Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients

Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients ory haisraely, Marcia Jaffe, Yaacov Lawerence, Alicia Talianksy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4436485/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Whole-brain irradiation (WBRT) remains a standard treatment for patients with extensive brain metastases, providing symptom relief and prolonging survival. However, patients often experience recurrent metastases, necessitating re-irradiation. This study evaluates the efficacy and safety of cerebellar-only re-irradiation for improving symptoms and reducing toxicity in patients with recurrent cerebellar metastases following WBRT. Methods A retrospective review was conducted on patients who underwent cerebellar re-irradiation between 2017 and 2023 after prior WBRT for symptomatic cerebellar metastases. Clinical, dosimetric, and outcome data were collected. Symptom improvement was assessed based on patient, caregiver, and physician reports three months post-treatment. Results The study included 56 patients with a median age of 53 years. Symptom domains included gait dysfunction, nausea/vomiting, dysarthria, movement disorder, dizziness, and headache. Breast cancer was the most common histology. The median interval from WBRT to cerebellar re-irradiation was 15 months. Symptomatic improvement was observed in 75% of patients, with notable improvements in nausea/vomiting (84.6%) and headache (80%). Age, dose deliver and time from WBRT were significant for clinical improvement. Dexamethasone use decreased in 76.3% of patients post-treatment. Radiological responses correlated with clinical improvements in 90% of cases. Only one patient developed symptomatic radiation necrosis. Six-month overall survival and progression-free survival were 50% and 39.2%, respectively. Conclusion Cerebellar-only re-irradiation is an effective and safe option for managing recurrent cerebellar metastases, significantly improving symptoms with minimal toxicity. This approach also allows for subsequent systemic therapy or radiosurgery for supratentorial lesions, potentially reducing the need for additional WBRT. Further studies are required to validate these findings in larger cohorts. Brain metastases Radiotherapy Cerebellum Figures Figure 1 Figure 2 Figure 3 Introduction Whole-brain irradiation (WBRT) remains a standard choice of treatment and is indicated for many patients with these tumors. {1} Although hypofractionated stereotactic radiotherapies (SRTs) have become more common for treating patients with minimal brain metastases, some patients are not eligible to undergo SRT or surgery because of extensive brain metastases; instead, they receive whole-brain (WB) radiotherapy (WBRT) as first-line treatment. {2} For patients with extensive intra-cranial metastatic disease, WBRT provides symptom relief and prolongs survival. Several studies have also shown that cancer patients with brain metastases had an overall response rate of 75–85%, as estimated by symptom improvement or stabilization, and had an appreciable progression-free survival (PFS) period after receiving WBRT. {3}. Unfortunately, for some patients, re-irradiation is needed due to progressive brain disease. For these patients, re-WBRT may improve symptoms due to brain metastasis recurrence.{4} Central nervous system toxicity is an essential concern for physicians when considering re-WBRT, especially in patients for whom cognitive decline is a significant concern. {5} While most of these cancers metastasize to the supratentorial space, approximately 10–20% also metastasize to the posterior fossa.{6) Unlike most supratentorial counterparts, Cerebellar metastases can cause significant symptoms that are out of proportion with their size. These cerebellar lesions can cause obstructive hydrocephalus, brainstem compression, and herniation with acute neurological decline. This increased propensity for rapidly progressive symptoms makes these lesions appear clinically distinct from supratentorial lesions, with different presenting symptoms, risk profiles, treatment strategies, and potential outcomes.{7) In addition to unique clinical presentation, Patients with significant cerebellar disease have poorer prognosis. {7.8} Treating the cerebellum only in re-radiation may improve symptoms, control rapidly deteriorating disease, and decrease some side effects of re-WBRT. In addition, it may create an opportunity for response to systemic therapy or salvage radiosurgery for supra-tentorial lesions. This study aimed to determine whether cerebellar-only brain re-irradiation with or without focal stereotactic radiosurgery for supra-tentorial lesions was beneficial by conducting a retrospective analysis of cases from our institution. Methods Following institutional review board approval (0265-23-SMC), a retrospective review of patients undergoing re-irradiation between 2017 and 2023 for symptomatic brain metastases in the cerebellum after whole-brain radiotherapy was conducted. Clinical, dosimetric, and outcome data were collected and analyzed. Symptom data was searched in the patients' files before and three months after cerebellar radiation. Improvement of de-conditioning was considered based on patients' reports, caregiver reports, or physician reports. Statistical analyses were performed utilizing SPSS software (IBM, Chicago, USA version 29). All cases were discussed in a neuro-oncological tumor board meeting. In all cases, progressions of brain metastases were confirmed by MRI studies of the brain after the initial course of whole-brain irradiation. Results In this cohort, we analyzed 56 patients who had re-irradiation to the cerebellum only after WBRT. The median age was 53 (28-68). The Karnofsky performance status ranges from 70-90. All patients had cerebellar symptoms, which we divided into six main domains: 1) Gait dysfunction, 2) nausea and vomiting, 3) Dysarthria, 4) movement disorder, 5) dizziness, and 6) headache. In regards to histology, breast cancer was the most prevalent histology with 40 patients. The others were Small cell lung cancer (8), ovary adenocarcinoma (4), Non-small cell lung adenocarcinoma (3), and one Melanoma. The median time from WBRT to cerebellar RT was 15 months (8-25). The WBRT Technique was 3D in 85% and VMAT with hippocampal avoidance in 15%. 92% of patients received 30Gy in 10 fractions in the WBRT regiment, with the others 20Gy in 5 fractions. Figure 1,2,3. Cerebellar RT was delivered using 3D and VMAT in 57.2% and 42.8% of the cohort. Most (75%) received systemic therapy during or pre/post-RT course. 46% received radiosurgery for supra tentorial lesion after cerebellar RT treatment. With a median of 5 lesions (1-11) and a median dose of 20 (16-24), all received single-fraction treatment. The dose regiment was more heterogeneous: 20Gy in 10f (21.4%), 25Gy in 10f (21.4%), 25Gy in 5f (17.8%), 24Gy in 6f (17.8%), 30Gy in 12f (10.7%), and 30Gy in 10f (10.7%). Table 1 shows that the median follow-up time was 14 months (6-23). Symptomatic therapy with Dexamethasone dosages between 2mg-16mg per day was given to 67.8% (38) of the cohort before the second RT course. Clinical outcome All patients were symptomatic, with most presenting with more than one domain of cerebellar syndrome. The neuro-oncologist examination reported symptomatic improvement in 75% (42), with a median time to improvement ranging from 2 to 8 months post-radiation. Among the other 25% (7 patients), 4 had stable neurological symptoms, and in the other 3, there was deterioration. Among the 42 cases with symptomatic improvement, 38 had cerebellar metastasis disease only. Of the other 5 cases with supra-tentorial lesions, 4 had a significant burden with mass effect symptomatic motor weakness and aphasia. For them, radiosurgery was planned after cerebellar RT and was given successfully. One patient had only a minor disease, and the decision was made to treat only the cerebellum. The most common clinical improvement was in nausea and vomiting, with 22 out of 26 (84.6%) patients reporting improvement. Gait dysfunction improved in 8 out of 20 (40%) patients. Dysarthria improved in 6 out of 14 patients (42%), movement disorder in 10 out of 18 patients (55%), dizziness in 14 out of 24 (58.3%), and headache in 12 out of 15 (80%) patients. Dexamethasone use was decreased in 76.3% (29/38) of patients after RT treatment. In 89.8% (26/29), the reason was a symptomatic improvement. In 90% of patients with improved neurological function or neurological stability, there was a radiological response using the Radiological response assessment method. In comparison, in all patients with clinical deterioration, there was a radiological progression. Six months' overall survival from the start of re-radiation was 50%, with progression-free survival of 39.2%. Factors related to clinical improvement after cerebellar re-irradiation is shown in Table 2. in univariable analysis The following were significant factors related to clinical improvement after re-irradiation: age (18 months with OR of 0.67 {CI95%0.42-0.86}, P=0.034) and dose Equivalent dose in 2 Gy fractions (EQD2)(>30Gy with OR of 0.67 {CI95% 0.24-0.91}, p=0.042 ). Toxicity Among the 56 patients who were treated for re-RT in the cerebellum, only 1 developed symptomatic radiation necrosis (RN). This patient was 44 years old with a diagnosis of breast cancer. She received 30Gy in 10 fraction WBRT using the 3d technique, and five months later, due to progressive, symptomatic disease at the cerebellum, she received the second course of 25Gy in 5 fraction. She presented with headache and vomiting five months after 2nd RT course. At the Follow-up MRI, she had significant edema with a decrease in the size of metastatic lesions. After multi-parametric MRI, including a TRAM sequence, RNs favored it in a tumor board discussion. She needed to increase the Dexamethasone dosage up to 16 mg twice daily. Three weeks after Dexamethasone treatment, she had relief in symptomatic burden. Unfortunately, due to progressive systemic disease, this patient died eight months after the 2nd RT course. Discussion In this retrospective study, we aim to show that re-irradiation to the cerebellum is feasible and does have clinical benefits. Previous studies have shown that there have been a limited number of articles in the literature describing re-WBRT with acceptable toxicities, minimal side effects, and a treatment that provides symptomatic relief.{4.9} Over the years, radiation oncologists have become more generous when indicating a second course of WBRT, especially in patients where the time to prior WBRT is longer and extracranial disease remains controlled. Overall symptomatic improvement after Re-WBRT is between 24–74% among different studies [4,9,10]. Measuring symptomatic improvement is problematic and can result from significant bias dependent on the measurement toll. In our study, the overall symptomatic rate was higher than previously reported, with a 75% improvement after three months. Clinical variables impact symptomatic improvement, including longer intervals between RT course, age, and performance status. Age and performance status are known factors that impact OS in patients with brain metastases and are part of the GPA assessment. Longer time between RT courses may imply less aggressive intrinsic biology of the underlying metastases, creating an opportunity for average brain recovery.{11} In our study, symptoms of nausea, vomiting, and headache had the highest chance for improvement, with at least 80% improvement after RT. This may be because those symptoms relate to increasing ICP, perhaps due to pressure on the fourth ventricle. Decreasing the pressure by treating the underlying cause can result in a rapid and significant clinical response. Other symptomatic domains, including dizziness, gait ataxia, and movement disorder, are usually a result of intrinsic cerebellar injury, which is more difficult to recover from even after treatment. {12,13}. In our study, the measurement of symptomatic improvement was analyzed retrospectively by looking into patients' files and physician-reported free text summaries. This method has a significant intrinsic bias{14}, explaining the high percentage of clinical improvement. Another measurement of cerebellum burden, including patients' reported outcome using the 70-item Patient-Reported Outcome Measure of Ataxia, was scored on a 0–4 Likert scale. While validated and consistent, this measurement is time-consuming and difficult for metastatic oncologic patients with low-performance status. {15,16} The toxicity of re-irradiation is low, as previously published.{4.10} In our cohort, there was only one 1 case of symptomatic RN, which is 1.7% of the cohort. Several known factors impact RN incidence. Among them is the time between RT courses (higher incidence with interval 120Gy).{17} The fact that the patient in our cohort who developed RN had received a 2nd RT course less than six months and received a BED of 126.7Gy is consistent with previous knowledge. Another Late radiation toxicity is cognitive decline.{18} Most data is related to WBRT. The hippocampi are a well-known organ that relates to radiation injury and subsequent cognitive decline with robust data on dose constraints and radiation planning to avoid high doses to this organ.{19) The cerebellum impacts cognitive decline after RT, with most pediatric posterior fossa RT data. This mechanism of cerebellar injury after RT may be different and longer than the hippocampi injury mechanism.{20} Because most oncology patients who received the 2nd RT course have a poor prognosis with a median OS of 4–5 months, the cognitive decline after Cerebellar 2nd RT may not be as significant. Our study has several limitations, including retrospective analysis and measurement quality. Nonetheless, several strengths include a relatively large cohort of unique clinical approaches. Conclusion Despite the relative commonality of cerebellar metastases, studies on their clinical outcomes are limited. Most of these studies combine infratentorial and supratentorial lesions into the same study cohort, masking the outcomes for patients with less known cerebellar metastases. Our case series presents the outcomes of patients treated with cerebellar-only re-irradiation. This approach results in a high percentage of clinical symptomatic improvement with little toxicity. Age, dose deliver and time from WBRT were significant for clinical improvement. In addition, several patients were able to receive radiosurgery to supra tentorial lesions instead of re-WBRT after cerebellar-only re-RT, which may decrease toxicity. This approach needs to be validated in more extensive trials. Declarations Ethics approval and consent to participate-an IRB approval was given. 0265-23-SMC. in accordance with the Declaration of Helsinki Availability of data and materials -All information and data material are available. Funding -none. Patients treated in this cohort have had informed consent to the use of radiation planning and medical chard for research properties The experimental data and the simulation results that support the findings of this study are available Author Contribution OH -DATA analysis, statistical analysis, prepared figures and wrote main manuscrip MJ-english editing and scientific review YL-scintific review and radiation dataAT-scientific review and neurological data Acknowledgement i wish to acknowlegde the contibution of all neuro-oncological team at Sheba medical center References Gaspar, L., Scott, C., Murray, K., Curran, W. (1997). Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. International Journal of Radiation Oncology, Biology, Physics, 37(4), 745-75 Liang-Hua Ma et al, Hypofractionated stereotactic radiotherapy with or without whole-brain radiotherapy for patients with newly diagnosed brain metastases from non-small cell lung cancer, J Neurosurg2012 Dec:117 Suppl:49-56 Patchell, R.A., Tibbs, P.A., Walsh, J.W., Dempsey, R.J., Maruyama, Y., Kryscio, R.J. (1990). A randomized trial of surgery in the treatment of single metastases to the brain. New England Journal of Medicine, 322(8), 494-500 Ono T et al, Re-Whole Brain Radiotherapy May Be One of the Treatment Choices for Symptomatic Brain Metastases Patients, Cancers (Basel). 2022 Nov; 14(21): 5293 Sadikov E., Bezjak A., Yi Q.L., Wells W., Dawson L., Millar B.A., Laperriere N. Value of whole brain re-irradiation for brain metastases—Single centre experience. Clin. Oncol. (R. Coll. Radiol.) 2007;19:532–538 Steinruecke M et al, Survival and complications following supra- and infratentorial brain metastasis resection, The SurgeonVolume 21, Issue 5, October 2023, Pages e279-e286 Pompii A et al, Metastases to the cerebellum. Results and prognostic factors in a consecutive series of 44 operated patients, J Neurooncol2008 Jul;88(3):331-7. Keith J. Stelzer et al, Epidemiology and prognosis of brain metastases, SurgNeurol Int. 2013; 4(Suppl 4): S192–S202 Outcomes of reirradiation in the treatment of patients with multiple brain metastases of solid tumors: a retrospective analysis, Annals of translational medicine, Vol 3, No 21 Dec, 2015. Taso MN et al, Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases, Cochrane Database Syst Rev. 2012 Apr; 2012(4) Lambart AW et al, Emerging biology of metastatic disease, Cell. 2017 Feb 9; 168(4): 670–691. Changa AR, Czeisler BM, Lord AS. Management of Elevated Intracranial Pressure: a Review. CurrNeurolNeurosci Rep. 2019 Nov 26;19(12):99 Lig W et al, Consensus Paper: Management of Degenerative Cerebellar Disorders, Cerebellum. 2014 Apr; 13(2): 248–268. Marcott LM et al, Considerations of Bias and Reliability in Publicly Reported Physician Ratings, J Gen Intern Med. 2021 Dec; 36(12): 3857–3858 Schmahmann JD et al, Development and Validation of a Patient-Reported Outcome Measure of Ataxia, MovDisor, 2021 Oct;36(10):2367-2377 Potashman MH et al, Ataxia Rating Scales Reflect Patient Experience: an Examination of the Relationship Between Clinician Assessments of Cerebellar Ataxia and Patient-Reported Outcomes, Cerebellum. 2023 Dec;22(6):1257-1273. De Pietro R et al, The evolving role of reirradiation in the management of recurrent brain tumors, J Neurooncol. 2023; 164(2): 271–286 RÜba C et al, Radiation-Induced Brain Injury: Age Dependency of Neurocognitive Dysfunction Following Radiotherapy, Cancers (Basel). 2023 Jun; 15(11): 2999. Brown PD et al, Hippocampal Avoidance During Whole-Brain Radiotherapy PlusMemantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001, J ClinOncol. 2020 Apr 1; 38(10): 1019–1029. Jianpeng M et al, Investigation of high-dose radiotherapy's effect on brain structure aggravated cognitive impairment and deteriorated patient psychological status in brain tumor treatment, Sci Rep. May 2024; 14: 10149. Tables Table 1 Patients characteristics n 56 Age (mean, range) 53 (28-68) Histology Breast CA ER/PR +, Her-2 neg Breast CA HER-2 Positive Breast CA triple negative Small cell lung CA Ovary CA Non-small cell lung CA Melanoma 20 13 7 8 4 3 1 Median time from 1 RT 15 Month (8-25) 1 st RT dose (WBRT) 30GY in 10 fraction 20Gy in 5 fraction 92% 8% KPS in 2 RT 80 (70-90) Symptoms* Nausea Gait dysfunction and imbalance Dysarthria Movement disorder Dizziness Headache 46% 35.7% 25% 32.1% 42.8% 26.7% Symptomatic improvement at 3 month 75% *Total doesn't reach 100% with most patients presented with more than one symptom. CA-cancer, RT-radiotherapy, WBRT-whole brain radiation therapy, KPS-karnofsly performance status. Table 2 variables impact clinical improvement variable OR (CI95%), P Age 30Gy 0.67 (0.24-0.91),0.042 Histology breast Ca 0.84 (0.3-1.5), 0.091 Time from WBRT>18months 0.67 (0.42-0.86), 0.034 KPS>70 0.79 (0.057-2.2), 0.12 EQD2-equivalent dose at 2 Gy fractions, CA-cancer, WBRT-whole brain radiation therapy, KPS-karnofsly performance status. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4436485","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":309380459,"identity":"73d296e5-55ae-4bd6-bd5e-3a932043bb9d","order_by":0,"name":"ory haisraely","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIie2RsYrCQBCGZxmJTby0LnucrzApAyc+S7D1uHuCkCOwaaK1V/kW1hdS2OQBAluojZVF7MKR4jaCYKNJKbhfM1P8H8PwAxgMDwmTANQsGEKph9XvrrCQLRsF289YFzdE+3ytJe+ITO6qr+DTib+leP9bj14QWHma3Vb4wo/dhDJvmadSfCyUKxGQ/6xvK5QzObTpl6DwtZIophULBy0Krymg0XYvhZeoSSdF2IREhV6gUn6rwhOdfKWM3NyPvHmophJZdPcXx+4f+LEO6G2TpUVVq/EqjtLydEe5pjdsam0K6pbXYAl157DBYDA8Ef+eSE1bOS+RjQAAAABJRU5ErkJggg==","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":true,"prefix":"","firstName":"ory","middleName":"","lastName":"haisraely","suffix":""},{"id":309380460,"identity":"b9045ea4-b109-4b43-bf28-64067b6f7320","order_by":1,"name":"Marcia Jaffe","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Marcia","middleName":"","lastName":"Jaffe","suffix":""},{"id":309380461,"identity":"35d08577-9a47-4d19-a2c0-7f4cc3dc2c66","order_by":2,"name":"Yaacov Lawerence","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yaacov","middleName":"","lastName":"Lawerence","suffix":""},{"id":309380462,"identity":"0dd368ab-d795-45d0-a987-e1d90620c4ec","order_by":3,"name":"Alicia Talianksy","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Alicia","middleName":"","lastName":"Talianksy","suffix":""}],"badges":[],"createdAt":"2024-05-17 11:40:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4436485/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4436485/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58147874,"identity":"4c00d85d-ff79-486f-9d24-9003d7f9200c","added_by":"auto","created_at":"2024-06-11 18:46:08","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21359,"visible":true,"origin":"","legend":"\u003cp\u003eMRI T1 with Gd. 52 year old Breast cancer patient. She was presented with cerebellar progression disease (White arrow), 16 month after whole brain radiotherapy.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4436485/v1/cc56a70f4ca1381f83cb6e8f.jpg"},{"id":58146744,"identity":"b0ee01cb-4f2d-4680-96c8-440d246a4770","added_by":"auto","created_at":"2024-06-11 18:38:08","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29695,"visible":true,"origin":"","legend":"\u003cp\u003eradiation planning using 3D approach.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4436485/v1/9059859661e21cfbcc6289f9.jpg"},{"id":58147875,"identity":"5d324e72-b24b-4450-a540-d1c617920341","added_by":"auto","created_at":"2024-06-11 18:46:08","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":29683,"visible":true,"origin":"","legend":"\u003cp\u003eMRI T1+Gd. 3 month after Radiotherapy.Radiological response.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4436485/v1/fe3ec580d7b982e7ac31c6ef.jpg"},{"id":61766202,"identity":"84c713ef-abbb-468c-8241-aafc39b3561f","added_by":"auto","created_at":"2024-08-05 10:31:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":365811,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4436485/v1/673f8869-5d7c-40fd-abae-083fef1c80d5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWhole-brain irradiation (WBRT) remains a standard choice of treatment and is indicated for many patients with these tumors. {1}\u003c/p\u003e \u003cp\u003eAlthough hypofractionated stereotactic radiotherapies (SRTs) have become more common for treating patients with minimal brain metastases, some patients are not eligible to undergo SRT or surgery because of extensive brain metastases; instead, they receive whole-brain (WB) radiotherapy (WBRT) as first-line treatment. {2} For patients with extensive intra-cranial metastatic disease, WBRT provides symptom relief and prolongs survival. Several studies have also shown that cancer patients with brain metastases had an overall response rate of 75\u0026ndash;85%, as estimated by symptom improvement or stabilization, and had an appreciable progression-free survival (PFS) period after receiving WBRT. {3}.\u003c/p\u003e \u003cp\u003eUnfortunately, for some patients, re-irradiation is needed due to progressive brain disease. For these patients, re-WBRT may improve symptoms due to brain metastasis recurrence.{4} Central nervous system toxicity is an essential concern for physicians when considering re-WBRT, especially in patients for whom cognitive decline is a significant concern. {5}\u003c/p\u003e \u003cp\u003eWhile most of these cancers metastasize to the supratentorial space, approximately 10\u0026ndash;20% also metastasize to the posterior fossa.{6) Unlike most supratentorial counterparts, Cerebellar metastases can cause significant symptoms that are out of proportion with their size. These cerebellar lesions can cause obstructive hydrocephalus, brainstem compression, and herniation with acute neurological decline. This increased propensity for rapidly progressive symptoms makes these lesions appear clinically distinct from supratentorial lesions, with different presenting symptoms, risk profiles, treatment strategies, and potential outcomes.{7)\u003c/p\u003e \u003cp\u003eIn addition to unique clinical presentation, Patients with significant cerebellar disease have poorer prognosis. {7.8}\u003c/p\u003e \u003cp\u003eTreating the cerebellum only in re-radiation may improve symptoms, control rapidly deteriorating disease, and decrease some side effects of re-WBRT. In addition, it may create an opportunity for response to systemic therapy or salvage radiosurgery for supra-tentorial lesions.\u003c/p\u003e \u003cp\u003eThis study aimed to determine whether cerebellar-only brain re-irradiation with or without focal stereotactic radiosurgery for supra-tentorial lesions was beneficial by conducting a retrospective analysis of cases from our institution.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eFollowing institutional review board approval (0265-23-SMC), a retrospective review of patients undergoing re-irradiation between 2017 and 2023 for symptomatic brain metastases in the cerebellum after whole-brain radiotherapy was conducted. Clinical, dosimetric, and outcome data were collected and analyzed. Symptom data was searched in the patients' files before and three months after cerebellar radiation. Improvement of de-conditioning was considered based on patients' reports, caregiver reports, or physician reports.\u003c/p\u003e \u003cp\u003eStatistical analyses were performed utilizing SPSS software (IBM, Chicago, USA version 29). All cases were discussed in a neuro-oncological tumor board meeting. In all cases, progressions of brain metastases were confirmed by MRI studies of the brain after the initial course of whole-brain irradiation.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn this cohort, we analyzed 56 patients who had re-irradiation to the cerebellum only after WBRT. \u0026nbsp;The median age was 53 (28-68). The Karnofsky performance status ranges from 70-90. All patients had cerebellar symptoms, which we divided into six main domains: 1) Gait dysfunction, 2) nausea and vomiting, 3) Dysarthria, 4) movement disorder, 5) dizziness, and 6) headache. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn regards to histology, breast cancer was the most prevalent histology with 40 patients. The others were Small cell lung cancer (8), ovary adenocarcinoma (4), Non-small cell lung adenocarcinoma (3), and one Melanoma. The median time from WBRT to cerebellar RT was 15 months (8-25). The WBRT Technique was 3D in 85% and VMAT with hippocampal avoidance in 15%. 92% of patients received 30Gy in 10 fractions in the WBRT regiment, with the others 20Gy in 5 fractions. Figure 1,2,3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCerebellar RT was delivered using 3D and VMAT in 57.2% and 42.8% of the cohort. Most (75%) received systemic therapy during or pre/post-RT course. 46% received radiosurgery for supra tentorial lesion after cerebellar RT treatment. With a median of 5 lesions (1-11) and a median dose of 20 (16-24), all received single-fraction treatment. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe dose regiment was more heterogeneous: 20Gy in 10f (21.4%), 25Gy in 10f (21.4%), 25Gy in 5f (17.8%), 24Gy in 6f (17.8%), 30Gy in 12f (10.7%), and 30Gy in 10f (10.7%). Table 1 shows that the median follow-up time was 14 months (6-23). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSymptomatic therapy with Dexamethasone dosages between 2mg-16mg per day was given to 67.8% (38) of the cohort before the second RT course.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eClinical outcome\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were symptomatic, with most presenting with more than one domain of cerebellar syndrome. The neuro-oncologist examination reported symptomatic improvement in 75% (42), with a median time to improvement ranging from 2 to 8 months post-radiation. Among the other 25% (7 patients), 4 had stable neurological symptoms, and in the other 3, there was deterioration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the 42 cases with symptomatic improvement, 38 had cerebellar metastasis disease only. Of the other 5 cases with supra-tentorial lesions, 4 had a significant burden with mass effect symptomatic motor weakness and aphasia. For them, radiosurgery was planned after cerebellar RT and was given successfully. One patient had only a minor disease, and the decision was made to treat only the cerebellum. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe most common clinical improvement was in nausea and vomiting, with 22 out of 26 (84.6%) patients reporting improvement. Gait dysfunction improved in 8 out of 20 (40%) patients. Dysarthria improved in 6 out of 14 patients (42%), movement disorder in 10 out of 18 patients (55%), dizziness in 14 out of 24 (58.3%), and headache in 12 out of 15 (80%) patients. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDexamethasone use was decreased in 76.3% (29/38) of patients after RT treatment. In 89.8% (26/29), the reason was a symptomatic improvement. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn 90% of patients with improved neurological function or neurological stability, there was a radiological response using the Radiological response assessment method.\u0026nbsp;In comparison, in all patients with clinical deterioration, there was a radiological progression.\u003c/p\u003e\n\u003cp\u003eSix months' overall survival from the start of re-radiation was 50%, with progression-free survival of 39.2%. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFactors related to clinical improvement after cerebellar re-irradiation is shown in Table\u0026nbsp;2. in univariable analysis The following were significant factors related to clinical improvement after re-irradiation: age (\u0026lt;40 with OR of 0.56 {CI95% 0.1-0.86}, p=0.023), time from 1st RT (\u0026gt;18 months with OR of 0.67 {CI95%0.42-0.86}, P=0.034) and dose Equivalent dose in 2 Gy fractions (EQD2)(\u0026gt;30Gy with OR of \u0026nbsp;0.67 {CI95% 0.24-0.91}, p=0.042 ).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eToxicity\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 56 patients who were treated for re-RT in the cerebellum, only 1 developed symptomatic radiation necrosis (RN). This patient was 44 years old with a diagnosis of breast cancer. She received 30Gy in 10 fraction WBRT using the 3d technique, and five months later, due to progressive, symptomatic disease at the cerebellum, she received the second course of 25Gy in 5 fraction. She presented with headache and vomiting five months after 2nd RT course. At the Follow-up MRI, she had significant edema with a decrease in the size of metastatic lesions. After multi-parametric MRI, including a TRAM sequence, RNs favored it in a tumor board discussion. She needed to increase the Dexamethasone dosage up to 16 mg twice daily. Three weeks after Dexamethasone treatment, she had relief in symptomatic burden. Unfortunately, due to progressive systemic disease, this patient died eight months after the 2nd RT course.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective study, we aim to show that re-irradiation to the cerebellum is feasible and does have clinical benefits. Previous studies have shown that there have been a limited number of articles in the literature describing re-WBRT with acceptable toxicities, minimal side effects, and a treatment that provides symptomatic relief.{4.9} Over the years, radiation oncologists have become more generous when indicating a second course of WBRT, especially in patients where the time to prior WBRT is longer and extracranial disease remains controlled.\u003c/p\u003e \u003cp\u003eOverall symptomatic improvement after Re-WBRT is between 24\u0026ndash;74% among different studies [4,9,10]. Measuring symptomatic improvement is problematic and can result from significant bias dependent on the measurement toll. In our study, the overall symptomatic rate was higher than previously reported, with a 75% improvement after three months. Clinical variables impact symptomatic improvement, including longer intervals between RT course, age, and performance status. Age and performance status are known factors that impact OS in patients with brain metastases and are part of the GPA assessment. Longer time between RT courses may imply less aggressive intrinsic biology of the underlying metastases, creating an opportunity for average brain recovery.{11}\u003c/p\u003e \u003cp\u003eIn our study, symptoms of nausea, vomiting, and headache had the highest chance for improvement, with at least 80% improvement after RT. This may be because those symptoms relate to increasing ICP, perhaps due to pressure on the fourth ventricle. Decreasing the pressure by treating the underlying cause can result in a rapid and significant clinical response. Other symptomatic domains, including dizziness, gait ataxia, and movement disorder, are usually a result of intrinsic cerebellar injury, which is more difficult to recover from even after treatment. {12,13}.\u003c/p\u003e \u003cp\u003eIn our study, the measurement of symptomatic improvement was analyzed retrospectively by looking into patients' files and physician-reported free text summaries. This method has a significant intrinsic bias{14}, explaining the high percentage of clinical improvement. Another measurement of cerebellum burden, including patients' reported outcome using the 70-item Patient-Reported Outcome Measure of Ataxia, was scored on a 0\u0026ndash;4 Likert scale. While validated and consistent, this measurement is time-consuming and difficult for metastatic oncologic patients with low-performance status. {15,16}\u003c/p\u003e \u003cp\u003eThe toxicity of re-irradiation is low, as previously published.{4.10} In our cohort, there was only one 1 case of symptomatic RN, which is 1.7% of the cohort. Several known factors impact RN incidence. Among them is the time between RT courses (higher incidence with interval\u0026thinsp;\u0026lt;\u0026thinsp;6 months) and the cumulative BED (higher incidence with dose\u0026thinsp;\u0026gt;\u0026thinsp;120Gy).{17} The fact that the patient in our cohort who developed RN had received a 2nd RT course less than six months and received a BED of 126.7Gy is consistent with previous knowledge.\u003c/p\u003e \u003cp\u003eAnother Late radiation toxicity is cognitive decline.{18} Most data is related to WBRT. The hippocampi are a well-known organ that relates to radiation injury and subsequent cognitive decline with robust data on dose constraints and radiation planning to avoid high doses to this organ.{19) The cerebellum impacts cognitive decline after RT, with most pediatric posterior fossa RT data. This mechanism of cerebellar injury after RT may be different and longer than the hippocampi injury mechanism.{20} Because most oncology patients who received the 2nd RT course have a poor prognosis with a median OS of 4\u0026ndash;5 months, the cognitive decline after Cerebellar 2nd RT may not be as significant.\u003c/p\u003e \u003cp\u003eOur study has several limitations, including retrospective analysis and measurement quality. Nonetheless, several strengths include a relatively large cohort of unique clinical approaches.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDespite the relative commonality of cerebellar metastases, studies on their clinical outcomes are limited. Most of these studies combine infratentorial and supratentorial lesions into the same study cohort, masking the outcomes for patients with less known cerebellar metastases.\u003c/p\u003e \u003cp\u003eOur case series presents the outcomes of patients treated with cerebellar-only re-irradiation. This approach results in a high percentage of clinical symptomatic improvement with little toxicity. Age, dose deliver and time from WBRT were significant for clinical improvement. In addition, several patients were able to receive radiosurgery to supra tentorial lesions instead of re-WBRT after cerebellar-only re-RT, which may decrease toxicity. This approach needs to be validated in more extensive trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp dir=\"LTR\"\u003eEthics approval and consent to participate-an IRB approval was given. 0265-23-SMC.\u0026nbsp;in accordance with the Declaration of Helsinki\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e-All information and data material are available.\u0026nbsp;\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eFunding\u003c/strong\u003e-none.\u0026nbsp;\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003ePatients treated in this cohort have had informed consent to the use of radiation planning and medical chard for research properties\u0026nbsp;\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eThe experimental data and the simulation results that support the findings of this study are available\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eOH -DATA analysis, statistical analysis, prepared figures and wrote main manuscrip MJ-english editing and scientific review YL-scintific review and radiation dataAT-scientific review and neurological data\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003ei wish to acknowlegde the contibution of all neuro-oncological team at Sheba medical center\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGaspar, L., Scott, C., Murray, K., Curran, W. (1997). Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. International Journal of Radiation Oncology, Biology, Physics, 37(4), 745-75\u003c/li\u003e\n\u003cli\u003eLiang-Hua Ma et al, Hypofractionated stereotactic radiotherapy with or without whole-brain radiotherapy for patients with newly diagnosed brain metastases from non-small cell lung cancer, J Neurosurg2012 Dec:117 Suppl:49-56\u003c/li\u003e\n\u003cli\u003ePatchell, R.A., Tibbs, P.A., Walsh, J.W., Dempsey, R.J., Maruyama, Y., Kryscio, R.J. (1990). A randomized trial of surgery in the treatment of single metastases to the brain. New England Journal of Medicine, 322(8), 494-500\u003c/li\u003e\n\u003cli\u003eOno T et al, Re-Whole Brain Radiotherapy May Be One of the Treatment Choices for Symptomatic Brain Metastases Patients, Cancers (Basel). 2022 Nov; 14(21): 5293\u003c/li\u003e\n\u003cli\u003eSadikov E., Bezjak A., Yi Q.L., Wells W., Dawson L., Millar B.A., Laperriere N. Value of whole brain re-irradiation for brain metastases\u0026mdash;Single centre experience. Clin. Oncol. (R. Coll. Radiol.) 2007;19:532\u0026ndash;538\u003c/li\u003e\n\u003cli\u003eSteinruecke M et al, Survival and complications following supra- and infratentorial brain metastasis resection, The SurgeonVolume 21, Issue 5, October 2023, Pages e279-e286\u003c/li\u003e\n\u003cli\u003ePompii A et al, Metastases to the cerebellum. Results and prognostic factors in a consecutive series of 44 operated patients, J Neurooncol2008 Jul;88(3):331-7.\u003c/li\u003e\n\u003cli\u003eKeith J. Stelzer et al, Epidemiology and prognosis of brain metastases, SurgNeurol Int. 2013; 4(Suppl 4): S192\u0026ndash;S202\u003c/li\u003e\n\u003cli\u003eOutcomes of reirradiation in the treatment of patients with multiple brain metastases of solid tumors: a retrospective analysis, Annals of translational medicine, Vol 3, No 21 Dec, 2015.\u003c/li\u003e\n\u003cli\u003eTaso MN et al, Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases, Cochrane Database Syst Rev. 2012 Apr; 2012(4)\u003c/li\u003e\n\u003cli\u003eLambart AW et al, Emerging biology of metastatic disease, Cell. 2017 Feb 9; 168(4): 670\u0026ndash;691.\u003c/li\u003e\n\u003cli\u003eChanga AR, Czeisler BM, Lord AS. Management of Elevated Intracranial Pressure: a Review. CurrNeurolNeurosci Rep. 2019 Nov 26;19(12):99\u003c/li\u003e\n\u003cli\u003eLig W et al, Consensus Paper: Management of Degenerative Cerebellar Disorders, Cerebellum. 2014 Apr; 13(2): 248\u0026ndash;268.\u003c/li\u003e\n\u003cli\u003eMarcott LM et al, Considerations of Bias and Reliability in Publicly Reported Physician Ratings, J Gen Intern Med. 2021 Dec; 36(12): 3857\u0026ndash;3858\u003c/li\u003e\n\u003cli\u003eSchmahmann JD et al, Development and Validation of a Patient-Reported Outcome Measure of Ataxia, MovDisor, 2021 Oct;36(10):2367-2377\u003c/li\u003e\n\u003cli\u003ePotashman MH et al, Ataxia Rating Scales Reflect Patient Experience: an Examination of the Relationship Between Clinician Assessments of Cerebellar Ataxia and Patient-Reported Outcomes, Cerebellum. 2023 Dec;22(6):1257-1273. \u003c/li\u003e\n\u003cli\u003eDe Pietro R et al, The evolving role of reirradiation in the management of recurrent brain tumors, J Neurooncol. 2023; 164(2): 271\u0026ndash;286\u003c/li\u003e\n\u003cli\u003eR\u0026Uuml;ba C et al, Radiation-Induced Brain Injury: Age Dependency of Neurocognitive Dysfunction Following Radiotherapy, Cancers (Basel). 2023 Jun; 15(11): 2999.\u003c/li\u003e\n\u003cli\u003eBrown PD et al, Hippocampal Avoidance During Whole-Brain Radiotherapy PlusMemantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001, J ClinOncol. 2020 Apr 1; 38(10): 1019\u0026ndash;1029.\u003c/li\u003e\n\u003cli\u003eJianpeng M et al, Investigation of high-dose radiotherapy\u0026apos;s effect on brain structure aggravated cognitive impairment and deteriorated patient psychological status in brain tumor treatment, Sci Rep. May 2024; 14: 10149.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Patients characteristics\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eAge (mean, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e53 (28-68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eHistology\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBreast CA ER/PR +, Her-2 neg\u003c/p\u003e\n \u003cp\u003eBreast CA HER-2 Positive\u003c/p\u003e\n \u003cp\u003eBreast CA triple negative\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSmall cell lung CA\u003c/p\u003e\n \u003cp\u003eOvary CA\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNon-small cell lung CA\u003c/p\u003e\n \u003cp\u003eMelanoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMedian time from 1 RT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e15 Month (8-25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e RT dose (WBRT)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30GY in 10 fraction\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20Gy in 5 fraction\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e92%\u003c/p\u003e\n \u003cp\u003e8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eKPS in 2 RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e80 (70-90)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSymptoms*\u003c/p\u003e\n \u003cp\u003eNausea\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eGait dysfunction and imbalance \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eDysarthria\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMovement disorder\u003c/p\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003cp\u003eHeadache\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e46%\u003c/p\u003e\n \u003cp\u003e35.7%\u003c/p\u003e\n \u003cp\u003e25%\u003c/p\u003e\n \u003cp\u003e32.1%\u003c/p\u003e\n \u003cp\u003e42.8%\u003c/p\u003e\n \u003cp\u003e26.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSymptomatic improvement at 3 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e75%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Total doesn\u0026apos;t reach 100% with most patients presented with more than one symptom. CA-cancer, RT-radiotherapy, WBRT-whole brain radiation therapy, KPS-karnofsly performance status.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 variables impact clinical improvement \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003evariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.86274509803921%\" valign=\"top\"\u003e\n \u003cp\u003eOR (CI95%), P\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003eAge \u0026lt;40y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.86274509803921%\" valign=\"top\"\u003e\n \u003cp\u003e0.56(0.1-0.86), 0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003eEQD2\u0026gt;30Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.86274509803921%\" valign=\"top\"\u003e\n \u003cp\u003e0.67 (0.24-0.91),0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003eHistology breast Ca\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.86274509803921%\" valign=\"top\"\u003e\n \u003cp\u003e0.84 (0.3-1.5), 0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003eTime from WBRT\u0026gt;18months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.86274509803921%\" valign=\"top\"\u003e\n \u003cp\u003e0.67 (0.42-0.86), 0.034\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.13725490196079%\" valign=\"top\"\u003e\n \u003cp\u003eKPS\u0026gt;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"56.86274509803921%\" valign=\"top\"\u003e\n \u003cp\u003e0.79 (0.057-2.2), 0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eEQD2-equivalent dose at 2 Gy fractions, CA-cancer, WBRT-whole brain radiation therapy, KPS-karnofsly performance status.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Brain metastases, Radiotherapy, Cerebellum ","lastPublishedDoi":"10.21203/rs.3.rs-4436485/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4436485/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eIntroduction\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWhole-brain irradiation (WBRT) remains a standard treatment for patients with extensive brain metastases, providing symptom relief and prolonging survival. However, patients often experience recurrent metastases, necessitating re-irradiation. This study evaluates the efficacy and safety of cerebellar-only re-irradiation for improving symptoms and reducing toxicity in patients with recurrent cerebellar metastases following WBRT.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA retrospective review was conducted on patients who underwent cerebellar re-irradiation between 2017 and 2023 after prior WBRT for symptomatic cerebellar metastases. Clinical, dosimetric, and outcome data were collected. Symptom improvement was assessed based on patient, caregiver, and physician reports three months post-treatment.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe study included 56 patients with a median age of 53 years. Symptom domains included gait dysfunction, nausea/vomiting, dysarthria, movement disorder, dizziness, and headache. Breast cancer was the most common histology. The median interval from WBRT to cerebellar re-irradiation was 15 months. Symptomatic improvement was observed in 75% of patients, with notable improvements in nausea/vomiting (84.6%) and headache (80%). Age, dose deliver and time from WBRT were significant for clinical improvement. Dexamethasone use decreased in 76.3% of patients post-treatment. Radiological responses correlated with clinical improvements in 90% of cases. Only one patient developed symptomatic radiation necrosis. Six-month overall survival and progression-free survival were 50% and 39.2%, respectively.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCerebellar-only re-irradiation is an effective and safe option for managing recurrent cerebellar metastases, significantly improving symptoms with minimal toxicity. This approach also allows for subsequent systemic therapy or radiosurgery for supratentorial lesions, potentially reducing the need for additional WBRT. Further studies are required to validate these findings in larger cohorts.\u003c/p\u003e","manuscriptTitle":"Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-11 18:38:03","doi":"10.21203/rs.3.rs-4436485/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7eaf5185-f476-497d-bd50-ba39778777a7","owner":[],"postedDate":"June 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-22T14:38:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-11 18:38:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4436485","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4436485","identity":"rs-4436485","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}