Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting

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Previous trial data showed the addition of TTFields to standard TMZ-based therapy to significantly improve overall survival (OS), but real-world data is lacking, particularly with long follow-up duration. Here, we report real-world survival, patterns of progression, and patterns of use for patients for patients with ndGBM treated with or without TTFields. Methods Patients diagnosed with GBM and treated with standard of care therapy at the Medical College of Wisconsin between March 2015–March 2023 were included. Survival outcomes were assessed, and compared across groups who received or did not receive TTFields therapy during maintenance treatment. Patients were followed through March 1, 2024. Results A total of 208 patients (TTFields: n = 109; No-TTFields: n = 99) were included for analysis. Baseline characteristics were consistent across groups. Median OS and PFS were significantly improved for the TTFields group vs No-TTFields group (median OS: 21.7 vs 17.7 months, P = 0.029; median PFS: 12.4 vs 9.6 months, P = 0.047 ). Patients treated with TTFields exhibited a higher rate of non-local progression vs No-TTFields group. Median OS and PFS were each significantly longer for the ≥ 75% usage group compared with < 75% via matched analysis. Conclusion The results of this study reveal an association between TTFields use and long-term survival benefit, consistent with pivotal trial findings. TTFields use is associated with a higher incidence of non-local patterns of progression, and TTFields device usage ≥ 75% is associated with increased progression-free and long-term survival. Tumor-Treating Fields glioblastoma progression usage Figures Figure 1 Figure 2 Figure 3 Introduction Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS), making up over 50% of all malignant CNS tumors. 1 Despite significant improvements in the field of neuro-oncology, overall survival (OS) for GBM remains low at a median 14–16 months with standard therapy and ~ 5% 5-year OS rate. 2 – 4 Molecular markers such as Methylguanine methyltransferase (MGMT) gene methylation are useful for prognostication of GBM wherein positive MGMT methylation prolongs OS. 2 , 5 , 6 Standard of care (SOC) includes maximal safe resection followed by radiotherapy (RT) with concurrent daily temozolomide (TMZ), followed by maintenance TMZ for 6 to 12 months. 4 , 7 , 8 Since the approval of TMZ for treatment of newly-diagnosed GBM, few randomized controlled trials have succeeded in identifying a similarly efficacious treatment modality. 9 , 10 In 2015, the Tumor-Treating Fields (TTFields) device was approved by the Food and Drug Administration (FDA) for treatment of patients with newly diagnosed GBM (ndGBM). 11 TTFields delivers alternating electric fields to mapped brain regions via a portable battery-powered device with arrays that are placed on the surface of the scalp. 12 – 14 The alternating electric fields disrupt mitosis via several mechanisms, including disruption of the mitotic spindle, to arrest tumor cell growth and ultimately trigger apoptosis. 15 – 19 The pivotal phase III trial (EF-14) by Stupp et al. demonstrated that TTFields paired with SOC TMZ significantly prolonged median OS to 20.9 months and median progression-free survival (PFS) to 6.7 months compared to 16 months OS and 4 months PFS with TMZ alone independent of other factors. 20 A meta-analysis study published in 2023 corroborated these results in the clinical practice setting, finding significantly improved median OS from 17.4 months with SOC alone to 22.6 months with SOC plus TTFields. 21 A dose effect from using the TTFields device has been suggested from studies examining higher levels of device usage by the patient, as well as higher field intensities delivered to the tumor bed by the arrays.. 20 , 22 – 24 Post-hoc analyses of the pivotal trials in both newly diagnosed and recurrent GBM have shown that using the device at least 75% of the time, or 18 hours on average out of a 24-hour period, is correlated with improved OS. 20 , 21 , 25 , 26 Following a separate analysis of the EF-14 trial showing a link between higher TTFields dose and improved survival, 22 further analyses of the spatial patterns of disease progression revealed that patients treated with TTFields and TMZ experienced more distant patterns of progression than patients treated with TMZ alone, and for TTFields-treated patients, normal brain areas that did not exhibit tumor progression received a higher dose of TTFields. 24 However, these effects have yet to be corroborated outside of the clinical trial setting. After nearly a decade of the use of TTFields for the treatment of ndGBM, questions related to long-term survival benefit, patterns of progression, and the impact of device usage on survival outcomes in the real-world setting remain. Retrospective studies investigating these phenomena have been limited by the lack of sufficiently large patient populations and suitable granularity of data. The patient cohort at the Medical College of Wisconsin and Froedtert Hospital (MCW-FH) is one of the largest, single-institution datasets of TTFields users in the United States, which makes it an ideal cohort to evaluate TTFields in the clinical setting. This study aims to investigate real-world survival, patterns of progression, and patterns of device use across a large cohort of patients with ndGBM treated with or without TTFields. Methods Patient characteristics and data collection All patients included in this retrospective study were diagnosed and treated for GBM at MCW-FH. Data was collected in accordance with local IRB approval to ensure patient privacy and safety. Consecutive patients with supratentorial ndGBM who were treated with SOC therapy between March 2015 and March 2023 were included for analysis. SOC consisted of concurrent radiotherapy with TMZ followed by maintenance TMZ with or without the addition of TTFields therapy, which became part of the SOC regimen at our institution in 2015, following results of the EF-14 study. Further criteria for cohort selection included completion of TMZ-based chemoradiotherapy and initiation of maintenance TMZ (minimum 1 cycle). A minimum 30 days of device use was required for the TTFields group. Grade 4 GBM diagnosis was confirmed histologically in all but four patients. Molecular criteria were met in three of these four patients, leaving one patient in the combined cohort (in TTFields group) with IDH-wildtype astrocytoma grade 3. Demographic, tumor, and treatment characteristics were collected for all patients and survival outcomes were assessed. Patients were followed through March 1, 2024. Progression pattern assessment Local and distal (non-local) patterns of tumor progression were identified from manual review of baseline and follow-up MRI scans at the time of first documented progression. Local progression was defined as contiguous enhancement with the baseline lesion or enhancement within the T2 FLAIR region of vasogenic edema associated with the baseline lesion. Non-local sites of progression were defined as regions of non-contiguous enhancement in distinct anatomic locations relative to the baseline lesion: distant lesion in same hemisphere, contralateral hemisphere, leptomeningeal disease, and posterior fossa. Location of progression was documented for all cases of radiographic progression in each treatment group. Assessment of TTFields use patterns TTFields device usage information was extracted from the device log files of each patient. For quantifying the average rate of usage over time, the time period between when a patient first turned the device on and when the device was last operated served as the source of usage data. Average usage for each treatment month was calculated across the cohort. For quantifying the level of device usage for each patient, the average monthly usage was calculated over the first 12 months of treatment, unless otherwise specified. Statistical analysis Overall survival was measured from the date of diagnosis to the date of patient death or last known contact. PFS was measured from the date of diagnosis to the date of disease progression or death, whichever occurred first, or last known contact. Medians and rates of survival were compared between groups using the Kaplan-Meier method with Cox proportional hazards model. P values were calculated and P < 0.05 was considered statistically significant. Propensity score matching and multivariate Cox regression were utilized where indicated to control for confounders between groups. Differences in categorical variables at baseline were evaluated using chi-squared or Wilcoxon tests for proportions or continuous variables, respectively. Differences in the rates of non-local progression were conducted using a chi-squared test. Results Patient and treatment characteristics Between March, 2015 and March, 2023, 231 patients were diagnosed at our institution and treated for GBM. Of those patients, 214 patients completed concurrent radiotherapy with TMZ and initiated maintenance TMZ treatment with or without TTFields therapy. The TTFields group comprised patients who received TTFields for a minimum of 30 days (n = 109), whereas the non-TTFields group comprised patients who did not receive TTFields at all in their first-line treatment (n = 99). Patient demographics, tumor, and treatment characteristics for the TTFields and non-TTFields groups are shown in Table 1 . Baseline characteristics were balanced between groups, not accounting for subgroups with missing MGMT promoter methylation or isocitrate dehydrogenase (IDH) mutational status. The median age for the TTFields group was 60 and for the non-TTFields group was 64. The male to female ratio was equal between groups. The proportions of patients having GTR and biopsy were slightly higher in the TTFields group. The median number of TMZ cycles was 7 in the TTFields group and 5 in the non-TTFields group. Table 1 Patient, tumor, and treatment characteristics by cohort Characteristic TTFields (n = 109) No TTFields (n = 99) Age, y Median (range) 60 (27–86) 64 (28–88) Sex Men 62 (57) 56 (57) Women 47 (43) 43 (43) Tumor grade/histology Grade 4 108 (99) 99 (100) Tumor presentation Multifocal disease 6 (6) 3 (3) Frontal 35 (32) 32 (32) Occipital 6 (6) 4 (4) Parietal 20 (18) 20 (20) Temporal 26 (24) 31 (31) Frontoparietal 5 (5) 2 (2) Frontotemporal 3 (3) 0 (0) Temporal-occipital 2 (2) 1 (1) Temporal-parietal 3 (3) 4 (4) Parieto-occipital 3 (3) 2 (2) IDH1 Status Mutated 6 (6) 3 (3) Wildtype 102 (94) 92 (93) Unknown 1 (1) 4 (4) MGMT promoter methylation status Methylated 37 (34) 31 (31) Unmethylated 44 (40) 47 (47) Unknown 28 (26) 21 (21) Resection status Gross total resection 46 (42) 34 (34) Sub-total resection 51 (47) 59 (60) Biopsy 12 (11) 6 (6) Maintenance TMZ Median cycles (range) 7 (1–65) 5 (1–27) TTFields therapy duration Median (range), months 6.8 (1–94) - Survival outcomes Overall survival for patients in the TTFields group was significantly improved over patients in the non-TTFields group (HR: 0.71 (0.52–0.97), p = 0.029; Fig. 1 a). Median OS was 21.7 months (95% CI 18.7–24.8) for the TTFields group and 17.7 months (14.6–20.6) for the Non-TTFields group, with 5-year OS rates of 17% (95% CI 11–28) and 12% (95% CI 6–23), respectively. Multivariate analysis showed treatment with TTFields to have a significant effect on OS when adjusting for known prognostic factors including age, gender, IDH mutational status, MGMT methylation status, and extent of resection (p = 0.017). PFS was also significantly improved for the TTFields group compared with the non-TTFields group (p = 0.047; Fig. 1 b), but the difference was not found to be significant when adjusting for known prognostic factors (p = 0.069). Median PFS was 12.4 months (95% CI 10.5–14.4) for the TTFields group and 9.6 months (95% CI 8.5–12.8) for the non-TTFields group. To understand the profile of patients surviving ≥ 2 years and assess factors predisposing patients to living longer, we examined patient characteristics for the two treatment groups (Table 2 ). As expected, median age was lower and IDH-mutant status, MGMT-methylation status, and gross total resection were higher for both treatment groups. No significant differences were noted between TTFields-treated and non-TTFields-treated patients across factors we evaluated. Survival curves are shown in Supp. Figure 1 . For the TTFields-treated patients surviving > 5 years (n = 9), 4 were still on treatment at the time of data cutoff and 6 had IDH-wildtype tumors. Table 2 Patient characteristics and survival among subgroup surviving 2 years or longer TTFields (n = 40) No TTFields (n = 28) Patient and treatment characteristics among 2-year survivors Age, y Median (range) 57 (29–75) 56 (28–83) Sex Men 23 (58) 14 (50) Women 17 (43) 14 (50) Multifocal disease 2 (5) 0 (0) IDH1 Status Mutated 6 (15) 3 (11) Wildtype 34 (85) 24 (86) Unknown 0 (0) 1 (4) MGMT promoter methylation status Methylated 19 (48) 13 (46) Unmethylated 13 (33) 12 (43) Unknown 8 (20) 3 (11) Resection status Gross total resection 17 (43) 15 (54) Sub-total resection 20 (50) 13 (46) Biopsy 3 (8) 0 (0) Maintenance TMZ Median cycles (range) 12 (1–65) 12 (1–27) ≥ 6 cycles 36 (90) 21 (75) TTFields therapy duration Median (range), months 13.1 (1.6–93.8) - ≥ 6 months 34 (85) - Survival outcomes for patients surviving ≥ 2 years Death events, n 20 17 OS, additional 2 years, % (CI) 51 (36–70) 52 (35–78) OS, additional 3 years, % (CI) 42 (27–64) 38 (21–69) OS, additional 4 years, % (CI) 42 (27–64) 9 (2–57) Patterns of progression Spatial patterns of tumor progression were radiologically assessed for each treatment group. The rate of non-local progression was significantly higher for the TTFields group compared with the non-TTFields group (28% vs 14%, p = 0.028), and the difference was significant on multivariate analysis when adjusting for other prognostic factors (p = 0.031) (Fig. 2 a). Progression in the contralateral hemisphere was the most frequent type of non-local progression for TTFields patients, followed by distal progression within the same hemisphere (Fig. 2 b). Rates of non-local progression subtypes were numerically higher for TTFields-treated patients across categories, but samples were too small to compare statistically. Examples of non-local, intraparenchymal patterns within the TTFields cohort are shown in Fig. 2 c. Patterns of device use with TTFields therapy To better understand how patients in the TTFields group complied with using their device, a temporal analysis of device usage rate was conducted. A total of 108 patients treated with TTFields had device usage data available for analysis. Across the cohort, the average rate of device usage was maintained over time and did not diminish with prolonged use (Fig. 3 a). Instances of usage rate declines were transient in nature. A period of sustained usage decline was observed during the immediate 4 months following treatment start but recovered thereafter. Usage rates were similarly found to be maintained over time for both long- and short-term users of the device (Fig. 3 b), with the average rate of usage higher for the ≥ 2-year users compared with the < 2-year group. Transient drop-offs in usage were more pronounced at month 13 and month 19 in the < 2-year and ≥ 2-year groups, respectively. When examining the association of usage and duration more closely, the duration of treatment with TTFields was found to increase in a graded manner with higher rates of usage (Supp. Figure 2 ). To further examine the impact of device usage on patient outcomes in a real-world setting, survival was evaluated across high and low usage groups. A usage threshold of 75% (average use of 18 hours per day) was applied as it is a common usage target for patients and was evaluated in previous trial settings. 20 , 25 Approximately half the patients in the TTFields cohort had an average usage level of 75%. Due to the high usage rates observed among patients with IDH-mutant tumors in our cohort, usage groups were restricted to IDH-wildtype patients to avoid bias in the analysis of survival. Upon initial inspection, OS and PFS did not significantly differ between patients in the ≥ 75% and < 75% groups (Fig. 3 c and Supp Fig. 3 a), with only a trend of increased OS and PFS for the high usage patients. However, baseline characteristics were not balanced between the cohorts and missingness in MGMT methylation status remained (Supp Table 2 ). With propensity score matching applied to match the usage cohorts on known prognostic factors, OS and PFS were each significantly longer for the ≥ 75% group compared with the < 75% group (HR(OS): 0.46 (0.26–0.82), p = 0.008; HR(PFS): 0.51 (0.30–0.85); p = 0.011) (Fig. 3 d and Supp Fig. 3 b). The effect remained significant on multivariate analysis when adjusting for the same covariates used for matching. Discussion As experience with TTFields therapy for ndGBM has increased over the past decade, understanding the real-world treatment patterns and outcomes associated with using this device are necessary for informed treatment decision-making. From retrospective analysis of a large real-world cohort of patients with GBM, this study provided complementary evidence to the pivotal trial results of Stupp et al., in which the addition of TTFields therapy to SOC led to increased OS and PFS over SOC alone. 11 In our study, treatment with TTFields was found to significantly improve OS for patients with ndGBM compared to treatment with SOC alone, with durable long-term survival benefit that did not appear to depend on known GBM prognostic factors. Additionally, this study revealed correlations between higher usage and prolonged OS and PFS, as well as an association of more distal patterns of disease recurrence with TTFields treatment, the first time being demonstrated in a real-world GBM population. Our analysis of patterns of recurrence is comparable to the results of Glas et al. with some additional strengths. While Glas et al. evaluated the frequency of distant recurrence in patients using TTFields, this study did not further categorize regions of recurrence relative to the initial lesion, such as differentiating between same-hemisphere recurrence versus contralateral hemisphere recurrence versus recurrence in the posterior fossa. 24 We show that patients treated with TTFields and SOC are significantly more likely to experience non-local progression, with a measurable increase in contralateral and distal progression within the same hemisphere. While some previous studies have suggested a potential relationship with OS and more distal forms of progression, 24 , 27 we did not observe a difference in survival between patterns of progression. This lack of observed difference may be due to sample size limitations, although in general more work is needed to further understand the relationship between patient outcomes and spatial-temporal patterns of disease progression within the brain. Our results for device usage are also in alignment with previous studies. 20,21,25,26 ≥75% device usage significantly prolonged OS and PFS after propensity score matching was applied to match the usage cohorts on known prognostic factors. Furthermore, the temporal trends in device usage we observed suggest subjective user experiences with the device that affect percent daily usage and likelihood of continuation. Overall, we did not observe a decline in the average usage rate over time; rather, the average device usage rate was sustained, and generally correlated with treatment duration. The period of sustained decline during the immediate 4 months following treatment start may reflect patients who eventually discontinued TTFields within 1 year. Tumor response to TTFields develops slowly; patients who terminated TTFields use after a short period of time may not have experienced an OS benefit, 28 although the minimum duration of TTFields treatment to achieve clinical benefit remains unknown. The transient drop-offs in usage at month 13 and month 19 in the 5 years, all 9 patients had a device usage rate > 50%, with 5 patients > 75%. Six of these patients were progression-free for > 4 years. Previous results from EF-14 showed OS to be incrementally improved with higher rates of usage, with maximal survival benefit observed for patients with average usage rates > 90%. 23 Further analysis could compare these patients to others with similar long-term survival, though this analysis would likely be limited by a small cohort. This leaves the potential for a multi-institution retrospective analysis of long-term survivors on TTFields. There remains a need to understand the clinical limitations to TTFields. Treatment with TTFields does not increase toxicities associated with other cancer treatments 29 or significantly impair quality of life. 30 There are few complications caused by TTFields other than mild-to-moderate skin irritation at the site of array placement, 11 , 20 yet some patients report low usage rates or will discontinue device usage within a year of starting therapy. Since the approval of TTFields, multiple studies have helped clarify treatment planning and skin management best practices. 31 – 33 Despite these efforts, barriers to effective use of the device continue to exist, and may include convenience, mobility issues, subjective discomfort, and limitation of daily activities (i.e., swimming). Future studies can consider collecting subjective patient data on reasons for < 75% usage and/or device termination. This study is not without limitations. Generally, prospective studies with randomized designs yield stronger results than retrospective cohort studies. To limit the potential for patient selection biases across comparative groups, we utilized multivariate regression and propensity score matching to help control for confounding variables. Also, while our cohort represents the largest single institution analysis of TTFields to date, 34 a larger cohort size may have permitted more in-depth analyses of progression pattern subtypes, particularly for the rarer leptomeningeal disease and posterior fossa recurrence, as well as analysis of outcomes across multiple usage thresholds and dose metrics. Finally, while our study followed patients between March 2015 to March 2023, there still remains a subset of patients who have yet to experience recurrence, particularly patients whose disease was diagnosed within a year of the end of analysis. Longer follow-up would provide additional insight both into long-term patterns of disease recurrence > 10 years and allow for additional data on patterns of recurrence in recently-diagnosed patients. Conclusion Analysis of patients from a large single institutional dataset reveals an association between TTFields use and long-term survival benefit, consistent with pivotal trial findings. TTFields use is associated with a higher incidence of non-local patterns of progression. TTFields device usage ≥ 75% is associated with increased progression-free and long-term survival when controlled for prognostic factors between cohorts. Future studies can consider further analyzing subtypes of non-local progression and subjective patient experiences that lead to < 75% device usage or early discontinuation. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing interests Authors Devon C. Riegel, Britta L. Bureau, and Jennifer M. Connelly declare they have no financial interests. Patrick Conlon and Gordon Chavez are current employees of Novocure Inc. Author contributions All authors contributed to the study conception and design. Material preparation and data collection were performed by Devon C. Riegel and Britta L. Bureau. Analysis was performed by Patrick Conlon and Gordon Chavez. The first draft of the manuscript was written by Devon C. Riegel and all authors commented on previous versions of the manuscript. Jennifer M. Connelly presided over the study as principal investigator. All authors read and approved the final manuscript. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Institutional Review Board (IRB) approval was granted by the Ethics Committee of the Medical College of Wisconsin (11/11/2019, PRO00036224). Consent to participate and publish Participant consent was waived per IRB. 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BMC Med Phys 9:1. 10.1186/1756-6649-9-1 Taphoorn MJB, Dirven L, Kanner AA et al (2018) Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 4(4):495–504. 10.1001/jamaoncol.2017.5082 Wenger C, Salvador R, Basser PJ, Miranda PC (2016) Improving Tumor Treating Fields Treatment Efficacy in Patients With Glioblastoma Using Personalized Array Layouts. Int J Radiat Oncol Biol Phys 94(5):1137–1143. 10.1016/j.ijrobp.2015.11.042 Trusheim J, Dunbar E, Battiste J et al (2017) A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. CNS Oncol 6(1):29–43. 10.2217/cns-2016-0032 Lacouture ME, Anadkat MJ, Ballo MT et al (2020) Prevention and Management of Dermatologic Adverse Events Associated With Tumor Treating Fields in Patients With Glioblastoma. Front Oncol 10:1045. 10.3389/fonc.2020.01045 Chen C, Xu H, Song K et al (2022) Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center. J Clin Med 11(19). 10.3390/jcm11195855 Additional Declarations Competing interest reported. Authors Patrick Conlon and Gordon Chavez are current employees of Novocure Inc. Devon C. Riegel, Britta L. Bureau, and Jennifer M. Connelly declare they have no financial interests. Supplementary Files SupplementaryfiguresRiegeletal.docx Cite Share Download PDF Status: Published Journal Publication published 31 Mar, 2025 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 21 Dec, 2024 Reviews received at journal 21 Dec, 2024 Reviewers agreed at journal 12 Dec, 2024 Reviews received at journal 12 Nov, 2024 Reviewers agreed at journal 12 Nov, 2024 Reviewers agreed at journal 04 Nov, 2024 Reviewers agreed at journal 04 Nov, 2024 Reviewers agreed at journal 02 Nov, 2024 Reviewers invited by journal 02 Nov, 2024 Editor assigned by journal 02 Nov, 2024 Submission checks completed at journal 02 Nov, 2024 First submitted to journal 01 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-5375767","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":377313484,"identity":"741ec5bc-461c-4771-afe7-1c719ca9bebd","order_by":0,"name":"Devon Cassidy Riegel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuElEQVRIiWNgGAWjYDCCA4wNQNJCDsJjI16LhDEpWsCkRGID0Vr4bh9ufPilQiJ9bfsZA4YPZYcJa5E8l9hsLHNGInfbmRwDxhnniNBicIaxTVqyDajlBu8GZt424rS0/5b8J5FuBtLyl0gtbYwfGyQSwFoYidEieYaxWZrhmIThtjP5Hw72nEsnrIXvDPvDjz9qbOTNjh9LfPCjzJqwFhBg5oEyDhCnHggYfxCtdBSMglEwCkYkAACBNz31srUQaAAAAABJRU5ErkJggg==","orcid":"","institution":"Medical College of Wisconsin","correspondingAuthor":true,"prefix":"","firstName":"Devon","middleName":"Cassidy","lastName":"Riegel","suffix":""},{"id":377313486,"identity":"d2e7b0cf-7d6c-4342-bab3-b245b3a3f097","order_by":1,"name":"Britta L Bureau","email":"","orcid":"","institution":"Medical College of Wisconsin","correspondingAuthor":false,"prefix":"","firstName":"Britta","middleName":"L","lastName":"Bureau","suffix":""},{"id":377313489,"identity":"b6442da2-4dcc-46e9-8cb9-ecc5b39c98cc","order_by":2,"name":"Patrick Conlon","email":"","orcid":"","institution":"Novocure (United States)","correspondingAuthor":false,"prefix":"","firstName":"Patrick","middleName":"","lastName":"Conlon","suffix":""},{"id":377313495,"identity":"f5d2b811-2e7b-4fdb-b9fa-80b94da9a140","order_by":3,"name":"Gordon Chavez","email":"","orcid":"","institution":"Novocure (United States)","correspondingAuthor":false,"prefix":"","firstName":"Gordon","middleName":"","lastName":"Chavez","suffix":""},{"id":377313498,"identity":"2a746e5b-86e5-4435-8a6e-3eedff576166","order_by":4,"name":"Jennifer M Connelly","email":"","orcid":"","institution":"Medical College of Wisconsin","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"M","lastName":"Connelly","suffix":""}],"badges":[],"createdAt":"2024-11-01 23:38:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5375767/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5375767/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-025-04946-w","type":"published","date":"2025-03-31T15:57:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70297008,"identity":"39ba3ce4-93ba-4619-8bec-316028edd2de","added_by":"auto","created_at":"2024-12-02 00:43:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":487505,"visible":true,"origin":"","legend":"\u003cp\u003eOverall and progression-free survival for patients by TTFields therapy cohort\u003c/p\u003e","description":"","filename":"Figure1Riegeletal.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5375767/v1/0e3519bce4d84c431f8022e7.jpg"},{"id":70297006,"identity":"157941a5-3316-4ffa-b100-c36130576b43","added_by":"auto","created_at":"2024-12-02 00:43:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":790720,"visible":true,"origin":"","legend":"\u003cp\u003eSpatial pattern of progression for patients by TTFields therapy cohort\u003c/p\u003e","description":"","filename":"Figure2Riegeletal.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5375767/v1/1ac9ec6484e90b530478dc21.jpg"},{"id":70297405,"identity":"56b0314b-688e-4b82-a62b-a646c7b5468a","added_by":"auto","created_at":"2024-12-02 00:51:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":840096,"visible":true,"origin":"","legend":"\u003cp\u003ePatterns of TTFields device usage and correlation with overall survival\u003c/p\u003e","description":"","filename":"Figure3Riegeletal.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5375767/v1/b17171bd13bcfced6d7cd8a5.jpg"},{"id":80082012,"identity":"837b3537-411d-4540-bd60-678509206947","added_by":"auto","created_at":"2025-04-07 16:05:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2976914,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5375767/v1/28fd13a2-130f-46bc-b72b-52ecd4a73623.pdf"},{"id":70297007,"identity":"46b2523a-eac7-4f67-a952-be63b3075d7b","added_by":"auto","created_at":"2024-12-02 00:43:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":158415,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryfiguresRiegeletal.docx","url":"https://assets-eu.researchsquare.com/files/rs-5375767/v1/9f5c74d4fe530542c749d6be.docx"}],"financialInterests":"Competing interest reported. Authors Patrick Conlon and Gordon Chavez are current employees of Novocure Inc. Devon C. Riegel, Britta L. Bureau, and Jennifer M. Connelly declare they have no financial interests.","formattedTitle":"Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS), making up over 50% of all malignant CNS tumors.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Despite significant improvements in the field of neuro-oncology, overall survival (OS) for GBM remains low at a median 14\u0026ndash;16 months with standard therapy and ~\u0026thinsp;5% 5-year OS rate.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Molecular markers such as \u003cem\u003eMethylguanine methyltransferase\u003c/em\u003e (MGMT) gene methylation are useful for prognostication of GBM wherein positive MGMT methylation prolongs OS.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Standard of care (SOC) includes maximal safe resection followed by radiotherapy (RT) with concurrent daily temozolomide (TMZ), followed by maintenance TMZ for 6 to 12 months.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Since the approval of TMZ for treatment of newly-diagnosed GBM, few randomized controlled trials have succeeded in identifying a similarly efficacious treatment modality.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn 2015, the Tumor-Treating Fields (TTFields) device was approved by the Food and Drug Administration (FDA) for treatment of patients with newly diagnosed GBM (ndGBM).\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e TTFields delivers alternating electric fields to mapped brain regions via a portable battery-powered device with arrays that are placed on the surface of the scalp.\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The alternating electric fields disrupt mitosis via several mechanisms, including disruption of the mitotic spindle, to arrest tumor cell growth and ultimately trigger apoptosis.\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The pivotal phase III trial (EF-14) by Stupp et al. demonstrated that TTFields paired with SOC TMZ significantly prolonged median OS to 20.9 months and median progression-free survival (PFS) to 6.7 months compared to 16 months OS and 4 months PFS with TMZ alone independent of other factors.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e A meta-analysis study published in 2023 corroborated these results in the clinical practice setting, finding significantly improved median OS from 17.4 months with SOC alone to 22.6 months with SOC plus TTFields.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA dose effect from using the TTFields device has been suggested from studies examining higher levels of device usage by the patient, as well as higher field intensities delivered to the tumor bed by the arrays..\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Post-hoc analyses of the pivotal trials in both newly diagnosed and recurrent GBM have shown that using the device at least 75% of the time, or 18 hours on average out of a 24-hour period, is correlated with improved OS.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Following a separate analysis of the EF-14 trial showing a link between higher TTFields dose and improved survival,\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e further analyses of the spatial patterns of disease progression revealed that patients treated with TTFields and TMZ experienced more distant patterns of progression than patients treated with TMZ alone, and for TTFields-treated patients, normal brain areas that did not exhibit tumor progression received a higher dose of TTFields.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e However, these effects have yet to be corroborated outside of the clinical trial setting.\u003c/p\u003e \u003cp\u003eAfter nearly a decade of the use of TTFields for the treatment of ndGBM, questions related to long-term survival benefit, patterns of progression, and the impact of device usage on survival outcomes in the real-world setting remain. Retrospective studies investigating these phenomena have been limited by the lack of sufficiently large patient populations and suitable granularity of data. The patient cohort at the Medical College of Wisconsin and Froedtert Hospital (MCW-FH) is one of the largest, single-institution datasets of TTFields users in the United States, which makes it an ideal cohort to evaluate TTFields in the clinical setting. This study aims to investigate real-world survival, patterns of progression, and patterns of device use across a large cohort of patients with ndGBM treated with or without TTFields.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics and data collection\u003c/h2\u003e \u003cp\u003eAll patients included in this retrospective study were diagnosed and treated for GBM at MCW-FH. Data was collected in accordance with local IRB approval to ensure patient privacy and safety. Consecutive patients with supratentorial ndGBM who were treated with SOC therapy between March 2015 and March 2023 were included for analysis. SOC consisted of concurrent radiotherapy with TMZ followed by maintenance TMZ with or without the addition of TTFields therapy, which became part of the SOC regimen at our institution in 2015, following results of the EF-14 study. Further criteria for cohort selection included completion of TMZ-based chemoradiotherapy and initiation of maintenance TMZ (minimum 1 cycle). A minimum 30 days of device use was required for the TTFields group. Grade 4 GBM diagnosis was confirmed histologically in all but four patients. Molecular criteria were met in three of these four patients, leaving one patient in the combined cohort (in TTFields group) with IDH-wildtype astrocytoma grade 3. Demographic, tumor, and treatment characteristics were collected for all patients and survival outcomes were assessed. Patients were followed through March 1, 2024.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProgression pattern assessment\u003c/h3\u003e\n\u003cp\u003eLocal and distal (non-local) patterns of tumor progression were identified from manual review of baseline and follow-up MRI scans at the time of first documented progression. Local progression was defined as contiguous enhancement with the baseline lesion or enhancement within the T2 FLAIR region of vasogenic edema associated with the baseline lesion. Non-local sites of progression were defined as regions of non-contiguous enhancement in distinct anatomic locations relative to the baseline lesion: distant lesion in same hemisphere, contralateral hemisphere, leptomeningeal disease, and posterior fossa. Location of progression was documented for all cases of radiographic progression in each treatment group.\u003c/p\u003e\n\u003ch3\u003eAssessment of TTFields use patterns\u003c/h3\u003e\n\u003cp\u003eTTFields device usage information was extracted from the device log files of each patient. For quantifying the average rate of usage over time, the time period between when a patient first turned the device on and when the device was last operated served as the source of usage data. Average usage for each treatment month was calculated across the cohort. For quantifying the level of device usage for each patient, the average monthly usage was calculated over the first 12 months of treatment, unless otherwise specified.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eOverall survival was measured from the date of diagnosis to the date of patient death or last known contact. PFS was measured from the date of diagnosis to the date of disease progression or death, whichever occurred first, or last known contact. Medians and rates of survival were compared between groups using the Kaplan-Meier method with Cox proportional hazards model. P values were calculated and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Propensity score matching and multivariate Cox regression were utilized where indicated to control for confounders between groups. Differences in categorical variables at baseline were evaluated using chi-squared or Wilcoxon tests for proportions or continuous variables, respectively. Differences in the rates of non-local progression were conducted using a chi-squared test.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient and treatment characteristics\u003c/h2\u003e \u003cp\u003eBetween March, 2015 and March, 2023, 231 patients were diagnosed at our institution and treated for GBM. Of those patients, 214 patients completed concurrent radiotherapy with TMZ and initiated maintenance TMZ treatment with or without TTFields therapy. The TTFields group comprised patients who received TTFields for a minimum of 30 days (n\u0026thinsp;=\u0026thinsp;109), whereas the non-TTFields group comprised patients who did not receive TTFields at all in their first-line treatment (n\u0026thinsp;=\u0026thinsp;99).\u003c/p\u003e \u003cp\u003ePatient demographics, tumor, and treatment characteristics for the TTFields and non-TTFields groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Baseline characteristics were balanced between groups, not accounting for subgroups with missing MGMT promoter methylation or isocitrate dehydrogenase (IDH) mutational status. The median age for the TTFields group was 60 and for the non-TTFields group was 64. The male to female ratio was equal between groups. The proportions of patients having GTR and biopsy were slightly higher in the TTFields group. The median number of TMZ cycles was 7 in the TTFields group and 5 in the non-TTFields group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient, tumor, and treatment characteristics by cohort\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 \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTTFields\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo TTFields\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;99)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (27\u0026ndash;86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (28\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\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\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor grade/histology\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e108 (99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor presentation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifocal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrontal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOccipital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParietal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemporal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrontoparietal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrontotemporal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemporal-occipital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemporal-parietal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParieto-occipital\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIDH1 Status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWildtype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102 (94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92 (93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMGMT promoter methylation status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnmethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eResection status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross total resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSub-total resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaintenance TMZ\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian cycles (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (1\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (1\u0026ndash;27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTTFields therapy duration\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.8 (1\u0026ndash;94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival outcomes\u003c/h3\u003e\n\u003cp\u003eOverall survival for patients in the TTFields group was significantly improved over patients in the non-TTFields group (HR: 0.71 (0.52\u0026ndash;0.97), p\u0026thinsp;=\u0026thinsp;0.029; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Median OS was 21.7 months (95% CI 18.7\u0026ndash;24.8) for the TTFields group and 17.7 months (14.6\u0026ndash;20.6) for the Non-TTFields group, with 5-year OS rates of 17% (95% CI 11\u0026ndash;28) and 12% (95% CI 6\u0026ndash;23), respectively. Multivariate analysis showed treatment with TTFields to have a significant effect on OS when adjusting for known prognostic factors including age, gender, IDH mutational status, MGMT methylation status, and extent of resection (p\u0026thinsp;=\u0026thinsp;0.017). PFS was also significantly improved for the TTFields group compared with the non-TTFields group (p\u0026thinsp;=\u0026thinsp;0.047; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb), but the difference was not found to be significant when adjusting for known prognostic factors (p\u0026thinsp;=\u0026thinsp;0.069). Median PFS was 12.4 months (95% CI 10.5\u0026ndash;14.4) for the TTFields group and 9.6 months (95% CI 8.5\u0026ndash;12.8) for the non-TTFields group.\u003c/p\u003e \u003cp\u003eTo understand the profile of patients surviving\u0026thinsp;\u0026ge;\u0026thinsp;2 years and assess factors predisposing patients to living longer, we examined patient characteristics for the two treatment groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). As expected, median age was lower and IDH-mutant status, MGMT-methylation status, and gross total resection were higher for both treatment groups. No significant differences were noted between TTFields-treated and non-TTFields-treated patients across factors we evaluated. Survival curves are shown in Supp. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. For the TTFields-treated patients surviving\u0026thinsp;\u0026gt;\u0026thinsp;5 years (n\u0026thinsp;=\u0026thinsp;9), 4 were still on treatment at the time of data cutoff and 6 had IDH-wildtype tumors.\u003c/p\u003e \u003cp\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\u003ePatient characteristics and survival among subgroup surviving 2 years or longer\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\u003eTTFields\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;40)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo TTFields\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003ePatient and treatment characteristics among 2-year survivors\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAge, y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (29\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (28\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"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\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifocal disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eIDH1 Status\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWildtype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eMGMT promoter methylation status\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnmethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eResection status\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross total resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSub-total resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eMaintenance TMZ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian cycles (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (1\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (1\u0026ndash;27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;6 cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTTFields therapy duration\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.1 (1.6\u0026ndash;93.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurvival outcomes for patients surviving\u0026thinsp;\u0026ge;\u0026thinsp;2 years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath events, n\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\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOS, additional 2 years, % (CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (36\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (35\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOS, additional 3 years, % (CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (27\u0026ndash;64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (21\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOS, additional 4 years, % (CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (27\u0026ndash;64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (2\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003ePatterns of progression\u003c/h3\u003e\n\u003cp\u003eSpatial patterns of tumor progression were radiologically assessed for each treatment group. The rate of non-local progression was significantly higher for the TTFields group compared with the non-TTFields group (28% vs 14%, p\u0026thinsp;=\u0026thinsp;0.028), and the difference was significant on multivariate analysis when adjusting for other prognostic factors (p\u0026thinsp;=\u0026thinsp;0.031) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). Progression in the contralateral hemisphere was the most frequent type of non-local progression for TTFields patients, followed by distal progression within the same hemisphere (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Rates of non-local progression subtypes were numerically higher for TTFields-treated patients across categories, but samples were too small to compare statistically. Examples of non-local, intraparenchymal patterns within the TTFields cohort are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatterns of device use with TTFields therapy\u003c/h2\u003e \u003cp\u003eTo better understand how patients in the TTFields group complied with using their device, a temporal analysis of device usage rate was conducted. A total of 108 patients treated with TTFields had device usage data available for analysis. Across the cohort, the average rate of device usage was maintained over time and did not diminish with prolonged use (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). Instances of usage rate declines were transient in nature. A period of sustained usage decline was observed during the immediate 4 months following treatment start but recovered thereafter. Usage rates were similarly found to be maintained over time for both long- and short-term users of the device (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb), with the average rate of usage higher for the \u0026ge;\u0026thinsp;2-year users compared with the \u0026lt;\u0026thinsp;2-year group. Transient drop-offs in usage were more pronounced at month 13 and month 19 in the \u0026lt;\u0026thinsp;2-year and \u0026ge;\u0026thinsp;2-year groups, respectively. When examining the association of usage and duration more closely, the duration of treatment with TTFields was found to increase in a graded manner with higher rates of usage (Supp. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo further examine the impact of device usage on patient outcomes in a real-world setting, survival was evaluated across high and low usage groups. A usage threshold of 75% (average use of 18 hours per day) was applied as it is a common usage target for patients and was evaluated in previous trial settings.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Approximately half the patients in the TTFields cohort had an average usage level of 75%. Due to the high usage rates observed among patients with IDH-mutant tumors in our cohort, usage groups were restricted to IDH-wildtype patients to avoid bias in the analysis of survival. Upon initial inspection, OS and PFS did not significantly differ between patients in the \u0026ge;\u0026thinsp;75% and \u0026lt;\u0026thinsp;75% groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec and Supp Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea), with only a trend of increased OS and PFS for the high usage patients. However, baseline characteristics were not balanced between the cohorts and missingness in MGMT methylation status remained (Supp Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). With propensity score matching applied to match the usage cohorts on known prognostic factors, OS and PFS were each significantly longer for the \u0026ge;\u0026thinsp;75% group compared with the \u0026lt;\u0026thinsp;75% group (HR(OS): 0.46 (0.26\u0026ndash;0.82), p\u0026thinsp;=\u0026thinsp;0.008; HR(PFS): 0.51 (0.30\u0026ndash;0.85); p\u0026thinsp;=\u0026thinsp;0.011) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed and Supp Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). The effect remained significant on multivariate analysis when adjusting for the same covariates used for matching.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs experience with TTFields therapy for ndGBM has increased over the past decade, understanding the real-world treatment patterns and outcomes associated with using this device are necessary for informed treatment decision-making. From retrospective analysis of a large real-world cohort of patients with GBM, this study provided complementary evidence to the pivotal trial results of Stupp et al., in which the addition of TTFields therapy to SOC led to increased OS and PFS over SOC alone.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In our study, treatment with TTFields was found to significantly improve OS for patients with ndGBM compared to treatment with SOC alone, with durable long-term survival benefit that did not appear to depend on known GBM prognostic factors. Additionally, this study revealed correlations between higher usage and prolonged OS and PFS, as well as an association of more distal patterns of disease recurrence with TTFields treatment, the first time being demonstrated in a real-world GBM population.\u003c/p\u003e \u003cp\u003eOur analysis of patterns of recurrence is comparable to the results of Glas et al. with some additional strengths. While Glas et al. evaluated the frequency of distant recurrence in patients using TTFields, this study did not further categorize regions of recurrence relative to the initial lesion, such as differentiating between same-hemisphere recurrence versus contralateral hemisphere recurrence versus recurrence in the posterior fossa.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e We show that patients treated with TTFields and SOC are significantly more likely to experience non-local progression, with a measurable increase in contralateral and distal progression within the same hemisphere. While some previous studies have suggested a potential relationship with OS and more distal forms of progression,\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e we did not observe a difference in survival between patterns of progression. This lack of observed difference may be due to sample size limitations, although in general more work is needed to further understand the relationship between patient outcomes and spatial-temporal patterns of disease progression within the brain.\u003c/p\u003e \u003cp\u003eOur results for device usage are also in alignment with previous studies.\u003csup\u003e20,21,25,26\u003c/sup\u003e \u0026ge;75% device usage significantly prolonged OS and PFS after propensity score matching was applied to match the usage cohorts on known prognostic factors. Furthermore, the temporal trends in device usage we observed suggest subjective user experiences with the device that affect percent daily usage and likelihood of continuation. Overall, we did not observe a decline in the average usage rate over time; rather, the average device usage rate was sustained, and generally correlated with treatment duration. The period of sustained decline during the immediate 4 months following treatment start may reflect patients who eventually discontinued TTFields within 1 year. Tumor response to TTFields develops slowly; patients who terminated TTFields use after a short period of time may not have experienced an OS benefit,\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e although the minimum duration of TTFields treatment to achieve clinical benefit remains unknown. The transient drop-offs in usage at month 13 and month 19 in the \u0026lt;\u0026thinsp;2-year and \u0026ge;\u0026thinsp;2-year groups may be associated with clinical decline or patient preference associated with disease recurrence.\u003c/p\u003e \u003cp\u003eIn the subgroup of patients surviving\u0026thinsp;\u0026gt;\u0026thinsp;5 years, all 9 patients had a device usage rate\u0026thinsp;\u0026gt;\u0026thinsp;50%, with 5 patients\u0026thinsp;\u0026gt;\u0026thinsp;75%. Six of these patients were progression-free for \u0026gt;\u0026thinsp;4 years. Previous results from EF-14 showed OS to be incrementally improved with higher rates of usage, with maximal survival benefit observed for patients with average usage rates\u0026thinsp;\u0026gt;\u0026thinsp;90%.\u003csup\u003e23\u003c/sup\u003eFurther analysis could compare these patients to others with similar long-term survival, though this analysis would likely be limited by a small cohort. This leaves the potential for a multi-institution retrospective analysis of long-term survivors on TTFields.\u003c/p\u003e \u003cp\u003eThere remains a need to understand the clinical limitations to TTFields. Treatment with TTFields does not increase toxicities associated with other cancer treatments\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e or significantly impair quality of life.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e There are few complications caused by TTFields other than mild-to-moderate skin irritation at the site of array placement,\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e yet some patients report low usage rates or will discontinue device usage within a year of starting therapy. Since the approval of TTFields, multiple studies have helped clarify treatment planning and skin management best practices.\u003csup\u003e\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Despite these efforts, barriers to effective use of the device continue to exist, and may include convenience, mobility issues, subjective discomfort, and limitation of daily activities (i.e., swimming). Future studies can consider collecting subjective patient data on reasons for \u0026lt;\u0026thinsp;75% usage and/or device termination.\u003c/p\u003e \u003cp\u003eThis study is not without limitations. Generally, prospective studies with randomized designs yield stronger results than retrospective cohort studies. To limit the potential for patient selection biases across comparative groups, we utilized multivariate regression and propensity score matching to help control for confounding variables. Also, while our cohort represents the largest single institution analysis of TTFields to date,\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e a larger cohort size may have permitted more in-depth analyses of progression pattern subtypes, particularly for the rarer leptomeningeal disease and posterior fossa recurrence, as well as analysis of outcomes across multiple usage thresholds and dose metrics. Finally, while our study followed patients between March 2015 to March 2023, there still remains a subset of patients who have yet to experience recurrence, particularly patients whose disease was diagnosed within a year of the end of analysis. Longer follow-up would provide additional insight both into long-term patterns of disease recurrence\u0026thinsp;\u0026gt;\u0026thinsp;10 years and allow for additional data on patterns of recurrence in recently-diagnosed patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAnalysis of patients from a large single institutional dataset reveals an association between TTFields use and long-term survival benefit, consistent with pivotal trial findings. TTFields use is associated with a higher incidence of non-local patterns of progression. TTFields device usage\u0026thinsp;\u0026ge;\u0026thinsp;75% is associated with increased progression-free and long-term survival when controlled for prognostic factors between cohorts. Future studies can consider further analyzing subtypes of non-local progression and subjective patient experiences that lead to \u0026lt;\u0026thinsp;75% device usage or early discontinuation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interests\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAuthors Devon C. Riegel, Britta L. Bureau, and Jennifer M. Connelly declare they have no financial interests. Patrick Conlon and Gordon Chavez are current employees of Novocure Inc.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthor contributions\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation and data collection were performed by Devon C. Riegel and Britta L. Bureau. Analysis was performed by Patrick Conlon and Gordon Chavez. The first draft of the manuscript was written by Devon C. Riegel and all authors commented on previous versions of the manuscript. Jennifer M. Connelly presided over the study as principal investigator. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eData availability\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eEthics approval\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Institutional Review Board (IRB) approval was granted by the Ethics Committee of the Medical College of Wisconsin (11/11/2019, PRO00036224).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConsent to participate and publish\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eParticipant consent was waived per IRB. De-identified data was used for analysis and all participants remain de-identified in the body of the manuscript and figures.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOstrom QT, Price M, Neff C et al (2023) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016\u0026ndash;2020. 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BMC Med Phys 9:1. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/1756-6649-9-1\u003c/span\u003e\u003cspan address=\"10.1186/1756-6649-9-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaphoorn MJB, Dirven L, Kanner AA et al (2018) Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. 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CNS Oncol 6(1):29\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2217/cns-2016-0032\u003c/span\u003e\u003cspan address=\"10.2217/cns-2016-0032\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLacouture ME, Anadkat MJ, Ballo MT et al (2020) Prevention and Management of Dermatologic Adverse Events Associated With Tumor Treating Fields in Patients With Glioblastoma. Front Oncol 10:1045. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2020.01045\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2020.01045\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen C, Xu H, Song K et al (2022) Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center. J Clin Med 11(19). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm11195855\u003c/span\u003e\u003cspan address=\"10.3390/jcm11195855\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Tumor-Treating Fields, glioblastoma, progression, usage","lastPublishedDoi":"10.21203/rs.3.rs-5375767/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5375767/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTumor Treating Fields therapy (TTFields) is an FDA-approved locoregional treatment for patients with newly diagnosed glioblastoma (ndGBM). Previous trial data showed the addition of TTFields to standard TMZ-based therapy to significantly improve overall survival (OS), but real-world data is lacking, particularly with long follow-up duration. Here, we report real-world survival, patterns of progression, and patterns of use for patients for patients with ndGBM treated with or without TTFields.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients diagnosed with GBM and treated with standard of care therapy at the Medical College of Wisconsin between March 2015\u0026ndash;March 2023 were included. Survival outcomes were assessed, and compared across groups who received or did not receive TTFields therapy during maintenance treatment. Patients were followed through March 1, 2024.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 208 patients (TTFields: n\u0026thinsp;=\u0026thinsp;109; No-TTFields: n\u0026thinsp;=\u0026thinsp;99) were included for analysis. Baseline characteristics were consistent across groups. Median OS and PFS were significantly improved for the TTFields group vs No-TTFields group (median OS: 21.7 vs 17.7 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029; median PFS: 12.4 vs 9.6 months, \u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.047\u003c/em\u003e). Patients treated with TTFields exhibited a higher rate of non-local progression vs No-TTFields group. Median OS and PFS were each significantly longer for the \u0026ge;\u0026thinsp;75% usage group compared with \u0026lt;\u0026thinsp;75% via matched analysis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe results of this study reveal an association between TTFields use and long-term survival benefit, consistent with pivotal trial findings. TTFields use is associated with a higher incidence of non-local patterns of progression, and TTFields device usage\u0026thinsp;\u0026ge;\u0026thinsp;75% is associated with increased progression-free and long-term survival.\u003c/p\u003e","manuscriptTitle":"Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 00:43:53","doi":"10.21203/rs.3.rs-5375767/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-21T20:21:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-21T12:18:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294698199151114158947282931022669098093","date":"2024-12-12T19:39:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-12T17:27:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271969352384826816318743399509194168026","date":"2024-11-12T13:53:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92741989203534837439486360023725707254","date":"2024-11-04T15:28:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"34665880437650848270197213897901510809","date":"2024-11-04T11:46:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73212597659722407838385278941336840599","date":"2024-11-02T11:50:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-02T11:11:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-02T07:50:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-02T07:50:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2024-11-01T23:24:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e5eb673a-0283-4d3c-bf41-d56ac46b45c3","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-07T16:00:14+00:00","versionOfRecord":{"articleIdentity":"rs-5375767","link":"https://doi.org/10.1007/s11060-025-04946-w","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2025-03-31 15:57:19","publishedOnDateReadable":"March 31st, 2025"},"versionCreatedAt":"2024-12-02 00:43:53","video":"","vorDoi":"10.1007/s11060-025-04946-w","vorDoiUrl":"https://doi.org/10.1007/s11060-025-04946-w","workflowStages":[]},"version":"v1","identity":"rs-5375767","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5375767","identity":"rs-5375767","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}