melanoma brain metastases
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2022 ◽  
Vol 11 ◽  
Author(s):  
Aidan M. Burke ◽  
Michael Carrasquilla ◽  
Walter C. Jean ◽  
Brian T. Collins ◽  
Amjad N. Anaizi ◽  
...  

Purpose/ObjectivesClinical trials of anti-Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein (CTLA-4) therapies have demonstrated a clinical benefit with low rates of neurologic adverse events in patients with melanoma brain metastases (MBMs). While the combined effect of these immunotherapies (ITs) and stereotactic radiosurgery (SRS) has yielded impressive results with regard to local control (LC) and overall survival (OS), it has also been associated with increased rates of radiation necrosis (RN) compared to historical series of SRS alone. We retrospectively reviewed patients treated with IT in combination with SRS to report on predictors of clinical outcomes.Materials and MethodsPatients were included if they had MBMs treated with SRS within 1 year of receiving anti-PD-1 and/or CTLA-4 therapy. Clinical outcomes including OS, LC, intracranial death (ID), and RN were correlated with type and timing of IT with SRS, radiation dose, total volume, and size and number of lesions treated.ResultsTwenty-nine patients with 171 MBMs were treated between May 2012 and May 2018. Patients had a median of 5 lesions treated (median volume of 6.5 cm3) over a median of 2 courses of SRS. The median dose was 21 Gy. Most patients were treated with ipilimumab (n = 13) or nivolumab-ipilimumab (n = 10). Most patients underwent SRS concurrently or within 3 months of receiving immunotherapy (n = 21). Two-year OS and LC were 54.4% and 85.5%, respectively. In addition, 14% of patients developed RN; however, only 4.7% of the total treated lesions developed RN. The median time to development of RN was 9.5 months. Patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID (p = 0.05) and RN (p = 0.03). There was no difference in OS, ID, or RN with regard to type of IT, timing of SRS and IT, number of SRS courses, SRS dose, or number of cumulative lesions treated.ConclusionsIn our series, patients treated with SRS and IT for MBMs had excellent rates of OS and LC; however, patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID and RN. Given the efficacy of combined anti-PD-1/CTLA-4 therapy for MBM management, further study of optimal selection criteria for the addition of SRS is warranted.


Author(s):  
Mehran Yusuf ◽  
Abbas Rattani ◽  
Jeremy Gaskins ◽  
Alexandria L. Oliver ◽  
Steven F. Mandish ◽  
...  

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi127-vi128
Author(s):  
Anna-Katharina Meissner ◽  
Robin Gutsche ◽  
Norbert Galldiks ◽  
Martin Kocher ◽  
Stephanie T Juenger ◽  
...  

Abstract BACKGROUND The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases. PATIENTS AND METHODS Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) were operated with subsequent genetic analysis of the intracranial BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. RESULTS Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using the best performing six parameter radiomics signature, a linear support vector machine classifier yielded an area under the ROC curve (AUC) of 0.92 (sensitivity, 83%; specificity, 88%) in the test data. CONCLUSION The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi147-vi147
Author(s):  
Stephen Lowe ◽  
Christopher Wang ◽  
Amanda Brisco ◽  
John Arrington ◽  
Kamran Ahmed ◽  
...  

Abstract Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, portending a poor prognosis with an estimated median survival of 4-6 weeks if left untreated. Several reports have suggested surgical resection as a potential causative factor. Herein, we explore if surgical and anatomical factors are correlated with development of LMD in patients with melanoma brain metastases. METHODS: Patients treated at our institution between 1999-2019 for primary melanoma with brain metastasis were compiled into a database based on ICD9/10 coding. 1,079 patients with melanoma brain metastases and appropriate imaging were identified, and 834 patients with a minimum of 3 months’ follow up were included. Patients were dichotomized by development of LMD or lack thereof, and categorized into an overall cohort, and surgical and non-surgical cohorts. Anatomic factors and ventricular access during surgery were investigated as possible correlative factors for the development of LMD. RESULTS: In the overall cohort, female gender(p=0.033), presence of dural metastasis(p=0.018), presence of periventricular lesions(p< .001), presence of intraventricular lesions(p< .001), and ventricular access during surgery(p< .001) were significantly associated with LMD. Patients undergoing surgery, or those undergoing surgery without ventricular access, were not at higher risk of LMD. On multivariate analysis, female gender(p=.033), presence of periventricular lesions (p< .001), presence of intraventricular lesions(p< .002), and presence of dural metastasis(p=0.032) were significantly associated with development of LMD. In patients who had surgery, iatrogenic ventricular access(p< .001) was significantly correlated with LMD. In the group of patients without surgery, those with periventricular lesions had significantly higher odds of LMD(p< .001). CONCLUSIONS: In a retrospective cohort of patients with melanoma metastatic to the brain, surgical intervention does not increase odds of LMD; however, iatrogenic access to the CSF space during surgery is highly correlated with LMD development. Anatomic contact with the CSF space predicts LMD regardless of surgical status.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi74-vi74
Author(s):  
Naema Nayyar ◽  
Mohini Singh ◽  
Magali de Sauvage ◽  
Ashish Dahal ◽  
Michael Brehm ◽  
...  

Abstract While immune checkpoint inhibitors (ICI) have revolutionized treatment of metastatic melanoma, few of the 75% of patients who develop brain metastases benefit from immunotherapy. Inhibition of CDK4/6 pathway – altered in ~90% of melanoma patients – can reportedly increase tumor inflammation and sensitize extracranial tumors to ICI. To determine whether intracranial melanoma can be similarly sensitized, we studied efficacy of combination CDK4/6 inhibitor Abemaciclib and ICI in immunocompetent mouse models of melanoma brain metastases bearing concurrent intracranial and extracranial tumors. 8-week-old female C57BL/6 mice received subcutaneous injections of 2x105 YUMM1.7 or B16-F10 melanoma cells 3 days prior to intracranial injections of 5x104 YUMM1.7 cells or 5x103 B16-F10 cells respectively. Mice were randomized into 6 treatment groups (n=5-7/group): Abemaciclib alone, anti-PD-1 monotherapy, anti-PD-1 and anti-CTLA4 combined (combination ICI), Abemaciclib and anti-PD-1, Abemaciclib combined with anti-PD-1 and anti-CTLA4 (triple therapy), and treatment with vehicle and isotype-matched antibodies as control. In mice bearing YUMM1.7 tumors, subcutaneous tumor growth was significantly reduced compared to control in mice treated with Abemaciclib alone (p< 0.05), combination ICI (p< 0.05) and triple therapy (p< 0.05). However, improvement in survival was only observed with triple therapy (p=0.039) compared to control group. In mice bearing B16-F10 tumors, we observed striking reduction in subcutaneous tumor growth in mice treated with Abemaciclib and anti-PD-1 compared to control-treated mice (p=0.0016) or to mice receiving anti-PD-1 monotherapy (p=0.000056). This further corresponded to a significant increase in survival of Abemaciclib and anti-PD-1 treated mice compared to control (p=0.02). Additionally, we observed improved survival in mice treated with combination ICI (p=0.006) or triple therapy (p=0.01). These results indicate CDK4/6 inhibition with Abemaciclib can improve both extracranial and intracranial responses to ICI and sensitize melanoma brain metastases to immunotherapy. Our pre-clinical findings warrant further investigation to determine whether this combination approach can improve patient outcomes.


2021 ◽  
Vol 3 (Supplement_5) ◽  
pp. v43-v51
Author(s):  
Jianbo Wang ◽  
Hussein A Tawbi

Abstract Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients’ overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%–20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.


2021 ◽  
Vol 23 (Supplement_4) ◽  
pp. iv16-iv16
Author(s):  
Philip Webb ◽  
Mark Zorman ◽  
Rhona Watson ◽  
Gemma Austin ◽  
Carol Thurgood ◽  
...  

Abstract Aims Melanoma brain metastases (MBM) are a common presentation to the neuro-oncology MDT. Stereotactic radiosurgery (SRS) is a highly effective treatment for cerebral metastases, with at least 70% control rates of individual metastases,[1] whilst immune checkpoint blockade has revolutionised the management of metastatic melanoma in recent years.[2] Recent studies have demonstrated that immune checkpoint inhibition alone also has activity in the brain, with MBM response rates of 50% or more.[3, 4] When MBM are treated with combination immunotherapy and SRS together, 12-month intracranial progression free survival (PFS) rates of 85% have been achieved.[4, 5] The aim of the current study was to evaluate the local control of MBM treated at our tertiary referral centre, which benefits from specialist neuro-radiology peer review of SRS contour volumes, and further to investigate whether overall survival is also improved, and what the mechanism of this may be. Method A retrospective analysis of all patients treated with SRS for brain metastases at our teriary SRS centre between June 2017 – January 2020 was performed. Inclusion criteria included patients treated for MBM, who received at least 2 doses of any combination of immune checkpoint inhibition concurrently with (defined as at the time of or commenced within 3 months of) SRS. The primary endpoints were the intracranial and extracranial response rates and survival rate at 12 months. Response was defined as complete response, partial response or stable disease. Secondary endpoints included the rate of imaging-defined radionecrosis, median lesional progression free survival (mPFSlesion), non-lesional intracranial PFS (mPFSintracranial), extracranial PFS (mPFSextracranial) and overall survival (mOS), measured from the start date of SRS to the date of event or censored at the start date of data collection. Kaplan-Meier curves and survival statistics were generated using SPSS v26. Results 33 MBM from 18 patients were identified. The median follow up was 25.8 months (minimum 12 months). Of the 18 patients: the median age was 60 (IQR 48 – 72); 17 (94%) patients were ECOG performance status 0-1; the median number of extracranial disease sites was 2 (pre-immunotherapy) and 1 (pre-SRS); the median duration of immunotherapy treatment was 17.6 (12.9 – 28.5) months, and the median number of metastases treated per patient was 2. Of the 33 metastases: 31 (94%) were supratentorial; 6 (18%) underwent prior neurosurgical resection; the median GTV volume (cc) of unresected metastases was 0.5cc (0.1 – 2.7), and 21 (64%) were treated with single fraction SRS. The median OS and PFS for all subtypes were not reached. The rates of OS, PFSlesion, PFSintracranial and PFSextracranial at 12 months were 93.9%, 87.9%, 81.8% & 75.8% respectively. Conclusion Our cohort of MBM patients appear to perform favourably when compared with the current literature. When compared to a recent extensive systematic review of modern management of MBM, our lesional control rate is as good as the weighted average of concurrent SRS + immunotherapy studies (87.9% vs 85.4% 12-month PFS), however we demonstrate a significantly improved 12-month OS rate (93.9% vs 52.8%) compared to the same (mOS of 15.8 – 17.4 months in other studies).[6,7] Our extra-lesional PFS is high and, compared to extracranial PFS rates from 51% at 6-months to 70.4% at 9-months in the literature,[3,4] our 75.8% control at 12 months suggests that extracranial control could drive the OS benefit. This suggests a benefit of SRS beyond the local control of MBM and questions whether patients without brain metastases may benefit from body SABR to extracranial metastases, to elicit a similar, potentially abscopal type effect.


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