Patterns of Failure after Stereotactic Radiosurgery for Brain Metastases from Small Cell Lung Cancer: Outcomes in the Immunotherapy Era

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Marwaha, Yun Liang, Matthew J. Shepard, Alexander Yu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5350119/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Dec, 2024 Read the published version in Journal of Neuro-Oncology → Version 1 posted 11 You are reading this latest preprint version Abstract Purpose/Objective(s) : Small cell lung cancer (SCLC) is known to have high rates of development of brain metastases. Standard treatment has been whole brain radiation therapy (WBRT) but the role for more focused treatment and hippocampal avoidance has arisen in the past decade. In addition, with possible penetration of the central nervous system by more modern immunotherapies, the risk of distant failure may be lower. As such, we reviewed patients at our institution treated with stereotactic radiosurgery (SRS) to look at patterns, locations, and predictors of failure in the brain. Materials/Methods : A retrospective review and analysis of charts was done on 46 patients treated with SRS (no history of prior WBRT) for their brain metastases from SCLC. Multivariate analysis was used to determine significant prognostic factors influencing survival and local/distant failure. We tracked timing and type of immunotherapy, if any, as well as if patients failed in the hippocampus or required WBRT. Results : There were 46 patients with 97 total brain metastases treated with SRS in this study. Median number of metastases was 2 (1–5). The median dose of radiation was 20Gy (20–30) in 3 fractions (1–5) for all 97 tumors. 11 patients did not receive immunotherapy, whereas 35 patients had immunotherapy of some sort. Median overall survival (OS) for the entire cohort was 13 months, with a 12 month OS of 59% and 2-year OS of 30%. Cox regression did not reveal any significant predictors of OS, including age, sex, total volume, extracranial disease, KPS, immunotherapy, or number of metastases. 12 month and 24 month local control of disease was 95% and 80%, respectively. There were no significant predictors of local failure including volume, dose, or immunotherapy. 25 of the patients had distant brain failure, with a rate of distant failure of 38% and 64% for 6 and 12 months, respectively. Immunotherapy, number of metastases, total target volume, nor presence of extracranial disease was predictive of distant brain failure. WBRT free survival was also measured and found to be 73% at one year. There were no significant predictors for this measure. Lastly, 5 patients in this cohort showed failure in the hippocampus, where the rate of failure at 6 and 12 months was 16%. Conclusion : Rates of distant brain failure in SCLC patients after SRS remain similar to those of NSCLC patients in the immunotherapy era. We did not show a decrease in distant failure rate based on immunotherapy use. The rate of hippocampal failure was quite low and should provide reassurance that SRS and techniques such as HA-IMRT can be reasonably used in these patients. Ongoing clinical trials will help provide more definitive answers in this arena. Immunotherapy Stereotactic radiosurgery Brain metastases Hippocampal-avoidance whole-brain radiation therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Small Cell Lung Cancer (SCLC) is an aggressive malignancy with high predilection for metastasis to the brain, affecting 40–50% of patients throughout the course of their disease 1 , 2 , 3 . It has such high rate of central nervous system (CNS) spread that, in limited stage patients, many are treated with prophylactic cranial irradiation 1 , 4 . In the past 10–15 years, interest has arisen in using more modern, focused techniques such as Stereotactic Radiosurgery (SRS) for these patients or even hippocampal avoidance whole brain radiation therapy (HA-WBRT) 5 . In the modern era, both the FIRE and CROSS-FIRE studies have shown similar rates of distant brain failure in SCLC compared to non-small cell lung cancer (NSCLC) after treatment with SRS 6 , 7 . In addition, immunotherapy is now a standard of care for Extensive Stage SCLC (ES-SCLC) which has some penetration into the CNS, and in NSCLC has showed reasonable rates of intracranial control 8 , 9 , 10 . With the above concepts in mind, we sought to review outcomes in patients with brain metastases from SCLC treated with SRS with or without immunotherapy. Methods This study was designed as an IRB approved retrospective cohort analysis conducted at [ANONYMIZED FOR REVIEW]. We included 46 patients diagnosed with brain metastases from SCLC who were treated with SRS and had no history of prior WBRT. Patients were excluded if they had prior WBRT or incomplete medical records. Data was obtained from electronic medical records, focusing on patient demographics, tumor characteristics, and treatment details. We specifically tracked the timing and type of immunotherapy received, if any, and noted instances of local and distant brain failure. Local failure was defined using RANO criteria 11 and distant brain failure was defined as new brain metastases outside of prior targets. Overall survival was calculated from time of SRS. We also documented patterns of distant brain failure in the form of hippocampal involvement and any subsequent radiation treatments (WBRT or repeat SRS). Statistical analysis was performed using SPSS (IBM, inc) version 29.0.1.0., employing multivariate cox regression to identify significant prognostic factors influencing survival and local/distant failure. A significance level of p < 0.05 was considered statistically significant. Results Patient Demographics and Treatment Characteristics In this study, 46 patients with a total of 97 brain metastases were treated with SRS. The median number of metastases per patient was 2 (1–5). The median prescribed dose was 27 Gy (20–30), delivered in a median of 3 fractions (1–5 fx) for all 97 tumors (Table 2 ). Out of the 46 patients, 11 (23.9%) did not receive any form of immunotherapy, while 35 (76.1%) patients were treated with various immunotherapy regimens. A vast majority of the patients received either atezolizumab or durvalumab as their immunotherapy regiment. Of the 35 patients that received immunotherapy, 23 (65.7%) received it prior to SRS, and 12 (34.3%) after. There were 42 total patients that had follow up imaging studies, and for these patients with imaging, the median number of follow up MRIs was 2 (1–17). For all the patients, the median imaging follow up was 8 months (1–52) and median clinical follow up was 10 months (1–52). Refer to Table 1 for more in-depth patient demographics and characteristics (Table 1 ). Table 1 Characteristics and demographics Characteristic N Valid N Missing Median Range Min Max n present % present Age 46 0 65 38 45 83 - - SEX 46 0 - - - - 21 M, 25 F 45.7% M, 54.3% F kps 46 0 80 30 60 90 - - extracranial disease 46 0 - - - - 29 Yes, 17 No 63% Yes, 37% No Number of metastases 46 0 2 4 1 5 - - surgery to metastases 46 0 - - - - 5 10.9% total volume (cc) 46 0 4.57 37.56 0.04 37.60 - - Table 2 Tumor characteristics Characteristic N Valid N Missing Median Min Max Volume (cc) 97 0 0.972 0.01 37.6 dose (gy) 97 0 27 20 30 fractions 97 0 3 1 5 Overall Survival The median overall survival (OS) for the entire cohort was 13 months. The 12-month OS rate was 59%, and the 2-year OS rate was 30% (Fig. 1 ). Cox regression did not identify any significant predictors of OS, including factors such as age, sex, total tumor volume, presence of extracranial disease, Karnofsky Performance Status (KPS), type of immunotherapy, or the number of metastases. The types of immunotherapies were categorized into atezolizumab, durvalumab, which were the vast majority of the two immunotherapy regiments used, or other immunotherapies. The immunotherapy regiments were also categorized into whether they were delivered before, during, or after SRS. Local Control At 12 months local control of the brain metastases was 95% with a 24-month rate of 80% (Fig. 2 ). Analysis of local failure revealed no significant predictors, including factors such as tumor volume, radiation dose, or receipt of immunotherapy. Distant Brain Failure and Location of Failure Twenty-five patients experienced distant brain failure, resulting in a distant failure rate of 38% at 6 months and 64% at 12 months (Fig. 3 ). Neither immunotherapy, number of metastases, total target volume, nor the presence of extracranial disease were found to be predictive of distant brain failure. WBRT Free Survival, Hippocampal Failure, and Toxicity Ten patients had WBRT for salvage of distant failure and 14 patients had SRS to new lesions. One patient opted for no further treatment and went on to hospice care. WBRT free survival was measured and found to be 73% at one year (Fig. 4 ). No significant predictors were identified for this measure. Five patients exhibited failure in the hippocampus with an actuarial rate of failure of 16% at both 6 and 12 months. With follow up, two patients were described to have late toxicity. One patient with two targets had confirmed grade 3 radiation necrosis (RN) in both targets, which were treated with laser interstitial thermal therapy (LITT). The other patient with late toxicity showed grade 1 RN on imaging findings only. This patient had no symptoms nor any intervention. Discussion Our study provides a comprehensive analysis of outcomes for patients with SCLC brain metastases treated with SRS. We observed a median OS of 13 months, with a 12-month OS rate of 59% and a 2-year OS rate of 30%. Local control was achieved in 95% of patients at 12 months and 80% at 24 months. Distant brain failure rates were 38% at 6 months and 64% at 12 months. Importantly, no significant predictors were identified for OS, local control, or distant brain failure, including immunotherapy use, tumor volume, or presence of extracranial disease. The rate of hippocampal failure was low at 16% at both 6 and 12 months, which supports the feasibility of using SRS and even HA-WBRT as hippocampal avoidance techniques in this patient population. These findings align with recent studies comparing SRS and WBRT in SCLC patients. The FIRE and CROSS-FIRE studies have demonstrated that SRS is comparable to WBRT in terms of distant brain failure rates, similar to what we observed in our cohort. The FIRE study showed a median OS of 8.5 months in patients who received first-line SRS to SCLC brain metastases, and when compared to WBRT, was similar in overall survival advantage 6 . When comparing brain metastases from SCLC and NSCLC, the CROSS-FIRE study showed a superior median OS in patients that received first-line SRS for NSCLC brain metastases (10.5 vs. 8.6 months, p < .001) 7 . Despite the growing use of immunotherapy in extensive stage SCLC 8 , 9 , 10 , we did not find a reduction in distant brain failure associated with its use; granted our sample size was on the smaller side. In the context of NSCLC brain metastases, studies have shown varying results regarding the role of immunotherapy when combined with SRS. For instance, one study indicated that concurrent immunotherapy with SRS significantly improved intracranial progression-free survival compared to SRS alone, with a hazard ratio of 0.107 (95% CI = 0.015–0.783) 12 . Another study found that the use of immune checkpoint inhibitors (ICIs) alongside SRS predicted decreased distant brain failure, decreased rates of neurologic death, and improved OS. The two-year local control rate was notably higher in patients receiving SRT plus ICIs compared to SRT alone (97% vs. 86%, respectively; P = .046) 13 . Despite these promising findings in NSCLC, our study did not show a significant decrease in distant brain failure or improvement in overall survival related to immunotherapy in SCLC. This discrepancy might be attributed to differences in the biology of SCLC versus NSCLC, as well as variations in how these cancers respond to immunotherapy. There are currently several open clinical trials regarding the usage of immunotherapy and SRS for NSCLC-induced brain metastases 14 , but more research needs to be done regarding SCLC-induced brain metastases treatments in the immunotherapy era. The integration of immunotherapy and SRS in the management of SCLC-induced brain metastases represents a significant advancement in treatment strategies. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has shown promising results in enhancing immune-mediated anticancer activity by targeting immune-attenuating interactions such as CTLA-4/B7 and PD-1/PD-L1 receptors. Recent trials are evaluating the efficacy of ICIs both concurrently and following chemoradiotherapy (CRT) for limited-stage SCLC (LS-SCLC). For instance, the [ANONYMIZED FOR REVIEW] trial is investigating the addition of atezolizumab to CRT, focusing on progression-free survival (PFS) and OS [ANONYMIZED FOR REVIEW] 15 . Similarly, the [ANONYMIZED FOR REVIEW] trial is exploring the effects of durvalumab and tremelimumab in patients who have not progressed after CRT, with PFS and OS as primary outcomes [ANONYMIZED FOR REVIEW] 16 . They so far found that durvalumab showed clinically meaningful and statistically significant benefits in OS and PFS, from the placebo’s median OS of 33.4 months to 55.9 months with durvalumab. The median PFS also improved from 9.2 months to 16.6 months. Additionally, research is underway to assess the combination of SRS with other therapies, such as nivolumab [ANONYMIZED FOR REVIEW] 17 and the [ANONYMIZED FOR REVIEW] 18 , which generates Tumor Treatment Fields to potentially enhance the effectiveness of SRS and immunotherapy [ANONYMIZED FOR REVIEW] 18 . Lastly, the [ANONYMIZED FOR REVIEW] 19 study is examining consolidation therapy with PD-L1 inhibitors post-CRT [ANONYMIZED FOR REVIEW] 19 . Other trials, like those exploring concurrent pembrolizumab with radiation therapy [ANONYMIZED FOR REVIEW] 20 and various combinations of immunotherapy and CRT, are expected to provide insights into optimizing these combined approaches. The data from these studies will be crucial in defining the optimal use of SRS and immunotherapy in the management of brain metastases from SCLC, highlighting the importance of continued research in this evolving field. The low rate of hippocampal failure observed in our study is consistent with previous research suggesting that SRS can effectively manage brain metastases while minimizing cognitive decline, as compared to WBRT 21 . This finding reinforces the rationale for adopting SRS and hippocampal avoidance techniques, particularly given the potential cognitive benefits over WBRT. [ANONYMIZED FOR REVIEW] 22 is an open phase III clinical trial looking at SRS versus HA-WBRT for 10 or fewer brain metastases stemmed from primary SCLC looking at oncologic outcomes and toxicity between the two arms, but primarily looking at the impact on cognitive function. Interestingly, another phase III trial, [ANONYMIZED FOR REVIEW] 23 , is trying to see the effects of delaying radiation until the actual spread of cancer by using brain MRI alone for surveillance in patients receiving PCI. For monitoring purposes, using an MRI that does not cause any radiation to the brain can potentially reduce side effects of PCI and help prolong a patient’s lifespan by improving their oncologic outcomes. Several limitations of this study should be considered. The retrospective design and relatively small sample size may limit the generalizability of our findings and imply an inherent selection bias. None of the patients had more than 5 metastases, and the median was 2, and therefore we cannot necessarily extrapolate our data to patients with greater than 5 SCLC brain metastases. The lack of significant predictors could be due to unmeasured variables or the variability in patient responses to treatment. Several aforementioned IO regiments were used to treat patients, both varying in timing of delivery and type of regiment, which could vary the results that were found in this study. Additionally, the observational nature of this study does not allow for causative conclusions about the effects of immunotherapy on distant brain failure rates. Conclusion Our study reinforces the role of SRS as an effective treatment for brain metastases in SCLC, with outcomes comparable to those reported in NSCLC studies. The observed low rate of hippocampal failure supports the use of SRS and hippocampal avoidance techniques. Ongoing research will be essential to refine treatment approaches and improve outcomes for patients with SCLC brain metastases. Declarations Funding: None Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by R.W. and A.M. The first draft of the manuscript was written by A.M. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements: Thank you to the entire AHN radiation oncology department in assisting me with this project, and special thanks to Dr. Wegner for being my mentor throughout my radiation oncology experience. Dr. Wegner has a research grant from Elekta, Inc. No other disclosures or conflicts of interest were reported. Research data are stored in an institutional repository and will be shared upon request to the corresponding author. References Komaki R Prophylactic cranial irradiation for small cell carcinoma of the lung. Cancer Treat Symp 1095;2:35–39 Arriagada R, Le Chevalier T, Borie F et al (1995) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. 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Cite Share Download PDF Status: Published Journal Publication published 07 Dec, 2024 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 15 Nov, 2024 Reviews received at journal 10 Nov, 2024 Reviews received at journal 05 Nov, 2024 Reviewers agreed at journal 04 Nov, 2024 Reviewers agreed at journal 01 Nov, 2024 Reviewers agreed at journal 31 Oct, 2024 Reviewers agreed at journal 30 Oct, 2024 Reviewers invited by journal 29 Oct, 2024 Editor assigned by journal 29 Oct, 2024 Submission checks completed at journal 29 Oct, 2024 First submitted to journal 28 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Marwaha","email":"","orcid":"","institution":"Allegheny Health Network","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"S.","lastName":"Marwaha","suffix":""},{"id":374383688,"identity":"34e0c861-77b2-41da-9a7f-bf5906d5e645","order_by":1,"name":"Yun Liang","email":"","orcid":"","institution":"Allegheny Health Network","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Liang","suffix":""},{"id":374383691,"identity":"cd25aa05-ff89-4f09-a829-7d4dc2f166f4","order_by":2,"name":"Matthew J. Shepard","email":"","orcid":"","institution":"Allegheny Health Network","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"J.","lastName":"Shepard","suffix":""},{"id":374383692,"identity":"6b7489db-203c-4921-835e-7e849e91b5f7","order_by":3,"name":"Alexander Yu","email":"","orcid":"","institution":"Allegheny Health Network","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Yu","suffix":""},{"id":374383693,"identity":"78085d08-82aa-48d0-9fb4-19b3c20b0c31","order_by":4,"name":"Stephen M. Karlovits","email":"","orcid":"","institution":"Allegheny Health Network","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"M.","lastName":"Karlovits","suffix":""},{"id":374383694,"identity":"3bbaf08e-d772-4831-bed4-441543182881","order_by":5,"name":"Rodney E. Wegner","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYHACAyR2BUMCqVrOkKyFsY0ILebtzdsefGxjSOznX3vwceU8uzxzBuZjH7/g0SJz5li54Uyglpkz3iUbnt2WXGzZwJY8WwaPFgmJHDNp3jaG3A03zphJNm5jTtxwgMeYWYKQlr9ALftvnDH/2TinnkgtjCBb+HvMGBsbDoO1MH7Ap4XnWJlkzzmJ+hk3eIwlG44dT9xwmC2ZGY8OBgn25m0SP8psjPn7zxh+bKipTtxwvPkw4w98ekCAkQ3odokEKA9oBTMPIS0Mf4CY/wCSGQRtGQWjYBSMgpEEAHNGTST/aLapAAAAAElFTkSuQmCC","orcid":"","institution":"Allegheny Health Network","correspondingAuthor":true,"prefix":"","firstName":"Rodney","middleName":"E.","lastName":"Wegner","suffix":""}],"badges":[],"createdAt":"2024-10-29 01:08:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5350119/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5350119/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-024-04895-w","type":"published","date":"2024-12-07T15:57:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69360412,"identity":"d9548f5e-6cb1-4fa7-a383-05ee45873d9d","added_by":"auto","created_at":"2024-11-19 14:17:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14251,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Curve showing overall survival\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5350119/v1/28cdb0b4e37315c2cd4a392a.png"},{"id":69362482,"identity":"01ac1570-2cb0-4fdc-a327-df2753bbf2dd","added_by":"auto","created_at":"2024-11-19 14:33:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11819,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Curve showing local control\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5350119/v1/f55eab6c13ec56641fe7367b.png"},{"id":69361752,"identity":"fee1b2e6-04d3-4dae-951d-32bb7d3c9ed7","added_by":"auto","created_at":"2024-11-19 14:25:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":17748,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Curve showing distant brain failure\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5350119/v1/239deee48ee0a475ea769fef.png"},{"id":69360413,"identity":"36c2d032-3659-4959-b459-769e4b936286","added_by":"auto","created_at":"2024-11-19 14:17:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":14325,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Curve showing whole brain radiation therapy-free (WBRT-free) survival\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5350119/v1/71cc4d0d9c8819b07b760f15.png"},{"id":70964822,"identity":"8ff1bc8f-7ef1-49d0-ba7f-90304d0d65f2","added_by":"auto","created_at":"2024-12-09 16:16:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":457348,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5350119/v1/312777ee-8d5c-442c-820d-b90373bccad4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Patterns of Failure after Stereotactic Radiosurgery for Brain Metastases from Small Cell Lung Cancer: Outcomes in the Immunotherapy Era","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSmall Cell Lung Cancer (SCLC) is an aggressive malignancy with high predilection for metastasis to the brain, affecting 40\u0026ndash;50% of patients throughout the course of their disease\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. It has such high rate of central nervous system (CNS) spread that, in limited stage patients, many are treated with prophylactic cranial irradiation\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In the past 10\u0026ndash;15 years, interest has arisen in using more modern, focused techniques such as Stereotactic Radiosurgery (SRS) for these patients or even hippocampal avoidance whole brain radiation therapy (HA-WBRT)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In the modern era, both the FIRE and CROSS-FIRE studies have shown similar rates of distant brain failure in SCLC compared to non-small cell lung cancer (NSCLC) after treatment with SRS\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. In addition, immunotherapy is now a standard of care for Extensive Stage SCLC (ES-SCLC) which has some penetration into the CNS, and in NSCLC has showed reasonable rates of intracranial control\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. With the above concepts in mind, we sought to review outcomes in patients with brain metastases from SCLC treated with SRS with or without immunotherapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This study was designed as an IRB approved retrospective cohort analysis conducted at [ANONYMIZED FOR REVIEW]. We included 46 patients diagnosed with brain metastases from SCLC who were treated with SRS and had no history of prior WBRT. Patients were excluded if they had prior WBRT or incomplete medical records. Data was obtained from electronic medical records, focusing on patient demographics, tumor characteristics, and treatment details. We specifically tracked the timing and type of immunotherapy received, if any, and noted instances of local and distant brain failure. Local failure was defined using RANO criteria\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e and distant brain failure was defined as new brain metastases outside of prior targets. Overall survival was calculated from time of SRS. We also documented patterns of distant brain failure in the form of hippocampal involvement and any subsequent radiation treatments (WBRT or repeat SRS).\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using SPSS (IBM, inc) version 29.0.1.0., employing multivariate cox regression to identify significant prognostic factors influencing survival and local/distant failure. A significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient Demographics and Treatment Characteristics\u003c/h2\u003e \u003cp\u003eIn this study, 46 patients with a total of 97 brain metastases were treated with SRS. The median number of metastases per patient was 2 (1\u0026ndash;5). The median prescribed dose was 27 Gy (20\u0026ndash;30), delivered in a median of 3 fractions (1\u0026ndash;5 fx) for all 97 tumors (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Out of the 46 patients, 11 (23.9%) did not receive any form of immunotherapy, while 35 (76.1%) patients were treated with various immunotherapy regimens. A vast majority of the patients received either atezolizumab or durvalumab as their immunotherapy regiment. Of the 35 patients that received immunotherapy, 23 (65.7%) received it prior to SRS, and 12 (34.3%) after. There were 42 total patients that had follow up imaging studies, and for these patients with imaging, the median number of follow up MRIs was 2 (1\u0026ndash;17). For all the patients, the median imaging follow up was 8 months (1\u0026ndash;52) and median clinical follow up was 10 months (1\u0026ndash;52). Refer to Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for more in-depth patient demographics and characteristics (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics and demographics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN Valid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN Missing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003en present\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e% present\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSEX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e21 M, 25 F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e45.7% M, 54.3% F\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ekps\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eextracranial disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29 Yes, 17 No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e63% Yes, 37% No\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esurgery to metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etotal volume (cc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e37.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTumor characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN Valid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN Missing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMax\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume (cc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.972\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edose (gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efractions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOverall Survival\u003c/h3\u003e\n\u003cp\u003eThe median overall survival (OS) for the entire cohort was 13 months. The 12-month OS rate was 59%, and the 2-year OS rate was 30% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Cox regression did not identify any significant predictors of OS, including factors such as age, sex, total tumor volume, presence of extracranial disease, Karnofsky Performance Status (KPS), type of immunotherapy, or the number of metastases. The types of immunotherapies were categorized into atezolizumab, durvalumab, which were the vast majority of the two immunotherapy regiments used, or other immunotherapies. The immunotherapy regiments were also categorized into whether they were delivered before, during, or after SRS.\u003c/p\u003e\n\u003ch3\u003eLocal Control\u003c/h3\u003e\n\u003cp\u003eAt 12 months local control of the brain metastases was 95% with a 24-month rate of 80% (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Analysis of local failure revealed no significant predictors, including factors such as tumor volume, radiation dose, or receipt of immunotherapy.\u003c/p\u003e\n\u003ch3\u003eDistant Brain Failure and Location of Failure\u003c/h3\u003e\n\u003cp\u003eTwenty-five patients experienced distant brain failure, resulting in a distant failure rate of 38% at 6 months and 64% at 12 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Neither immunotherapy, number of metastases, total target volume, nor the presence of extracranial disease were found to be predictive of distant brain failure.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eWBRT Free Survival, Hippocampal Failure, and Toxicity\u003c/h2\u003e \u003cp\u003eTen patients had WBRT for salvage of distant failure and 14 patients had SRS to new lesions. One patient opted for no further treatment and went on to hospice care. WBRT free survival was measured and found to be 73% at one year (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e4\u003c/span\u003e). No significant predictors were identified for this measure. Five patients exhibited failure in the hippocampus with an actuarial rate of failure of 16% at both 6 and 12 months. With follow up, two patients were described to have late toxicity. One patient with two targets had confirmed grade 3 radiation necrosis (RN) in both targets, which were treated with laser interstitial thermal therapy (LITT). The other patient with late toxicity showed grade 1 RN on imaging findings only. This patient had no symptoms nor any intervention.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study provides a comprehensive analysis of outcomes for patients with SCLC brain metastases treated with SRS. We observed a median OS of 13 months, with a 12-month OS rate of 59% and a 2-year OS rate of 30%. Local control was achieved in 95% of patients at 12 months and 80% at 24 months. Distant brain failure rates were 38% at 6 months and 64% at 12 months. Importantly, no significant predictors were identified for OS, local control, or distant brain failure, including immunotherapy use, tumor volume, or presence of extracranial disease. The rate of hippocampal failure was low at 16% at both 6 and 12 months, which supports the feasibility of using SRS and even HA-WBRT as hippocampal avoidance techniques in this patient population.\u003c/p\u003e \u003cp\u003eThese findings align with recent studies comparing SRS and WBRT in SCLC patients. The FIRE and CROSS-FIRE studies have demonstrated that SRS is comparable to WBRT in terms of distant brain failure rates, similar to what we observed in our cohort. The FIRE study showed a median OS of 8.5 months in patients who received first-line SRS to SCLC brain metastases, and when compared to WBRT, was similar in overall survival advantage\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. When comparing brain metastases from SCLC and NSCLC, the CROSS-FIRE study showed a superior median OS in patients that received first-line SRS for NSCLC brain metastases (10.5 vs. 8.6 months, p\u0026thinsp;\u0026lt;\u0026thinsp;.001)\u003csup\u003e7\u003c/sup\u003e. Despite the growing use of immunotherapy in extensive stage SCLC\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, we did not find a reduction in distant brain failure associated with its use; granted our sample size was on the smaller side.\u003c/p\u003e \u003cp\u003eIn the context of NSCLC brain metastases, studies have shown varying results regarding the role of immunotherapy when combined with SRS. For instance, one study indicated that concurrent immunotherapy with SRS significantly improved intracranial progression-free survival compared to SRS alone, with a hazard ratio of 0.107 (95% CI\u0026thinsp;=\u0026thinsp;0.015\u0026ndash;0.783)\u003csup\u003e12\u003c/sup\u003e. Another study found that the use of immune checkpoint inhibitors (ICIs) alongside SRS predicted decreased distant brain failure, decreased rates of neurologic death, and improved OS. The two-year local control rate was notably higher in patients receiving SRT plus ICIs compared to SRT alone (97% vs. 86%, respectively; P\u0026thinsp;=\u0026thinsp;.046)\u003csup\u003e13\u003c/sup\u003e. Despite these promising findings in NSCLC, our study did not show a significant decrease in distant brain failure or improvement in overall survival related to immunotherapy in SCLC. This discrepancy might be attributed to differences in the biology of SCLC versus NSCLC, as well as variations in how these cancers respond to immunotherapy.\u003c/p\u003e \u003cp\u003eThere are currently several open clinical trials regarding the usage of immunotherapy and SRS for NSCLC-induced brain metastases\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, but more research needs to be done regarding SCLC-induced brain metastases treatments in the immunotherapy era.\u003c/p\u003e \u003cp\u003eThe integration of immunotherapy and SRS in the management of SCLC-induced brain metastases represents a significant advancement in treatment strategies. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has shown promising results in enhancing immune-mediated anticancer activity by targeting immune-attenuating interactions such as CTLA-4/B7 and PD-1/PD-L1 receptors. Recent trials are evaluating the efficacy of ICIs both concurrently and following chemoradiotherapy (CRT) for limited-stage SCLC (LS-SCLC). For instance, the [ANONYMIZED FOR REVIEW] trial is investigating the addition of atezolizumab to CRT, focusing on progression-free survival (PFS) and OS [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Similarly, the [ANONYMIZED FOR REVIEW] trial is exploring the effects of durvalumab and tremelimumab in patients who have not progressed after CRT, with PFS and OS as primary outcomes [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. They so far found that durvalumab showed clinically meaningful and statistically significant benefits in OS and PFS, from the placebo\u0026rsquo;s median OS of 33.4 months to 55.9 months with durvalumab. The median PFS also improved from 9.2 months to 16.6 months. Additionally, research is underway to assess the combination of SRS with other therapies, such as nivolumab [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e and the [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, which generates Tumor Treatment Fields to potentially enhance the effectiveness of SRS and immunotherapy [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Lastly, the [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e study is examining consolidation therapy with PD-L1 inhibitors post-CRT [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Other trials, like those exploring concurrent pembrolizumab with radiation therapy [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and various combinations of immunotherapy and CRT, are expected to provide insights into optimizing these combined approaches. The data from these studies will be crucial in defining the optimal use of SRS and immunotherapy in the management of brain metastases from SCLC, highlighting the importance of continued research in this evolving field.\u003c/p\u003e \u003cp\u003eThe low rate of hippocampal failure observed in our study is consistent with previous research suggesting that SRS can effectively manage brain metastases while minimizing cognitive decline, as compared to WBRT\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. This finding reinforces the rationale for adopting SRS and hippocampal avoidance techniques, particularly given the potential cognitive benefits over WBRT. [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e is an open phase III clinical trial looking at SRS versus HA-WBRT for 10 or fewer brain metastases stemmed from primary SCLC looking at oncologic outcomes and toxicity between the two arms, but primarily looking at the impact on cognitive function. Interestingly, another phase III trial, [ANONYMIZED FOR REVIEW]\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, is trying to see the effects of delaying radiation until the actual spread of cancer by using brain MRI alone for surveillance in patients receiving PCI. For monitoring purposes, using an MRI that does not cause any radiation to the brain can potentially reduce side effects of PCI and help prolong a patient\u0026rsquo;s lifespan by improving their oncologic outcomes.\u003c/p\u003e \u003cp\u003eSeveral limitations of this study should be considered. The retrospective design and relatively small sample size may limit the generalizability of our findings and imply an inherent selection bias. None of the patients had more than 5 metastases, and the median was 2, and therefore we cannot necessarily extrapolate our data to patients with greater than 5 SCLC brain metastases. The lack of significant predictors could be due to unmeasured variables or the variability in patient responses to treatment. Several aforementioned IO regiments were used to treat patients, both varying in timing of delivery and type of regiment, which could vary the results that were found in this study. Additionally, the observational nature of this study does not allow for causative conclusions about the effects of immunotherapy on distant brain failure rates.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study reinforces the role of SRS as an effective treatment for brain metastases in SCLC, with outcomes comparable to those reported in NSCLC studies. The observed low rate of hippocampal failure supports the use of SRS and hippocampal avoidance techniques. Ongoing research will be essential to refine treatment approaches and improve outcomes for patients with SCLC brain metastases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by R.W. and A.M. The first draft of the manuscript was written by A.M. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThank you to the entire AHN radiation oncology department in assisting me with this project, and special thanks to Dr. Wegner for being my mentor throughout my radiation oncology experience.\u003c/p\u003e\n\u003cp\u003eDr. Wegner has a research grant from Elekta, Inc.\u003c/p\u003e\n\u003cp\u003eNo other disclosures or conflicts of interest were reported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResearch data are stored in an institutional repository and will be shared upon request to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKomaki R Prophylactic cranial irradiation for small cell carcinoma of the lung. 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JAMA 316(4):401\u0026ndash;409. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jama.2016.9839\u003c/span\u003e\u003cspan address=\"10.1001/jama.2016.9839\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e[ANONYMIZED FOR REVIEW]\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e[ANONYMIZED FOR REVIEW]\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Immunotherapy, Stereotactic radiosurgery, Brain metastases, Hippocampal-avoidance whole-brain radiation therapy","lastPublishedDoi":"10.21203/rs.3.rs-5350119/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5350119/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose/Objective(s)\u003c/strong\u003e: Small cell lung cancer (SCLC) is known to have high rates of development of brain metastases. Standard treatment has been whole brain radiation therapy (WBRT) but the role for more focused treatment and hippocampal avoidance has arisen in the past decade. In addition, with possible penetration of the central nervous system by more modern immunotherapies, the risk of distant failure may be lower. As such, we reviewed patients at our institution treated with stereotactic radiosurgery (SRS) to look at patterns, locations, and predictors of failure in the brain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials/Methods\u003c/strong\u003e: A retrospective review and analysis of charts was done on 46 patients treated with SRS (no history of prior WBRT) for their brain metastases from SCLC. Multivariate analysis was used to determine significant prognostic factors influencing survival and local/distant failure. We tracked timing and type of immunotherapy, if any, as well as if patients failed in the hippocampus or required WBRT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: There were 46 patients with 97 total brain metastases treated with SRS in this study. Median number of metastases was 2 (1–5). The median dose of radiation was 20Gy (20–30) in 3 fractions (1–5) for all 97 tumors. 11 patients did not receive immunotherapy, whereas 35 patients had immunotherapy of some sort. Median overall survival (OS) for the entire cohort was 13 months, with a 12 month OS of 59% and 2-year OS of 30%. Cox regression did not reveal any significant predictors of OS, including age, sex, total volume, extracranial disease, KPS, immunotherapy, or number of metastases. 12 month and 24 month local control of disease was 95% and 80%, respectively. There were no significant predictors of local failure including volume, dose, or immunotherapy. 25 of the patients had distant brain failure, with a rate of distant failure of 38% and 64% for 6 and 12 months, respectively. Immunotherapy, number of metastases, total target volume, nor presence of extracranial disease was predictive of distant brain failure. WBRT free survival was also measured and found to be 73% at one year. There were no significant predictors for this measure. Lastly, 5 patients in this cohort showed failure in the hippocampus, where the rate of failure at 6 and 12 months was 16%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Rates of distant brain failure in SCLC patients after SRS remain similar to those of NSCLC patients in the immunotherapy era. We did not show a decrease in distant failure rate based on immunotherapy use. The rate of hippocampal failure was quite low and should provide reassurance that SRS and techniques such as HA-IMRT can be reasonably used in these patients. Ongoing clinical trials will help provide more definitive answers in this arena.\u003c/p\u003e","manuscriptTitle":"Patterns of Failure after Stereotactic Radiosurgery for Brain Metastases from Small Cell Lung Cancer: Outcomes in the Immunotherapy Era","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-19 14:17:27","doi":"10.21203/rs.3.rs-5350119/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-16T03:53:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-10T18:26:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-05T13:21:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"201043919991823957329069946897598086314","date":"2024-11-04T19:37:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"250118737824902310204480061060001176904","date":"2024-11-01T10:43:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323578507345175011938620705846331683710","date":"2024-10-31T14:42:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192451136861983224222971614105044055762","date":"2024-10-30T11:49:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-29T10:34:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-29T06:25:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-29T06:24:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2024-10-29T01:01:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f80020ef-f421-41be-b35e-d7dc81f98173","owner":[],"postedDate":"November 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T16:05:05+00:00","versionOfRecord":{"articleIdentity":"rs-5350119","link":"https://doi.org/10.1007/s11060-024-04895-w","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2024-12-07 15:57:57","publishedOnDateReadable":"December 7th, 2024"},"versionCreatedAt":"2024-11-19 14:17:27","video":"","vorDoi":"10.1007/s11060-024-04895-w","vorDoiUrl":"https://doi.org/10.1007/s11060-024-04895-w","workflowStages":[]},"version":"v1","identity":"rs-5350119","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5350119","identity":"rs-5350119","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}