Patterns of Disease Progression in patients with newly diagnosed Primary Central Nervous System Lymphoma Following Treatment with High-Dose Methotrexate

Patterns of Disease Progression in patients with newly diagnosed Primary Central Nervous System Lymphoma Following Treatment with High-Dose Methotrexate | 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 Patterns of Disease Progression in patients with newly diagnosed Primary Central Nervous System Lymphoma Following Treatment with High-Dose Methotrexate Louis Cappelli, Allison Kayne, Jennifer Newman, Muhammad Sharif, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4254111/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 : Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma that primarily affects the brain, spinal cord, and/or eyes. Despite advances in treatment, PCNSL remains a formidable challenge due to its aggressive nature and limited understanding of disease progression. Recurrence of PCNSL within the central nervous system (CNS) is not uncommon, but patterns of intracranial recurrence following induction chemotherapy have not been extensively studied. This study aims to elucidate the patterns of recurrence in PCNSL, providing insight into the disease’s behavior. Methods : Patient charts and diagnostic imaging from those treated for PCNSL from 2 institutions and ≥ 18 years old from the years 2011-2023 were retrospectively reviewed. Relevant data from the charts to identify disease progression, patterns of recurrence, and survival was collected from the patient charts. The pattern of recurrence was reviewed by comparing the initial diagnostic MRI to the recurrence MRI (T1 post-contrast and T2/FLAIR sequences). The pattern of recurrence was classified as either local or distant depending on the anatomical location of the recurrent lesion. Distant recurrences were classified as those separate from the previous enhancing lesion and located outside of the initial T2/FLAIR abnormality appreciated on imaging. Local recurrences were classified as new lesions that overlapped with the primary enhancing lesion/T2/FLAIR abnormality. Results : 29 out of 47 patients met inclusion criteria with PCNSL and progressed through initial definitive treatment with high-dose methotrexate (HDMTX) or HDMTX and rituximab; with only 1 patient receiving initial management with radiation therapy. The median age at time of diagnosis was 73.0 years (range: 44.0-78.0), with 16 (55.2%) patients being male and 13 (44.8%) female. Eighteen of the 29 patients were found to have multifocal disease. 14/29 (48.3%) patients had distant recurrence only, 11/29 (37.9%) had only local recurrence, whereas 4/29 (13.8%) displayed both local and distant recurrence pattern. The median time until disease progression was 7.1 months (range: 1.3-69.0). Twelve of the 29 patients had a complete response (CR) to initial systemic therapy, 7 had a partial response (PR), and 10 patients had disease progression through HDMTX. Of the 18 patients who had multifocal disease at the time of diagnosis, 6 had disease progression through HDMTX, with 5 experiencing PR and only 7 achieved CR. Conclusion : Patterns of disease progression in patients diagnosed with PCNSL are not very well understood. In this retrospective review, we identified that the majority of disease recurrence in patients diagnosed with PCNSL who underwent HDMTX was outside or distant to the primary disease site vs solely local disease progression intracranially (62.1% vs 37.9%). Such findings need to be illustrated in a larger cohort to confirm such patterns; however, this insight raises awareness of the need for further advances in achieving higher and more durable rates of control for this rare disease. PCNSL HDMTX methotrexate CNS lymphoma pattern of progression newly diagnosed Adult Figures Figure 1 Figure 2 Figure 3 Introduction Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma, primarily affecting the brain, spinal cord, and eyes. Representing about 4–6% of extranodal lymphomas and 4% of primary brain tumors, PCNSL poses unique clinical challenges ( 1 ). The disease occurs in both immunocompetent and immunocompromised individuals, with a median overall survival of approximately 25 months ( 2 ). Unlike many primary brain tumors, PCNSL shows a favorable initial response to chemotherapy, particularly regimens centered around high-dose methotrexate (HDMTX), often combined with agents like cytarabine or rituximab ( 3 – 4 ). Despite initial responses, the disease's aggressive nature necessitates consolidation therapy post-induction to mitigate high relapse rates, which occur in most patients within five years without complete eradication of residual disease ( 2 ). A central challenge in the treatment of PCNSL stems from its aggressive nature and a limited understanding of disease progression. Recurrence of PCNSL within the central nervous system (CNS) is not uncommon, but patterns of intracranial recurrence following induction chemotherapy have not been extensively studied. A study by Plasswilm et al. looked at progression patterns after consolidative whole brain radiation therapy, finding up to 90% of recurrences to be local, whereas 10% were considered disseminated disease ( 5 ). Another limited study by Altendorneburg et al. of sixteen immunocompetent patients receiving a methotrexate-based polychemotherapy showed that four patients had local recurrence, six had bilateral involvement of the brain at recurrence, and two had a recurrence on the opposite side of the brain from which the original tumor was ( 6 ). Aside from the studies mentioned, there is very little additional literature analyzing the local and distant progression of PCNSL after induction chemotherapy. In the present study, we aimed to identify the patterns of recurrence in PCNSL after HDMTX-based induction chemotherapy. Having a better understanding of the progression of PCNSL can help us understand the disease’s behavior with implications for optimizing consolidation strategies to improve patient treatment outcomes. Methods This study was conducted with the approval of the Institutional Review Board (IRB) of Thomas Jefferson University and The Ohio State University. In compliance with ethical standards, patient confidentiality was rigorously maintained, and all data were anonymized prior to analysis. Given the retrospective design of the study, which involved the review of existing medical records and imaging data, the IRB provided a waiver for the requirement of individual patient consent. This study adheres to the ethical guidelines and standards for human research as outlined by Thomas Jefferson University and relevant regulatory bodies. Patients This is a retrospective chart and diagnostic imaging review of patients treated for PCNSL from the years 2011–2023, which was completed at Jefferson University and The Ohio State University. Immunocompetent patients ≥ 18 years old with PCNSL initially treated with a regimen including HDMTX and available MRIs illustrating the initial and recurrent disease were included in this study. Primary CNS lymphoma was diagnosed based on pathology diagnosis. All patients had brain biopsy or surgery. Systemic imaging was negative for systemic involvement of lymphoma. Treatment Relevant data from the medical charts including, patient demographics, tumor laterality, disease progression, patterns of recurrence, and survival, was collected from electronic health records. In addition, characteristics of each patient’s treatment were collected, including if they received initial radiation therapy, the number of HDMTX cycles, if additional chemotherapy agents were used, and which agents they were, along with the type of treatment at recurrence. Whether the patient had achieved a complete response (CR) or partial response (PR) was determined based on pre- and post-treatment MRI imaging comparison and the degree of tumor reduction. The International PCNSL collaborative group response criteria for PCNSL was used. Progression-free survival (PFS) was calculated as the time in months between the date of the initial scan showing PCNSL and the date of the MRI showing progression. Imaging Analysis The pattern of recurrence was reviewed by comparing the initial diagnostic MRI to the recurrence MRI (T1 post-contrast and T2/FLAIR sequence). The pattern of recurrence was classified as either local or distant, depending on the anatomical location of the recurrent lesion. Each diagnostic MRI was reviewed by two to three independent physicians to confirm the recurrence pattern. Local recurrences were classified as new lesions that overlapped with the primary enhancing lesion/FLAIR abnormality. Lesions of distant recurrence were classified as those separate from the previous enhancing lesion and located outside of the initial FLAIR abnormality appreciated on imaging. (Fig. 1 ) Statistics Descriptive statistics were used for calculating mean, median, and range of patient characteristics and the nature/involvement of disease involvement, as well as a Chi-square used to determine the statistical significance between two variables, were performed via R software. Results A total of 47 immunocompetent patients with newly diagnosed CNS/ocular lymphoma were identified. Four patients were found to have primary vitreoretinal lymphoma and excluded from the study. Twenty-nine of the remaining 43 patients were identified to have progressed through initial definitive treatment. The median age of diagnosis was 73.0 years (range: 44.0–78.0), with 16 (55.2%) patients being male and 13 (44.8%) female. At the time of diagnosis, 2 patients were found to have spinal involvement, 1 had ocular involvement, and 3 had cerebral spinal fluid (CSF) involvement. All patients were treated with high-dose methotrexate (HDMTX) or HDMTX and rituximab, with 1 of the 29 receiving additional initial management with radiation therapy. The average number of completed HDMTX cycles was 6, with an average dose of 3.5 g/m 2 (range: 2.0 g/m 2 − 6.0 g/m 2 ). Thirteen of the 29 patients were treated with both HDMTX and rituximab. Eighteen patients (65.5%) were found to have multifocal disease at the time of diagnosis. (Table 1 ) Twelve (41.4%) of the 29 patients had a complete response (CR) to initial systemic therapy, 7 (24.1%) had a partial response (PR), and 10 (34.5%) patients had refractory disease with HDMTX treatment. Following definitive HDMTX, 14 (48.3%) patients had distant recurrence only, 11 (37.9%) had only local recurrence, and 4 (13.8%) displayed both a local and distant recurrence pattern. (Fig. 2 ) The median time until disease progression was 7.1 months (range: 1.3–69.0, average 17.9). Three patients had distant sub-ependymal spread of disease, one from a patient that displayed distant progression, local progression, and local and distant progression. (Table 2 ) Of the 18 patients who had multifocal disease at the time of diagnosis, 6 were refractory to induction HDMTX, with 5 experiencing PR and 7 achieving CR (Fig. 3 ). Twelve of the 18 (66.7%) demonstrated either distant or local and distant disease progression at time or recurrence, vs. only 6 (33.3%) showing local spread of disease. (Table 2 ) Such findings evaluating multifocal disease at presentation to have an increased likelihood of developing distant disease progression compared to those without was not determined to be significant (p = 0.796, Chi-square). Discussion Although typically responsive to initial chemotherapy, PCNSL remains a difficult disease to treat. HDMTX is the mainstay chemotherapy of choice ( 7 ). HDMTX as monotherapy has been associated with less toxicity as compared to combination regimens; however, a methotrexate-based polychemotherapy regimen has proven higher response rates, longer progression-free survival, and a reduction in primary progression rates ( 8 – 11 ). Despite advances in the initial treatment of PCNSL with HDMTX for those who can tolerate it, there is limited understanding of the intracranial recurrence patterns appreciated in this disease. In a study by Gavrilovic et al. on 57 patients who received methotrexate-based chemotherapy with or without WBRT, 25 of the patients relapsed or progressed, with an average time to relapse of 10.5 months. 11 of the 25 patients relapsed in the brain, 3 had an either ocular or leptomeningeal recurrence, and 6 had relapsed in both the brain and another site like the leptomeninges ( 13 ). A post-hoc study on MRI characteristics of PCNSL by Tabouret et al. included 85 patients who were enrolled in the ANOCEF-GOELAMS phase II clinical trial that randomized patients in either receiving HDMTX, vincristine, procarbazine, and cytarabine or HDMTX and temozolomide. 52 of 89 patients relapsed in the brain, with 46% relapsing at the initial enhancing site, 40% at a different site, and 14% at both the initial site and a different site ( 14 ). In our cohort of 43 patients treated with a HDMTX-based chemotherapy regimen, we characterized local recurrences as new lesions that overlapped with the primary enhancing lesion/FLAIR abnormality and lesions of distant recurrence as those separate from the previous enhancing lesion and located outside of the initial FLAIR abnormality appreciated on imaging. We found that a total of 29 patients had disease recurrence or progression. Of the 29 patients, 37.9% had local recurrence, 48.3% had distant recurrence, and 13.8% displayed both local and distant recurrence patterns. These findings suggest that obtaining initial local control of PCNSL is important as the majority of patients in our study had disease recurrence, with the majority found in distant locations from the primary site of the disease. Established risk factors for local versus distant recurrence include ocular and CSF involvement at diagnosis, location of the primary lymphoma at diagnosis, and multifocal disease. A study by Ambady et al. analyzed 78 patients with newly diagnosed PCNSL who attained complete radiographic response during or after first-line treatment with HD-MTX. Of the 78 patients, 44 relapsed, and of those patients, 37 had new measurable enhancing lesions. 1 of those 37 patients had bone marrow involvement at diagnosis, and 7 had ocular involvement. 30 of the 37 patients had distant recurrences, while only 7 had local recurrences (within 2 centimeters of the T2 hyperintensity at initial diagnosis). They found that local recurrences were more common when the initial lesion involved the corpus callosum, sub-ependymal disease, leptomeninges, or the posterior fossa. The authors postulate that the greater proportion of distant recurrences seen in their patient population may be a result of seeding from occult reservoir lesions, such as the CSF and eye, or extra-CNS sites, such as the bone marrow ( 15 ). Understanding progression patterns is an important component of management as it can illustrate whether there is a need for more aggressive and targeted local control of disease. The high rate of recurrence seen in our cohort and demonstrated by previous research suggests the need for further advancements to improve local control. Relapsed PCNSL has an overall expected survival of around 2 to 14 months, depending on the initiation of salvage therapy, and there is currently no optimal standard salvage treatment for PCNSL ( 16 ). Studies have looked at whole brain radiation therapy and agents like topotecan, temozolomide, rituximab, and HDMTX as therapies for salvage therapy, but there is still much ongoing research into determining the optimal therapy ( 17 – 20 ). One study by Korfel et al. looked at the addition of whole brain radiation therapy after initial chemotherapy with HD-MTX and found that it did not significantly increase overall survival as compared to chemotherapy alone ( 21 ). The treatment of PCNSL is stratified into induction and consolidation therapy phases, employing a combination of HDMTX-based regimens and subsequent strategies to sustain remission and manage disease burden. Induction therapy, serving as the initial phase of treatment, has been significantly illuminated by the findings of the International Extranodal Lymphoma Study Group (IELSG32) trial. This pivotal study demonstrated that a combination of HDMTX and cytarabine outperforms HDMTX monotherapy in terms of efficacy. Further enhancement of the induction regimen with the addition of rituximab to HDMTX and cytarabine yielded superior results compared to the HDMTX and cytarabine combination alone, indicating a stratified improvement in treatment outcomes with the incorporation of immunotherapy ( 22 ). Other commonly used induction regimens include R-MVP (rituximab, methotrexate, procarbazine and vincristine) ( 23 ) and MT-R: methotrexate, temozolomide and rituximab) ( 24 ). Following the induction phase, consolidation therapy aims to solidify the initial response and prevent disease recurrence. The IELSG32 trial's insights extend into this phase, revealing that whole-brain radiation therapy (WBRT) and autologous stem cell transplantation (ASCT) provide equivalent effectiveness in disease control ( 22 ). However, a critical distinction lies in their impact on patients' quality of life, with ASCT showing a more favorable neurocognitive outcome profile compared to WBRT, thereby emphasizing the importance of considering long-term treatment ramifications in therapeutic decision-making. Additionally, the role of Stereotactic Radiosurgery (SRS) in managing PCNSL, particularly in cases refractory to HDMTX, deserves attention. Studies have shown that SRS, either as an adjunct to reduced-dose WBRT or as a standalone treatment, can achieve notable local control, underlining the necessity of meticulous patient selection based on clinical and disease characteristics to optimize outcomes ( 25 , 26 ). These advancements underscore a paradigm shift in PCNSL management, highlighting the nuanced interplay between therapeutic efficacy and patient quality of life. Study limitations: While providing valuable insights into the recurrence patterns of PCNSL, this study is not without limitations. Firstly, the retrospective nature of the study may introduce biases, particularly in patient selection and data collection. The sample size, although adequate for preliminary observations, is relatively small, which may limit the generalizability of our findings. Additionally, being a multi-institutional study, variations in treatment protocols and imaging techniques across different centers could have influenced the results. The lack of a control group also limits our ability to draw definitive conclusions about the efficacy of HDMTX-based chemotherapy compared to other treatment modalities. Furthermore, the reliance on MRI imaging for assessing disease progression and recurrence may not capture the complete biological behavior of PCNSL, especially in cases where imaging changes are subtle or non-specific. Finally, the exclusion of immunocompromised patients, who represent a significant portion of the PCNSL population, may limit the applicability of our findings to the broader patient population. Conclusions Our study sheds light on the recurrence patterns in PCNSL, revealing that 62.1% of patients (48.3% with solely distant and 13.8% with both distant and local recurrence) experienced disease progression beyond the primary site. While needing validation in larger cohorts, this finding highlights the necessity for advancements in achieving sustained intracranial control in PCNSL. Future research should focus on enhancing initial treatment efficacy and exploring novel approaches to manage this rare yet aggressive disease. Declarations Author Contribution L.C., A.K., W.S., J.P. and J.N. all helped with initial manuscript preparation. L.C., A.K., M.S., A.E., N.E, J.P., and W.S. completed data collection and analysis. All authors contributed to final manuscript draft edits and revisions. References Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014–2018. Neuro-oncology , 23 (Supplement_3), iii1-iii105 Song KW, Batchelor T (2021) Treatment of primary CNS lymphoma: maximizing clinical benefit, minimizing neurotoxicity. Curr Oncol Rep 23:1–11 Grommes C, Rubenstein JL, DeAngelis LM, Ferreri AJ, Batchelor TT (2019) Comprehensive approach to diagnosis and treatment of newly diagnosed primary CNS lymphoma. 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J Neurooncol 147:465–476 Tables Table 1 Patient Characteristics N = 29 Sex Male 16 55.2% Female 13 44.8% Median Age at Diagnosis (years) 73.0 (Range 44.0–80.0) Alive at time of study Yes 15 51.7% No 14 48,3% Multifocal Disease at Diagnosis 18 65.5% Spine Involvement at Diagnosis Yes 2 6.9% No 22 75.9% N/A 5 17.2% Ocular Involvement at Diagnosis Yes 1 3.4% No 20 69.0% N/A 8 27.6% CSF Involvement at Diagnosis Yes 3 10.3% No 22 75.9% N/A 4 13.8% Initial Radiation Therapy 1 3.4% Median cycles of HDMTX based induction regimen 6 (Range 1–21) Median HDMTX dose 3.5 g/m 2 (Range: 2.0-6.5 g/m 2 ) Induction HDMTX Regimen HDMTX 11 37.9% HDMTX + Rituximab 13 44.8% Other HDMTX based regimen* 5 17.2% *Other HDMTX based regimens included: HDMTX + cytarabine ( 2 ), HDMTX + rituximab + procarbazine ( 1 ), HDMTX + rituximab + procarbazine + vincristine ( 1 ), Table 2 Treatment Response and Patterns of Progression Following HDMTX-based therapy N = 29 Initial Complete Response 12 41.4% Initial Partial Response 7 24.1% Progressive Disease 10 34.5% Average Time to Disease Progression 17.9 months Range: 1.3–69.0 months Median Time to Disease Progression 7.13 months Local Recurrence 11 37.9% Sub-ependymal spread n = 1 Distant Recurrence 14 48.3% Sub-ependymal spread n = 1 Local and Distant Recurrence 4 13.8% Sub-ependymal spread n = 1 Multifocal Disease Patterns of Recurrence N = 18 Local 6 33.3% Distant 10 55.5% Local and Distant 2 11.1% Additional Declarations No competing interests reported. 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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-4254111","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":292479864,"identity":"cccb7f41-d4f7-4fed-993d-188cbc474f10","order_by":0,"name":"Louis Cappelli","email":"data:image/png;base64,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","orcid":"","institution":"Thomas Jeffersons Sidney Kimmel Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Louis","middleName":"","lastName":"Cappelli","suffix":""},{"id":292479865,"identity":"3e6bb8ad-a132-4dd0-ace4-15ca50b6a1af","order_by":1,"name":"Allison Kayne","email":"","orcid":"","institution":"Thomas Jefferson University, Sidney Kimmel Medical College","correspondingAuthor":false,"prefix":"","firstName":"Allison","middleName":"","lastName":"Kayne","suffix":""},{"id":292479866,"identity":"598dfd9f-f719-4829-b585-6b537b39f521","order_by":2,"name":"Jennifer Newman","email":"","orcid":"","institution":"Thomas Jefferson University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Newman","suffix":""},{"id":292479867,"identity":"b557e9c6-edb7-4567-acda-fcebf0e30d8d","order_by":3,"name":"Muhammad Sharif","email":"","orcid":"","institution":"Thomas Jeffersons Sidney Kimmel Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"","lastName":"Sharif","suffix":""},{"id":292479868,"identity":"3e34ed12-9061-49eb-8215-03830dbb5aea","order_by":4,"name":"Ahmed Elguindy","email":"","orcid":"","institution":"The Ohio State University Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Elguindy","suffix":""},{"id":292479869,"identity":"694b8f9b-3187-458a-b323-af162f3c080e","order_by":5,"name":"Narendranath Epperla","email":"","orcid":"","institution":"The Ohio State University Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Narendranath","middleName":"","lastName":"Epperla","suffix":""},{"id":292479870,"identity":"eda7e2ca-4de2-4dad-b87e-8c915bfd94fc","order_by":6,"name":"Joshua D. Palmer","email":"","orcid":"","institution":"The Ohio State University Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"D.","lastName":"Palmer","suffix":""},{"id":292479871,"identity":"eec2d067-445f-4470-baa8-8505dca3d67c","order_by":7,"name":"Iyad Alnahhas","email":"","orcid":"","institution":"Thomas Jeffersons Sidney Kimmel Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Iyad","middleName":"","lastName":"Alnahhas","suffix":""},{"id":292479872,"identity":"b55c5cd1-0f45-46c2-aa55-db46fb0b8a66","order_by":8,"name":"Wenyin Shi","email":"","orcid":"","institution":"Thomas Jeffersons Sidney Kimmel Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Wenyin","middleName":"","lastName":"Shi","suffix":""}],"badges":[],"createdAt":"2024-04-11 19:14:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4254111/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4254111/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54915113,"identity":"7e36fdbc-5e67-4a5b-b4b2-8ab2e807c734","added_by":"auto","created_at":"2024-04-18 14:00:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1036724,"visible":true,"origin":"","legend":"\u003cp\u003eA) Example of local tumor progression on T1 post-contrast FLAIR sequence MRI of the brain, with image on the left being prior to treatment with HDMTX. Note the progression of disease (Pink) within the initial hyperintense primary lesion.\u003c/p\u003e\n\u003cp\u003eB) Example of distant disease progression on T1 post-contrast FLAIR sequence MRI of the brain, with the image on the left demonstrating the area of disease progression (Pink) clearly outside of initial primary hyperintense lesion prior to HDMTX.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4254111/v1/bec2d4dbf56508b6fc0d0118.png"},{"id":54915115,"identity":"18a79a5c-dcde-42d5-be6d-0375f841f98c","added_by":"auto","created_at":"2024-04-18 14:00:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":119282,"visible":true,"origin":"","legend":"\u003cp\u003eVenn Diagram demonstrating pattern of disease progression following definitive HDMTX. 14/25 (48.3%) patients had distant (Blue) recurrence only, 11/29 (37.0%) had only local (Orange) recurrence, 4/29 (13.8%) displayed both a local and distant (Grey) recurrence pattern.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4254111/v1/c63636b9669b03213a888085.png"},{"id":54915552,"identity":"fba1d05a-6ca3-44af-a280-bc495d84b4bb","added_by":"auto","created_at":"2024-04-18 14:08:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83074,"visible":true,"origin":"","legend":"\u003cp\u003ePattern of disease progression of the 18 patients who had multifocal disease at time of diagnosis; 6 had disease progression (Grey) through HDMTX, with 5 achieved PR (Orange), and 7 achieved CR (Blue).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4254111/v1/8e5426fec0d307ea00ec65d1.png"},{"id":55756803,"identity":"befb3d58-03c8-48de-b42c-dfcaa2e5bace","added_by":"auto","created_at":"2024-05-02 17:21:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1555626,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4254111/v1/a74d8fe8-d948-434e-9728-cd013a824524.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Patterns of Disease Progression in patients with newly diagnosed Primary Central Nervous System Lymphoma Following Treatment with High-Dose Methotrexate","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma, primarily affecting the brain, spinal cord, and eyes. Representing about 4\u0026ndash;6% of extranodal lymphomas and 4% of primary brain tumors, PCNSL poses unique clinical challenges (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The disease occurs in both immunocompetent and immunocompromised individuals, with a median overall survival of approximately 25 months (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Unlike many primary brain tumors, PCNSL shows a favorable initial response to chemotherapy, particularly regimens centered around high-dose methotrexate (HDMTX), often combined with agents like cytarabine or rituximab (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Despite initial responses, the disease's aggressive nature necessitates consolidation therapy post-induction to mitigate high relapse rates, which occur in most patients within five years without complete eradication of residual disease (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA central challenge in the treatment of PCNSL stems from its aggressive nature and a limited understanding of disease progression. Recurrence of PCNSL within the central nervous system (CNS) is not uncommon, but patterns of intracranial recurrence following induction chemotherapy have not been extensively studied. A study by Plasswilm et al. looked at progression patterns after consolidative whole brain radiation therapy, finding up to 90% of recurrences to be local, whereas 10% were considered disseminated disease (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Another limited study by Altendorneburg et al. of sixteen immunocompetent patients receiving a methotrexate-based polychemotherapy showed that four patients had local recurrence, six had bilateral involvement of the brain at recurrence, and two had a recurrence on the opposite side of the brain from which the original tumor was (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Aside from the studies mentioned, there is very little additional literature analyzing the local and distant progression of PCNSL after induction chemotherapy.\u003c/p\u003e \u003cp\u003eIn the present study, we aimed to identify the patterns of recurrence in PCNSL after HDMTX-based induction chemotherapy. Having a better understanding of the progression of PCNSL can help us understand the disease\u0026rsquo;s behavior with implications for optimizing consolidation strategies to improve patient treatment outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This study was conducted with the approval of the Institutional Review Board (IRB) of Thomas Jefferson University and The Ohio State University. In compliance with ethical standards, patient confidentiality was rigorously maintained, and all data were anonymized prior to analysis. Given the retrospective design of the study, which involved the review of existing medical records and imaging data, the IRB provided a waiver for the requirement of individual patient consent. This study adheres to the ethical guidelines and standards for human research as outlined by Thomas Jefferson University and relevant regulatory bodies.\u003c/p\u003e \u003cp\u003ePatients\u003c/p\u003e \u003cp\u003e This is a retrospective chart and diagnostic imaging review of patients treated for PCNSL from the years 2011\u0026ndash;2023, which was completed at Jefferson University and The Ohio State University. Immunocompetent patients\u0026thinsp;\u0026ge;\u0026thinsp;18 years old with PCNSL initially treated with a regimen including HDMTX and available MRIs illustrating the initial and recurrent disease were included in this study. Primary CNS lymphoma was diagnosed based on pathology diagnosis. All patients had brain biopsy or surgery. Systemic imaging was negative for systemic involvement of lymphoma.\u003c/p\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003cp\u003eRelevant data from the medical charts including, patient demographics, tumor laterality, disease progression, patterns of recurrence, and survival, was collected from electronic health records. In addition, characteristics of each patient\u0026rsquo;s treatment were collected, including if they received initial radiation therapy, the number of HDMTX cycles, if additional chemotherapy agents were used, and which agents they were, along with the type of treatment at recurrence.\u003c/p\u003e \u003cp\u003eWhether the patient had achieved a complete response (CR) or partial response (PR) was determined based on pre- and post-treatment MRI imaging comparison and the degree of tumor reduction. The International PCNSL collaborative group response criteria for PCNSL was used. Progression-free survival (PFS) was calculated as the time in months between the date of the initial scan showing PCNSL and the date of the MRI showing progression.\u003c/p\u003e \u003cp\u003eImaging Analysis\u003c/p\u003e \u003cp\u003eThe pattern of recurrence was reviewed by comparing the initial diagnostic MRI to the recurrence MRI (T1 post-contrast and T2/FLAIR sequence). The pattern of recurrence was classified as either local or distant, depending on the anatomical location of the recurrent lesion. Each diagnostic MRI was reviewed by two to three independent physicians to confirm the recurrence pattern. Local recurrences were classified as new lesions that overlapped with the primary enhancing lesion/FLAIR abnormality. Lesions of distant recurrence were classified as those separate from the previous enhancing lesion and located outside of the initial FLAIR abnormality appreciated on imaging. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eStatistics\u003c/p\u003e \u003cp\u003eDescriptive statistics were used for calculating mean, median, and range of patient characteristics and the nature/involvement of disease involvement, as well as a Chi-square used to determine the statistical significance between two variables, were performed via R software.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 47 immunocompetent patients with newly diagnosed CNS/ocular lymphoma were identified. Four patients were found to have primary vitreoretinal lymphoma and excluded from the study. Twenty-nine of the remaining 43 patients were identified to have progressed through initial definitive treatment. The median age of diagnosis was 73.0 years (range: 44.0\u0026ndash;78.0), with 16 (55.2%) patients being male and 13 (44.8%) female. At the time of diagnosis, 2 patients were found to have spinal involvement, 1 had ocular involvement, and 3 had cerebral spinal fluid (CSF) involvement. All patients were treated with high-dose methotrexate (HDMTX) or HDMTX and rituximab, with 1 of the 29 receiving additional initial management with radiation therapy. The average number of completed HDMTX cycles was 6, with an average dose of 3.5 g/m\u003csup\u003e2\u003c/sup\u003e (range: 2.0 g/m\u003csup\u003e2\u003c/sup\u003e \u0026minus;\u0026thinsp;6.0 g/m\u003csup\u003e2\u003c/sup\u003e). Thirteen of the 29 patients were treated with both HDMTX and rituximab. Eighteen patients (65.5%) were found to have multifocal disease at the time of diagnosis. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eTwelve (41.4%) of the 29 patients had a complete response (CR) to initial systemic therapy, 7 (24.1%) had a partial response (PR), and 10 (34.5%) patients had refractory disease with HDMTX treatment. Following definitive HDMTX, 14 (48.3%) patients had distant recurrence only, 11 (37.9%) had only local recurrence, and 4 (13.8%) displayed both a local and distant recurrence pattern. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe median time until disease progression was 7.1 months (range: 1.3\u0026ndash;69.0, average 17.9). Three patients had distant sub-ependymal spread of disease, one from a patient that displayed distant progression, local progression, and local and distant progression. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOf the 18 patients who had multifocal disease at the time of diagnosis, 6 were refractory to induction HDMTX, with 5 experiencing PR and 7 achieving CR (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Twelve of the 18 (66.7%) demonstrated either distant or local and distant disease progression at time or recurrence, vs. only 6 (33.3%) showing local spread of disease. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) Such findings evaluating multifocal disease at presentation to have an increased likelihood of developing distant disease progression compared to those without was not determined to be significant (p\u0026thinsp;=\u0026thinsp;0.796, Chi-square).\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eAlthough typically responsive to initial chemotherapy, PCNSL remains a difficult disease to treat. HDMTX is the mainstay chemotherapy of choice (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). HDMTX as monotherapy has been associated with less toxicity as compared to combination regimens; however, a methotrexate-based polychemotherapy regimen has proven higher response rates, longer progression-free survival, and a reduction in primary progression rates (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite advances in the initial treatment of PCNSL with HDMTX for those who can tolerate it, there is limited understanding of the intracranial recurrence patterns appreciated in this disease. In a study by Gavrilovic et al. on 57 patients who received methotrexate-based chemotherapy with or without WBRT, 25 of the patients relapsed or progressed, with an average time to relapse of 10.5 months. 11 of the 25 patients relapsed in the brain, 3 had an either ocular or leptomeningeal recurrence, and 6 had relapsed in both the brain and another site like the leptomeninges (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). A post-hoc study on MRI characteristics of PCNSL by Tabouret et al. included 85 patients who were enrolled in the ANOCEF-GOELAMS phase II clinical trial that randomized patients in either receiving HDMTX, vincristine, procarbazine, and cytarabine or HDMTX and temozolomide. 52 of 89 patients relapsed in the brain, with 46% relapsing at the initial enhancing site, 40% at a different site, and 14% at both the initial site and a different site (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e In our cohort of 43 patients treated with a HDMTX-based chemotherapy regimen, we characterized local recurrences as new lesions that overlapped with the primary enhancing lesion/FLAIR abnormality and lesions of distant recurrence as those separate from the previous enhancing lesion and located outside of the initial FLAIR abnormality appreciated on imaging. We found that a total of 29 patients had disease recurrence or progression. Of the 29 patients, 37.9% had local recurrence, 48.3% had distant recurrence, and 13.8% displayed both local and distant recurrence patterns. These findings suggest that obtaining initial local control of PCNSL is important as the majority of patients in our study had disease recurrence, with the majority found in distant locations from the primary site of the disease.\u003c/p\u003e \u003cp\u003eEstablished risk factors for local versus distant recurrence include ocular and CSF involvement at diagnosis, location of the primary lymphoma at diagnosis, and multifocal disease. A study by Ambady et al. analyzed 78 patients with newly diagnosed PCNSL who attained complete radiographic response during or after first-line treatment with HD-MTX. Of the 78 patients, 44 relapsed, and of those patients, 37 had new measurable enhancing lesions. 1 of those 37 patients had bone marrow involvement at diagnosis, and 7 had ocular involvement. 30 of the 37 patients had distant recurrences, while only 7 had local recurrences (within 2 centimeters of the T2 hyperintensity at initial diagnosis). They found that local recurrences were more common when the initial lesion involved the corpus callosum, sub-ependymal disease, leptomeninges, or the posterior fossa. The authors postulate that the greater proportion of distant recurrences seen in their patient population may be a result of seeding from occult reservoir lesions, such as the CSF and eye, or extra-CNS sites, such as the bone marrow (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUnderstanding progression patterns is an important component of management as it can illustrate whether there is a need for more aggressive and targeted local control of disease. The high rate of recurrence seen in our cohort and demonstrated by previous research suggests the need for further advancements to improve local control. Relapsed PCNSL has an overall expected survival of around 2 to 14 months, depending on the initiation of salvage therapy, and there is currently no optimal standard salvage treatment for PCNSL (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Studies have looked at whole brain radiation therapy and agents like topotecan, temozolomide, rituximab, and HDMTX as therapies for salvage therapy, but there is still much ongoing research into determining the optimal therapy (\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). One study by Korfel et al. looked at the addition of whole brain radiation therapy after initial chemotherapy with HD-MTX and found that it did not significantly increase overall survival as compared to chemotherapy alone (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe treatment of PCNSL is stratified into induction and consolidation therapy phases, employing a combination of HDMTX-based regimens and subsequent strategies to sustain remission and manage disease burden. Induction therapy, serving as the initial phase of treatment, has been significantly illuminated by the findings of the International Extranodal Lymphoma Study Group (IELSG32) trial. This pivotal study demonstrated that a combination of HDMTX and cytarabine outperforms HDMTX monotherapy in terms of efficacy. Further enhancement of the induction regimen with the addition of rituximab to HDMTX and cytarabine yielded superior results compared to the HDMTX and cytarabine combination alone, indicating a stratified improvement in treatment outcomes with the incorporation of immunotherapy (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Other commonly used induction regimens include R-MVP (rituximab, methotrexate, procarbazine and vincristine) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) and MT-R: methotrexate, temozolomide and rituximab) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFollowing the induction phase, consolidation therapy aims to solidify the initial response and prevent disease recurrence. The IELSG32 trial's insights extend into this phase, revealing that whole-brain radiation therapy (WBRT) and autologous stem cell transplantation (ASCT) provide equivalent effectiveness in disease control (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). However, a critical distinction lies in their impact on patients' quality of life, with ASCT showing a more favorable neurocognitive outcome profile compared to WBRT, thereby emphasizing the importance of considering long-term treatment ramifications in therapeutic decision-making. Additionally, the role of Stereotactic Radiosurgery (SRS) in managing PCNSL, particularly in cases refractory to HDMTX, deserves attention. Studies have shown that SRS, either as an adjunct to reduced-dose WBRT or as a standalone treatment, can achieve notable local control, underlining the necessity of meticulous patient selection based on clinical and disease characteristics to optimize outcomes (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). These advancements underscore a paradigm shift in PCNSL management, highlighting the nuanced interplay between therapeutic efficacy and patient quality of life.\u003c/p\u003e \u003cp\u003eStudy limitations:\u003c/p\u003e \u003cp\u003eWhile providing valuable insights into the recurrence patterns of PCNSL, this study is not without limitations. Firstly, the retrospective nature of the study may introduce biases, particularly in patient selection and data collection. The sample size, although adequate for preliminary observations, is relatively small, which may limit the generalizability of our findings. Additionally, being a multi-institutional study, variations in treatment protocols and imaging techniques across different centers could have influenced the results. The lack of a control group also limits our ability to draw definitive conclusions about the efficacy of HDMTX-based chemotherapy compared to other treatment modalities. Furthermore, the reliance on MRI imaging for assessing disease progression and recurrence may not capture the complete biological behavior of PCNSL, especially in cases where imaging changes are subtle or non-specific. Finally, the exclusion of immunocompromised patients, who represent a significant portion of the PCNSL population, may limit the applicability of our findings to the broader patient population.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study sheds light on the recurrence patterns in PCNSL, revealing that 62.1% of patients (48.3% with solely distant and 13.8% with both distant and local recurrence) experienced disease progression beyond the primary site. While needing validation in larger cohorts, this finding highlights the necessity for advancements in achieving sustained intracranial control in PCNSL. Future research should focus on enhancing initial treatment efficacy and exploring novel approaches to manage this rare yet aggressive disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eL.C., A.K., W.S., J.P. and J.N. all helped with initial manuscript preparation. L.C., A.K., M.S., A.E., N.E, J.P., and W.S. completed data collection and analysis. All authors contributed to final manuscript draft edits and revisions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOstrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014\u0026ndash;2018. \u003cem\u003eNeuro-oncology\u003c/em\u003e, \u003cem\u003e23\u003c/em\u003e(Supplement_3), iii1-iii105\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSong KW, Batchelor T (2021) Treatment of primary CNS lymphoma: maximizing clinical benefit, minimizing neurotoxicity. Curr Oncol Rep 23:1\u0026ndash;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrommes C, Rubenstein JL, DeAngelis LM, Ferreri AJ, Batchelor TT (2019) Comprehensive approach to diagnosis and treatment of newly diagnosed primary CNS lymphoma. Neurooncology 21(3):296\u0026ndash;305\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiparuck, P., Boonsakan, P., Sutthippingkiat, T., Pukiat, S., Chantrathammachart,P., Phusanti, S., \u0026hellip; Atichartakarn, V. (2019). Treatment outcome and prognostic factors in PCNSL. \u003cem\u003eDiagnostic pathology\u003c/em\u003e, \u003cem\u003e14\u003c/em\u003e(1), 1\u0026ndash;8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlasswilm, L., Herrlinger, U., Korfel, A., Weller, M., K\u0026uuml;ker, W., Kanz, L., \u0026hellip; Bamberg,M. (2002). Primary central nervous system (CNS) lymphoma in immunocompetent patients.\u003cem\u003eAnnals of hematology\u003c/em\u003e, \u003cem\u003e81\u003c/em\u003e, 415\u0026ndash;423\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulte-Altedorneburg G, Heuser L, Pels H (2012) MRI patterns in recurrence of primary CNS lymphoma in immunocompetent patients. 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M., Rice, L., Schwartz, M., Chandler, J. P.,\u0026hellip; Grimm, S. A. (2012). Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. \u003cem\u003eCancer\u003c/em\u003e, \u003cem\u003e118\u003c/em\u003e(15), 3743\u0026ndash;3748\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHottinger AF, DeAngelis LM, Yahalom J, Abrey LE (2007) Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 69:1178\u0026ndash;1182\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFischer L et al (2006) Prospective trial on topotecan salvage therapy in primary CNS lymphoma. Ann Oncol 17:1141\u0026ndash;1145\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnting RH, Demopoulos A, DeAngelis LM, Abrey LE (2004) Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 63:901\u0026ndash;903\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlotkin SR et al (2004) Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res 10:5643\u0026ndash;5646\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorfel, A., Thiel, E., Martus, P., M\u0026ouml;hle, R., Griesinger, F., Rauch, M., \u0026hellip; Weller,M. (2015). Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. \u003cem\u003eNeurology\u003c/em\u003e, \u003cem\u003e84\u003c/em\u003e(12), 1242\u0026ndash;1248\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, Celico, IELSG32 study investigators et al (2022) Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial. Leukemia 36(7):1870\u0026ndash;1878. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41375-022-01582-5\u003c/span\u003e\u003cspan address=\"10.1038/s41375-022-01582-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOmuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ et al (2015) R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 125(9):1403\u0026ndash;1410. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1182/blood-2014-10-604561\u003c/span\u003e\u003cspan address=\"10.1182/blood-2014-10-604561\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant et al (2013) Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin oncology: official J Am Soc Clin Oncol 31(25):3061\u0026ndash;3068. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.2012.46.9957\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2012.46.9957\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForeman, B. E., Mullikin, T. C., Floyd, S. R., Kelsey, C. R., Patel, M. P., Peters,K. B., \u0026hellip; Vaios, E. J. (2023). Long-term outcomes with reduced-dose whole-brain radiotherapy and a stereotactic radiosurgery boost for primary central nervous system lymphoma. \u003cem\u003eNeuro-Oncology Advances\u003c/em\u003e, \u003cem\u003e5\u003c/em\u003e(1), vdad097\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalmer JD, Bhamidipati D, Shukla G, Epperla N, Glass J, Kim L, Wenyin Shi (2020) Outcomes after stereotactic radiosurgery for CNS lymphoma. J Neurooncol 147:465\u0026ndash;476\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":" \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\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;29\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Age at Diagnosis (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.0 (Range 44.0\u0026ndash;80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlive at time of study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48,3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifocal Disease at Diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpine Involvement at Diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOcular Involvement at Diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF Involvement at Diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial Radiation Therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian cycles of HDMTX based induction regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (Range 1\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian HDMTX dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5 g/m\u003csup\u003e2\u003c/sup\u003e (Range: 2.0-6.5 g/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction HDMTX Regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDMTX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDMTX\u0026thinsp;+\u0026thinsp;Rituximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther HDMTX based regimen*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Other HDMTX based regimens included: HDMTX\u0026thinsp;+\u0026thinsp;cytarabine (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), HDMTX\u0026thinsp;+\u0026thinsp;rituximab\u0026thinsp;+\u0026thinsp;procarbazine (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), HDMTX\u0026thinsp;+\u0026thinsp;rituximab\u0026thinsp;+\u0026thinsp;procarbazine\u0026thinsp;+\u0026thinsp;vincristine (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e),\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\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\u003eTreatment Response and Patterns of Progression Following HDMTX-based therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;29\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial Complete Response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial Partial Response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage Time to Disease Progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.9 months\u003c/p\u003e \u003cp\u003eRange: 1.3\u0026ndash;69.0 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Time to Disease Progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.13 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal Recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSub-ependymal spread\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistant Recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSub-ependymal spread\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal and Distant Recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSub-ependymal spread\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifocal Disease Patterns of Recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal and Distant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \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":"PCNSL, HDMTX, methotrexate, CNS lymphoma, pattern of progression, newly diagnosed, Adult","lastPublishedDoi":"10.21203/rs.3.rs-4254111/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4254111/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma that primarily affects the brain, spinal cord, and/or eyes. Despite advances in treatment, PCNSL remains a formidable challenge due to its aggressive nature and limited understanding of disease progression. Recurrence of PCNSL within the central nervous system (CNS) is not uncommon, but patterns of intracranial recurrence following induction chemotherapy have not been extensively studied. This study aims to elucidate the patterns of recurrence in PCNSL, providing insight into the disease’s behavior.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Patient charts and diagnostic imaging from those treated for PCNSL from 2 institutions and ≥ 18 years old from the years 2011-2023 were retrospectively reviewed. Relevant data from the charts to identify disease progression, patterns of recurrence, and survival was collected from the patient charts. The pattern of recurrence was reviewed by comparing the initial diagnostic MRI to the recurrence MRI (T1 post-contrast and T2/FLAIR sequences). The pattern of recurrence was classified as either local or distant depending on the anatomical location of the recurrent lesion. Distant recurrences were classified as those separate from the previous enhancing lesion and located outside of the initial T2/FLAIR abnormality appreciated on imaging. Local recurrences were classified as new lesions that overlapped with the primary enhancing lesion/T2/FLAIR abnormality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: 29 out of 47 patients met inclusion criteria with PCNSL and progressed through initial definitive treatment with high-dose methotrexate (HDMTX) or HDMTX and rituximab; with only 1 patient receiving initial management with radiation therapy. The median age at time of diagnosis was 73.0 years (range: 44.0-78.0), with 16 (55.2%) patients being male and 13 (44.8%) female. Eighteen of the 29 patients were found to have multifocal disease. 14/29 (48.3%) patients had distant recurrence only, 11/29 (37.9%) had only local recurrence, whereas 4/29 (13.8%) displayed both local and distant recurrence pattern.\u003c/p\u003e\n\u003cp\u003eThe median time until disease progression was 7.1 months (range: 1.3-69.0). Twelve of the 29 patients had a complete response (CR) to initial systemic therapy, 7 had a partial response (PR), and 10 patients had disease progression through HDMTX. Of the 18 patients who had multifocal disease at the time of diagnosis, 6 had disease progression through HDMTX, with 5 experiencing PR and only 7 achieved CR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Patterns of disease progression in patients diagnosed with PCNSL are not very well understood. In this retrospective review, we identified that the majority of disease recurrence in patients diagnosed with PCNSL who underwent HDMTX was outside or distant to the primary disease site vs solely local disease progression intracranially (62.1% vs 37.9%). Such findings need to be illustrated in a larger cohort to confirm such patterns; however, this insight raises awareness of the need for further advances in achieving higher and more durable rates of control for this rare disease.\u003c/p\u003e","manuscriptTitle":"Patterns of Disease Progression in patients with newly diagnosed Primary Central Nervous System Lymphoma Following Treatment with High-Dose Methotrexate","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-18 14:00:23","doi":"10.21203/rs.3.rs-4254111/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":"20592853-eedc-4a49-b6c3-079bf52a74ea","owner":[],"postedDate":"April 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-09T09:52:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-18 14:00:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4254111","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4254111","identity":"rs-4254111","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}