case highlights the rarity and challenging management of brain metastasis in colorectal cancer, particularly in the context of dMMR tumors. The successful use of immunotherapy in this case provides valuable insights into the potential efficacy of immune-based treatments for dMMR colorectal cancer with brain metastasis, underscoring the need for further research in this field.

Advancements without consensus: differing practice patterns highlight unanswered questions in the management of brain metastases from EGFR- and ALK-positive non-small cell lung cancer

Advancements without consensus: differing practice patterns highlight unanswered questions in the management of brain metastases from EGFR- and ALK-positive non-small cell lung cancer

Outcomes of a Single Isocenter Brain Multi-Metastases Linear Accelerator Delivered Stereotactic Radiosurgery (SRS)

The management of brain metastases has evolved from using 2D whole brain radiotherapy (WBRT) to more complex techniques like stereotactic radiosurgery (SRS) for patients with limited disease. Long-term control of lesions is challenging with WBRT techniques but treating multiple lesions with traditional SRS, where each lesion is treated on its own isocenter, can be time-consuming and difficult on patients, especially those with claustrophobia. Single Isocenter Multiple Metastases (SIMM) SRS has emerged as an option to deliver ablative SRS doses simultaneously to multiple brain metastases using a single isocenter, thereby limiting the duration of treatments for patients. Though appealing, SIMM SRS adds technical complexity and could potentially lead to worse outcomes or more complications relative to traditional SRS treatments. Given the current paucity of clinical evidence supporting SIMM SRS, we sought to retrospectively review our institution's outcomes and complications for patients treated with SIMM SRS to determine the efficacy and safety of this approach in our hands. Patients treated at our institution with SIMM SRS with at least one post-treatment brain MRI were identified. Date on patient clinical characteristics, planning, and treatment characteristics, and outcomes were retrospectively collected. Post-treatment tumor control was evaluated with follow-up MRI imaging based on RANO criteria. Correlation between tumor control and toxicity was done by assessing radiation doses, PTV coverage, and normal brain V12 constraints. A total of 27 patients received SIMM SRS from January 2015 to February 2022. The median age at first SIMM SRS was 61 (range: 38-87). The most common disease sites were lung (63.0%), breast (18.5%), and GI (7.4%). The 27 patients had 47 SIMM SRS treatments of 163 lesions total. The median number of lesions treated per isocenter was 3 (range: 2-9). 5 patients had 2 SIMM SRS isocenters treated on the same day, treating clusters of lesions (ranging from 5-11 lesions treated on that day). The most common locations involved were frontal, cerebellar, and parietal lobes (32.52%, 21.47%, and 15.34%). The modal dose was 22 Gy (range: 18-24 Gy). Median OS from initial primary diagnosis was 23.23 months, and 9.92 months after the first SIMM SRS treatment. The median imaging follow-up was 9.8 months per lesion, and the local control rate was 95.03%. 2 lesions (1.23%) developed radiation necrosis and the median time to RT necrosis among those lesions was 5.7 months after treatment. The utilization of SIMM SRS demonstrates acceptable efficacy and safety as it has been implemented at our institution. Further studies to evaluate this planning modality are warranted to establish suitable candidates for SIMM SRS as well as evaluate the long-term outcomes for these patients.

The Impact of Co-Alterations on Outcomes after Local Therapy for Patients with KRAS-Mutant Lung Adenocarcinoma Brain Metastases

Brain metastases are common in NSCLC with up to 25% of patients having brain metastases (BMs) at the time of diagnosis and 30% developing BMs during their disease course. KRAS is an oncogenic driver in approximately 25% of lung adenocarcinomas. Genomic alterations co-occurring with KRAS are associated with distinct biological landscapes which may influence prognosis. Herein, we sought to identify correlations between genomic profiles, intracranial progression free survival (iPFS), and overall survival (OS). We retrospectively reviewed 156 patients with KRAS-mutant lung adenocarcinoma BM who underwent SRS for their BMs at MSKCC from 2010-2022. Each patient had at least one tumor sample profiled with MSK-IMPACT, a custom FDA-cleared next-generation sequencing. Mutations, copy number alterations, and fusions were filtered for driver alterations using OncoKB. Survival outcomes were calculated from date of MRI indicating metastatic brain disease. Of the 156 patients, 80 patients presented with BMs at diagnosis whereas 76 developed BMs during their disease course, with a median 2 lines of therapy prior to BM diagnosis. The most common KRAS mutation was G12C (n = 64; 41%), G12V (n = 26, 17%), G12D (n = 17; 11%), and G12A (n = 11; 7%). The most frequently co-altered genes were TP53 (n = 71, 46%), STK11 (n = 51, 33%), CDKN2A (n = 27, 17%), KEAP1 (n = 17, 11%), and SMARCA4 (n = 10, 6%). The presence of a KEAP1 co-occurring alteration was associated with inferior iPFS (HR 1.95, 95% CI 1.05 - 3.59, p = 0.035) and the presence of SMARCA4 was also associated with inferior iPFS (HR 2.28, 95% CI 1.05 - 4.95, p = 0.038). The presence of an STK11 mutation was associated with worse OS (HR 1.57, 95% 1.01 - 2.43, p = 0.045). In a multi-variate clinico-genomic model, KEAP1 and STK11 co-occurring alterations remained significantly associated with iPFS. Patients with KEAP1-altered tumors had an increased incidence of intracranial regional progression. The 24-month cumulative incidence of regional progression amongst KEAP1-altered tumors was 57% (95% CI, 29%-77%) compared with 37% (95% CI, 29%-46%) among KEAP1-wildtype tumors (P = 0.041). Patients with CDKN2A-altered tumors had an increased incidence of leptomeningeal disease (LMD) as a form of intracranial progression. The 24-month cumulative incidence of LMD amongst CDKN2A-altered tumors was 11% (95% CI, 2.7%-27%) compared with 4.1% (95% CI, 1.5%-8.8%) among CDKN2A-wildtype tumors (P = 0.023). In our cohort of molecularly profiled KRAS-mutant lung adenocarcinoma BM patients treated with SRS, we found that co-occurring KEAP1 and STK11 were significantly associated with worse iPFS. We also observed that CDKN2A co-altered tumors had an increased incidence of LMD. These findings have implications for future efforts to personalize brain metastasis management based on comprehensive genomic profiling.

P03.04.B EFFICACY OF NEOADJUVANT STEREOTACTIC RADIOSURGERY IN SOLID CANCER BRAIN METASTASES: A SYSTEMATIC REVIEW AND METANALYSIS

Abstract BACKGROUND Neoadjuvant stereotactic radiosurgery (NaSRS) is a novel strategy for brain metastasis (BMs) management, promising to achieve lower rates of toxicity, leptomeningeal progression, and high percentage of local control. MATERIAL AND METHODS An extensive systematic literature review and meta-analysis of proportions were performed. A total of 8 papers were eligible for final analysis after searching MEDLINE via PubMed, Web-of-science, Cochrane Wiley, and Embase databases. RESULTS A total of 551 patients undergoing NaSRS to treat 583 lesions were included. Median age was 57.7 [56.5-61.1] years, with a median tumor volume of 9.1 [8.3-14.4] cc. The most frequent histology was non-small cell lung cancer (40.7%), followed by breast (20.5%), and melanoma (15.6%). Most of the lesions had a supratentorial location (77.6%). Treatment parameters were homogenous across the studies and showed a median dose of 16 [14.9-20.5] Gy at 80% isodose.Surgery was performed after a median of 1 [1-2] day and achieved gross-total extent in 92.4% of cases. Median follow-up was 12.9 [9.9-18.9] months.Pooled proportion of patients showed an overall mortality rate of 50% (CI 37-63; I2=87%), local failure of 15% (CI 12-20%; I2=12.1%) and a rate of distant brain failure of 42% (CI 35-49%; I2=55.3%). The median local progression-free survival (PFS) was 10.4 months, while median survival without distant failure was 8 months.Rate of radionecrosis (RN) and leptomeningeal dissemination (LMD) were 4% respectively. Median overall survival (OS) was 14.4 months. CONCLUSION Existing data suggest that NaSRS achieves good local control on BMs with relatively lower dose than adjuvant treatment and low incidence of RN and other complications. These results need to be confirmed by larger studies with higher level of evidence to address formal comparisons with other regimens.

Safety and efficacy of osimertinib plus bevacizumab as first-line treatment in EGFR-mutated NSCLC with brain metastasis instructed by dynamic monitoring circulating tumor DNA of paired cerebrospinal fluid and plasma.

e21182 Background: The management of brain metastases in lung cancer was always a global challenge. Studies have shown that erlotinib combined with bevacizumab could bring progression-free survival benefit for NSCLC. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor with higher CNS penetration. This study was to evaluate the safety and efficacy of osimertinib plus bevacizumab as the first-line treatment for patients with EGFR-positive NSCLC and brain metatases, and reveal the molecular characteristics of intracranial progression by matching plasma and CSF ctDNA. Methods: Patients with EGFR-positive NSCLC and brain metatases were treated with osimertinib (80mg, daily) plus bevacizumab (5mg/kg, every 4 week) as the first-line treatment. CSF and paird plasma ctDNA were collected before osimertinib and at the time of disease stable, intracranial progression and systematic progression, using the next-generation sequencing (NGS) to explore the dynamic changes between them. The primary end point was median CNS progression-free survival (PFS), CNS objective response rate (ORR). The second end point was to explore the molecular mechanism of CNS progression. Results: As the time of data cutoff (Jan 31, 2023), 15 patients were enrolled. 3 patients (20%) progressed in lung, 2 patients (13.3%) progressed in brain, and 1 patient (6.7%) progressed in leptomeningeal and bone, 2 of them still received oral osimertinib (80mg, daily). 9 patients (60%) were in partial or complete reponse and 8 of them continued to receive the original treatment. The median osimertinib exposure time was 16.8 months. The median bevacizumab exposure time was 9.1 months. The median CNS progression-free survival was 15.5 months (6.8 months to not reached). The CNS objective response rate was 93.33%. Six patients received gamma knife radiotherapy before Osimertinib, the median CNS progression-free survival was 14 months (6.8 months to not reached), the CNS objective response rate was 100%. After progression on Osimertinib, paired CSF and plasma ctDNA were analyzed and EGFR C797S, TP53, CDKN2A and etc could be found as resistanct mechanism. Adverse events of grade 3 or worse were observed in 1 patients (6.7%): severe ulcerative colitis, leading to the suspension of osimertinib. 2 patients (13.3%) stopped bevacizumab because of bleeding. Conclusions: This is a mid-term report with immature data. By the end of follow-up, we expected that osimertinib plus bevacizumab could better reduce the risk of intracranial progression and prolong the progression-free survival compared with osimertinib monotherapy. Clinical trial information: KY2021-155-02.

Sustained Improvement in the Management of Patients with Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocation: Where Are We Running?

ALK translocation amounts to around 3-7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges.

Screening and treatment of brain metastasis from papillary thyroid carcinoma: a case series

BackgroundThe brain metastasis from differentiated thyroid carcinoma (DTC) is a rare condition and its prognosis is poor. The standard protocol for screening and treatment of patients with brain metastases from papillary thyroid cancer (PTC) remains controversial. This report aims to share the experience of a single center in the management of brain metastases from DTC.Material and methodsFive patients with brain metastases were identified from 5000 patients with DTC attending the department of nuclear medicine, Hospital 108 between 2016 to 2022. The statistical software Statistical Package for Social Sciences (SPSS) 20.0 (SPSS Inc., Chicago, IL, USA) was used to analyze the data.ResultsFive patients with brain metastases from DTC were revealed by MRI, 18F-FDG PET/CT with contrast enhancement, and 131I-SPECT/CT. The median time of overall survival (OS) was 15 months, ranging from 10 to 65 months. Two out of the five patients underwent surgery, and futher 2 patients were treated with stereotactic surgery (SRS). All patients are still alive.ConclusionsBrain metastases from DTC are rare. MRI is the preferred imaging mobility to screen brain lesions in DTC. The primary treatment modalities are surgery and SRS.

Low-Energy X-Ray Intraoperative Radiation Therapy (Lex-IORT) for Resected Brain Metastases: A Single-Institution Experience

Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. Eighteen consecutive patients undergoing BM resection followed by immediate lex-IORT with 16-30 Gy applied to the spherical applicator were retrospectively analyzed. Demographic, RT-specific, radiographic and clinical data were reviewed to evaluate the effectiveness and safety of IORT for BM. Descriptive statistics and Kaplan-Meyer analysis were applied. The mean follow-up time was 10.8 months (range, 0-39 months). The estimated local control (LC), distant brain control (DBC) and overall survival (OS) at 12 months post IORT were 92.9% (95%-CI 79.3-100%), 71.4% (95%-CI 50.2-92.6%) and 58.0% (95%-CI 34.1-81.9%), respectively. Two patients developed radiation necrosis (11.1%) and wound infection (CTCAE grade III); both had additional adjuvant treatment after IORT. For five patients (27.8%), the time to the start or continuation of systemic treatment was ≤15 days and hence shorter than wound healing and adjuvant RT would have required. In accordance with previous series, this study demonstrates the effectiveness and safety of IORT in the management of brain metastases despite the small cohort and the retrospective characteristic of this analysis.