Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy

Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy Kevin Yijun Fan, Katarzyna Joanna Jerzak, Sudhir Kumar, Veronika Moravan, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4850268/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Oct, 2024 Read the published version in Journal of Neuro-Oncology → Version 1 posted 12 You are reading this latest preprint version Abstract Purpose: In patients with oligometastatic disease (OMD) treated with stereotactic body radiation therapy (SBRT), those who develop brain metastases (BrM) may have poor outcomes. We aimed to investigate variables associated with BrM development in this population. Methods: Patients with ≤ 5 extracranial metastases from solid tumors treated with SBRT from 2008–2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between extracranial progression and CIBrM using time-based conditional analysis. Results: Among 404 patients, the most common primary sites were lung, colorectal, prostate, breast and kidney. Median follow-up was 49 months. Median PFS was 25 months. Median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. On multivariable analysis, number of extracranial metastases, location of metastases, total planning target volume (PTV), and time from primary diagnosis to OMD were not associated with CIBrM, although several of these variables were associated with extracranial PFS and OS. Primary site was associated with CIBrM, with colorectal and prostate cancer associated with lower CIBrM compared to lung cancer. Widespread extracranial progression (≥ 5 sites) within 24, 36, 48 and 60 months of OMD diagnosis was independently associated with higher CIBrM. Conclusion: In patients with OMD treated with SBRT, baseline variables related to extracranial disease burden and distribution were not associated with BrM development, while primary site and widespread extracranial progression were associated with BrM development. Figures Figure 1 Figure 2 Introduction Oligometastatic disease (OMD) is an intermediate state between localized and polymetastatic disease( 1 – 3 ). Several recent trials have shown that SBRT (stereotactic body radiation therapy) improves overall survival (OS) and progression-free survival (PFS)( 4 – 6 ) in patients with OMD, supporting the paradigm that such patients can be treated with the intent of long-term disease control or cure. However, despite curative-intent treatment of OMD, a proportion of these patients go on to develop brain metastases (BrM), which is often an unexpected pivotal event associated with significant morbidity and mortality and finite treatment options. Between 10 and 40% of patients with cancer develop BrM, with common primary sites being non-small cell lung cancer (NSCLC), breast cancer, and melanoma( 7 – 9 ). The median overall survival of patients with BrM is 7–12 months( 10 – 12 ), although a small proportion of patients have long term survival( 13 ). Hence, there is a need to better understand the variables associated with the development of BrM in patients with OMD, in order to individualize treatment decisions and optimize patient selection and surveillance. In a retrospective Canadian cohort of patients with OMD treated with SBRT, we aimed to investigate clinical variables associated with development of BrM. Materials and Methods We investigated a retrospective cohort of 415 patients with OMD treated with SBRT between January 2008 and December 2016 at Sunnybrook Odette Cancer Centre (Toronto, Canada), as secondary use of local data originally part of a multi-institutional database that was previously described ( 14 ), with additional retrospective data collected on BrM. All patients were 18 years of age or older and had a pathologically confirmed diagnosis of a solid tumour malignancy. Patients with a primary diagnosis of hematological malignancy, primary central nervous system cancer or germ cell cancer, were excluded. All patients had ≤ 5 cumulative sites of metastatic disease seen on conventional staging investigations. Malignant lymph node(s), as defined by site-specific size criteria or PET avidity, were considered as site(s) of OMD. All patients had at least one site of OMD treated with SBRT. Patients with ≥ 1 site treated with conventional radical doses of radiation (> 60 Gy) were included as long as at least one site was treated with SBRT. Radiation therapy planning and treatment parameters were previously described( 15 ). All patients underwent complete imaging within 4 months of first SBRT treatment, including either a CT scan of the head, chest, abdomen and pelvis or a full body PET scan, with an MRI of the brain being an acceptable substitute for a head CT. Eleven patients had BrM at the time of OMD diagnosis. These patients were excluded from subsequent analyses below (which will focus on the 404 patients without pre-existing BrM), and will be described separately. Cumulative incidence of brain metastases (CIBrM), overall survival (OS), and progression-free survival (PFS) were examined, starting at the date of diagnosis of OMD, and censored at the most recent follow-up date. Baseline covariates examined included: primary cancer site, time from primary cancer diagnosis to OMD diagnosis (measured as a continuous variable), total number of extracranial metastases, location of extracranial metastases, and total planning target volume (total PTV, defined as the sum of the PTVs of all lesions treated at the time of initial OMD presentation, as a surrogate measure of total disease burden). Kaplan-Meier curves were generated for PFS and OS; the log-rank test was used to ascertain any statistically significant differences between curves. Cox proportional hazards regression was employed to evaluate variables associated with PFS and OS. CIBrM was analysed with death prior to BrM development as a competing risk. Cumulative Incidence Function (CIF) curves were estimated, charted, and visually inspected. The Fine-Gray test was employed to test for differences between CIF curves. The effect of covariates on the CIF was modelled using Fine-Gray subdistribution regression. Modeling the effect of covariates on the CIF allows one to estimate the effect of covariates on the absolute risk of the outcome over time. Multivariable analysis (MVA) for CIBrM, PFS and OS was done using all covariates. Plots of Schoenfeld residuals were used to evaluate the proportional hazard subdistribution assumption. Extracranial progression was not included as a covariate in the initial MVA as it was a temporal variable, rather than a baseline variable. We used conditional analysis to investigate the association between development of widespread extracranial progression (i.e. development of 5 or more sites of new extracranial disease) or any extracranial progression (i.e. widespread extracranial progression, extracranial oligoprogression, or extracranial local recurrence) within six pre-defined timeframes (i.e. within 6, 12, 24, 48 and 60 months from OMD diagnosis) and the CIBrM, after adjusting for the five baseline variables above. In this conditional analysis, all patients who died, were lost to follow-up, or developed BrM within each timeframe were excluded from that conditional analysis. All testing used the traditional significance level of α = .05. Analyses were performed using R software package, version 4.3.1 (R Core Team 2023, R Foundation for Statistical Computing, Vienna, Austria)( 16 ). Results Baseline characteristics In the full cohort of 415 patients, the median age was 71 years (range 32–94 years). 222 patients (53%) were male, and 193 patients (47%) were female. The five most common primary cancer sites were non-small cell lung cancer (NSCLC) (n = 136, 33%), colorectal cancer (n = 106, 26%), prostate cancer (n = 53, 13%), breast cancer (n = 43, 10%), renal cell carcinoma (n = 29, 7%). 126 patients (30%) presented with synchronous OMD (i.e. within 6 months of primary cancer diagnosis) and 289 patients (70%) presenting with metachronous OMD (Table 1 ). Table 1 Baseline and treatment characteristics. Abbreviations: BrM (brain metastasis), NSCLC (non-small cell lung cancer), OMD (oligometastatic disease), mets (metastases), SRS (stereotactic radiosurgery). All patients No BrM at diagnosis BrM at diagnosis n = 415 n = 404 n = 11 n % n % n % Age Median (range) 71 (32–94) 71 (32–94) 58 (46–83) Sex Male 222 53% 215 53% 7 64% Female 193 47% 189 47% 4 36% Primary site NSCLC 136 33% 131 32% 5 45% Colorectal 106 26% 104 26% 2 18% Prostate 53 13% 53 13% 0 0% Breast 43 10% 42 10% 1 9% Kidney 29 7% 28 7% 1 9% Skin (melanoma) 6 1% 4 1% 2 18% Endometrium 5 1% 5 1% 0 0% Stomach 4 1% 4 1% 0 0% Pancreas 4 1% 4 1% 0 0% Skin (non = melanoma) 3 1% 3 0% 0 18% Oropharynx 2 0% 2 0% 0 0% Thyroid 1 0% 1 0% 0 0% Nasopharynx 1 0% 1 0% 0 0% Hypopharynx 1 0% 1 0% 0 0% Cholangiocarcinoma 1 0% 1 0% 0 0% Anal canal 1 0% 1 0% 0 0% Other 19 5% 19 5% 0 0% Primary to OMD (months) Median (IQR) 18 (3.0–42) 18 (3.1–40) 40 (3.0–96) ≤ 6 months 126 30% 122 30% 4 36% > 6 months 289 70% 282 70% 7 64% Total number of mets 1 247 60% 247 61% 0 0% 2 100 24% 93 23% 7 64% 3 43 10% 42 10% 1 9% 4 19 5% 17 4% 2 18% 5 6 1% 5 1% 1 9% Number of BrM at OMD diagnosis 0 404 97% 404 100% 0 0% 1 10 2% 0 0% 10 91% 2 1 0% 0 0% 1 9% Location of mets Bone only 111 27% 108 27% 3 27% Lung or liver 273 66% 267 66% 6 55% Other 31 7% 29 7% 2 18% Total PTV (cc) Median (IQR) 51 (25–112) 51 (24–109) 69 (46–163) ≤50 202 49% 197 49% 5 45% > 50 213 51% 207 51% 6 55% Systemic therapy change after MDT Yes 134 32% 129 32% 5 45% No 281 68% 275 68% 6 55% Treatment of BrM present at diagnosis SRS NA NA NA NA 2 18% Craniotomy NA NA NA NA 9 82% Clinical outcomes: Cumulative incidence of BrM, progression-free survival, and overall survival Median follow-up was 49 (interquartile range [IQR]: 26–88) months. In total, 58 patients (14%) developed brain metastases. CIBrM was 5.3% (95% CI 3.4%-7.8%) at 24 months after OMD diagnosis, 12% (95% CI 9.0%-16%) at 60 months after OMD diagnosis, and 16% (95% CI 12%-21%) at 120 months after OMD diagnosis (Fig. 1 A). 186 patients (46%) died without BrM, and 160 patients (40%) were alive without BrM at the time of last follow-up. Median OS was 70 months (95% CI 59–85 months) (Fig. 1 C). Median PFS was 25 months (95% CI 22–28 months) (Fig. 1 B). Among the 265 patients (66%) who had disease progression, 84 (32%) were alive at the time of last followup. Fine-gray competing risks analysis of CIBrM Patients with different primary cancer sites had significantly different incidence of BrM (p < 0.001), with CIBrM at 5 years after OMD diagnosis of 22% (95% CI 11%-36%) in patients with breast cancer, 15% (95% CI 9.5%-22%) in patients with NSCLC, 15% (95% CI 4.6–32%) in patients with renal cell carcinoma, 5.3% (95% CI 2.0–11%) in patients with colorectal cancer, 0% in patients with prostate cancer, and 23% (95% CI 9.4–39%) in patients with other primary sites (Fig. 2 A). Patients with synchronous OMD had a 5-year CIBrM of 15% (95% CI 9.0–22%) compared to 11% (95% CI 7.4–15%) in patients with metachronous OMD (p = 0.3). Patients with a solitary metastasis had a 5-year CIBrM of 12% (95% CI 7.8–16%) compared to 13% (95% CI 8.0–19%) in patients with multiple metastases (p = 0.5). Patients with isolated bone metastases had a 5-year CIBrM of 11% (6.0–19%) compared to 13% (95% CI 13–24%) in patients with lung or liver metastases, and 7.6% (95% CI 1.2–22%) in patients with other sites of metastases (p = 0.5). Patients with a total PTV of 50 cc or less had a 5-year CIBrM of 7.8% (95% CI 4.6–12%) compared to 17% (95% CI 13–25%) in patients with a total PTV above 50 cc (p = 0.11) (Fig. 2 B-E). Multivariable analysis of covariates associated with CIBrM In a MVA for the outcome of CIBrM, among the five baseline covariates assessed, primary cancer site was the only variable that was independently associated with CIBrM (Likelihood ratio test (LRT) p < 0.001). Specifically, patients with colorectal cancer and prostate cancer had a significantly lower hazard ratio (HR) for CIBrM (HR 0.37 (95% CI 0.16–0.87, p = 0.022) and HR 0.00 (p < 0.001), respectively) compared to patients with NSCLC (Table 2 ). Number of extracranial metastases, location of extracranial metastases, total PTV, and time from primary cancer diagnosis to OMD diagnosis were not significantly associated with CIBrM (Table 2 ). Table 2 Variables associated with cumulative incidence of brain metastases (CIBrM), progression free survival (PFS), and overall survival (OS). Abbreviations: MVA (multivariate analysis), NSCLC (non-small cell lung cancer), OMD (oligometastatic disease), PTV (planning target volume), mets (metastases), LRT (likelihood ratio test). CIBrM MVA PFS MVA OS MVA n HR (95% CI) p LRT p HR (95% CI) p LRT p HR (95% CI) p LRT p Primary site NSCLC (ref) 131 1 < 0.001 1 < 0.001 1 < 0.001 Colorectal 104 0.34 (0.14,0.82) 0.017 0.96 (0.71, 1.3) 0.81 0.60 (0.42, 0.84) 0.04 Breast 42 1.8 (0.79, 4.2) 0.16 0.52 (0.34, 0.81) 0.004 0.29 (0.17, 0.50) < 0.001 Prostate 53 0.0 (0.0, 0.0) < 0.001 0.30 (0.18, 0.48) < 0.001 0.17 (0.090,0.33) < 0.001 Kidney 28 1.9 (0.82, 4.5) 0.13 0.48 (0.28, 0.82) 0.008 0.23 (0.11, 0.46) < 0.001 Other 46 1.2 (0.51, 2.9) 0.66 2.1 (1.4, 3.0) 1 157 1.22 (0.66, 2.3) 0.52 1.1 (0.86, 1.4) 0.46 1.0 (0.77, 1.4) 0.91 Location of mets Bone only (ref) 108 1 0.71 1 < 0.001 1 0.02 Lung or liver 267 1.3 (0.59, 2.7) 0.56 0.44 (0.31, 0.62) < 0.001 0.68 (0.46, 1.0) 0.065 Other 29 0.86 (0.24, 3.0) 0.81 0.51 (0.30, 0.86) 0.011 0.39 (0.19, 0.80) 0.01 Total PTV (cc) 404 1.00 (1.00, 1.00) 0.4 0.5 1.0 (1.0, 1.0) 0.03 0.042 1.0 (1.0, 1.0) 0.001 0.004 Multivariable analysis of covariates associated with PFS and OS In a MVA for the outcome of PFS, primary cancer site (LRT p < 0.001), location of metastases (LRT p < 0.001) and total PTV (LRT p = 0.042) were independently associated with PFS (Table 2 ). In a MVA for the outcome of OS, primary cancer site (LRT p < 0.001), location of metastases (LRT p = 0.02), total PTV (LRT p = 0.004) and time from primary cancer diagnosis to OMD (LRT p = 0.013) were independently associated with OS (Table 2 ). Conditional analysis of association between extracranial progression and CIBrM Development of widespread extracranial progression (i.e. five or more sites of new extracranial disease) within four of the six pre-defined time intervals, i.e. within 24, 36, 48 and 60 months of OMD diagnosis, was independently associated with higher CIBrM after that time interval, after adjusting for the five baseline covariates above (Table 3 ). Development of any extracranial progression (i.e. widespread extracranial progression, extracranial oligoprogression, or extracranial local recurrence) within 48 months of OMD diagnosis, but not within any of the other five timepoints investigated, was independently associated with higher CIBrM after that time interval, after adjusting for the five baseline covariates (Table 3 ). Table 3 Conditional analysis of cumulative incidence of brain metastases, based on ECP (extracranial progression) and WSP (widespread progression) within various time intervals. Abbreviations: MVA (multivariate analysis), LRT (likelihood ratio test). All time intervals are relative to date of diagnosis of oligometastatic disease. MVA adjusts for the five baseline variables investigated in Table 2 . ECP or WSP No ECP or WSP UVA HR (95% CI) LRT p MVA HR (95% CI) LRT p ECP within 6 months 25 373 1.7(0.65–4.3) 0.31 1.4(0.43–4.6) 0.53 ECP within 12 months 76 293 1.6 (0.85-3.0) 0.16 1.7(0.84–3.5) 0.14 ECP within 24 months 102 207 1.2(0.59–2.3) 0.66 1.3(0.62–2.6) 0.54 ECP within 36 months 99 148 1.6(0.76–3.2) 0.24 1.8(0.76–4.1) 0.18 ECP within 48 months 87 118 2.8(1.2–6.5) 0.021 4.0(1.6–9.9) 0.0041 ECP within 60 months 63 100 1.7(0.60-5.0) 0.33 3.0(1.1–8.6) 0.083 WSP within 6 months 16 382 1.6(0.48–5.2) 0.47 1.3(0.32–5.4) 0.69 WSP within 12 months 31 338 2.1(0.93–4.6) 0.1 2.6(0.96–7.1) 0.053 WSP within 24 months 41 268 3.1(1.5–6.6) 0.0082 4.1(1.5–12) 0.0041 WSP within 36 months 38 209 3.0(1.3–6.8) 0.017 3.7(1.3–11) 0.013 WSP within 48 months 28 177 2.4(0.88–6.7) 0.11 5.9(1.7–20) 0.0094 WSP within 60 months 15 148 2.2(0.47-10) 0.36 23(1.6–340) 0.017 Characteristics and outcomes of patients with pre-existing BrM In total, eleven patients had pre-existing BrM at the time of OMD diagnosis. Among these patients, ten had a single BrM, and one had two BrM. All patients had more than one site of OMD, and 4 patients had synchronous OMD. 5 patients had NSCLC, 2 had colorectal cancer, 2 had melanoma, 1 had breast cancer, and 1 had renal cell carcinoma. 9 patients underwent craniotomy: 4 underwent adjuvant whole brain radiotherapy, and 5 underwent adjuvant intensity modulated radiotherapy to the surgical cavity. Two patients were treated with stereotactic radiosurgery alone without surgery (Table 1 ). These eleven patients had poor prognosis, with median intracranial PFS of 6.2 months, median extracranial PFS of 13 months, and median OS of 23 months. Only two patients did not have intracranial progression, and they were also the only two patients alive at the time of last followup. Discussion This is the first study to identify variables associated with development of BrM in a population consisting exclusively of patients with OMD treated with SBRT. We found that variables associated with baseline burden and distribution of extracranial disease were not associated with CIBrM. We also found primary cancer site and extracranial progression were independently associated with CIBrM. We investigated several variables related to baseline metastatic burden and distribution at the time of OMD diagnosis, including: total number of metastases, total PTV (i.e. a surrogate measure of total metastatic burden), and location of extracranial metastases. While many of these variables were independently associated with PFS and OS, none of them were associated with CIBrM on univariable and multivariable analysis. These findings suggest that different underlying variables predict extracranial and intracranial progression. This calls for a need to investigate additional variables associated with the risk of developing BrM in this population. It is important to recognize that there were fewer events (n = 58) in the CIBrM analysis compared to the PFS and OS analyses, which reduced statistical power. It is well known that the incidence of BrM varies greatly depending on primary tumor site, and we demonstrate that this holds true in the setting of oligometastatic disease. In a population-based study of over 16,000 patients, Barnholtz-Sloan et al( 7 ) observed that the incidence of BrM was 9.6% for patients across all primary tumor sites, and highest among patients with lung cancer (19.9%), followed by melanoma (6.9%), renal cell carcinoma (6.5%), breast cancer (5.1%), and lowest among patients with colorectal (1.8%) cancer. Furthermore, is it known that patients with prostate cancer have an extremely low incidence of BrM ( 17 ). Our finding that patients with colorectal and prostate cancer had a significantly lower CIBrM compared to patients with NSCLC is consistent with what is known about these cancer types. Future studies will need to investigate variables associated with BrM development in individual cancer types by integrating histology-specific variables, such as receptor status and Ki67 index in breast cancer( 18 ), pathological subtype in lung cancer( 19 ), and primary location and mitotic rate in melanoma( 20 ), in order to provide more accurate prognostication. We observed that extracranial progression, particularly widespread extracranial progression (i.e. 5 or more sites of disease), was independently associated with CIBrM. A recent retrospective study had also identified an association between development of BrM and oligometastic-to-polymetastatic transition ( 21 ). Biologically, many of these cancers may exhibit an aggressive phenotype with a greater propensity to metastasize. Furthermore, these cancers may harbour more resistant clones to ongoing systemic therapies, or alternatively, the patient may no longer be actively receiving systemic therapy to control their disease. This calls for a need to investigate additional temporally dynamic variables when estimating the risk of developing BrM in patients with OMD. An example of a non-invasive dynamic variable is circulating tumour DNA (ctDNA), which has been shown to predict recurrence-free survival after curative-intent resection in oligometastatic colorectal cancer in a metanalysis of 23 studies( 22 ), and further studies are underway to investigate the utility of ctDNA in patients with various cancer types treated with SBRT for OMD( 4 ). Although our cohort only included 11 patients with pre-existing BrM, it is important to consider the very short median intracranial PFS and OS of this subgroup. In a meta-analysis of 68 studies, Li et al( 23 ) observed that patients with BrM with stable extracranial disease had a longer intracranial PFS compared to patients with disseminated or uncontrolled extracranial disease. In addition, in patients with oligometastatic NSCLC, Iyengar et al( 6 ) observed that SBRT to extracranial sites was associated with a numerically lower rate of intracranial progression. There is a complex association between the dynamics of extracranial and intracranial disease, involving the intrinsic metastatic potential of the tumour and the timing and choice of systemic therapies. It is important for future trials regarding OMD to include patients with BrM, in order to identify substrates necessary for long term intracranial control. Our study has a number of limitations. It is a single centre retrospective study, and the infrequent occurrence of BrM limited our statistical power. In addition, we chose to define temporal clinical outcomes in relation to the date of diagnosis of OMD rather than the end date of SBRT, as our primary objective was to investigate variables associated with development of BrM in patients with OMD, rather than to investigate the effect of SBRT on outcomes. When generalizing our findings, readers will need to be cognizant that all patients in our cohort received SBRT at some point. Conclusions In patients treated with SBRT for OMD, it is crucial to identify and integrate biomarkers to predict an individual patient’s risk of developing BrM, which are associated with significant morbidity and mortality. Our study shows that although variables related to baseline burden and distribution of extracranial disease are associated with extracranial progression, they are not associated with intracranial progression. Furthermore, as expected, primary cancer site and extracranial progression are independently associated with the development of BrM. This calls for a need to explore beyond traditional clinical variables and to investigate histology-specific and/or dynamic biomarkers that better reflect the underlying biology of intracranial metastogenesis, in order to identify patients with OMD at high risk of developing BrM who may benefit from screening and preventative treatment. Declarations Ethics approval and consent to participate: Ethics approval was obtained from the Sunnybrook Research Institute (REB SUN-5942). This study was performed in accordance with the Declaration of Helsinki. Consent for publication: Not applicable Competing Interests KJJ serves as a consultant and advisory board member for: Amgen, Astra-Zeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Gilead Sciences, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Seagen, Novartis, and Viatris. HC has received speaker's honoraria from Novartis. These organizations had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. No competing interests from other authors of this manuscript. Funding information: None Author Contribution KYF and KJJ contributed equally and are co-first authors of this manuscript. KYF, KJJ and HC conceptualized the study. KYF, and VM contributed to software development and implementation. Analyses were performed by KYF, KJJ, VM and HC. Data were collected by KYF, SK and BIS. Curation of data was conducted by KYF, KJJ, SK, VM and HC. The original draft was written by KYF, KJJ and HC. Reviewing and editing of the manuscript was performed by KYF, KJJ, SK, VM, BIS, SD, AVL, HS, AS and HC. Data visualization was conducted by KYF and VM. Project management and coordination was performed by KYF, KJJ and HC. Acknowledgement We acknowledge Hold’em for Life Oncology Fellowships for trainee support. 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J Clin Oncol Off J Am Soc Clin Oncol 38(13):1429–1441 Christ SM, Thiel GW, Heesen P, Mayinger M, Willmann J, Ahmadsei M et al Influence of brain metastases on the classification, treatment, and outcome of patients with extracranial oligometastasis: A single-center cross-sectional analysis [Internet]. 2024 [cited 2024 Jul 26]. https://www.researchsquare.com/article/rs-4559627/v1 Chidharla A, Rapoport E, Agarwal K, Madala S, Linares B, Sun W et al (2023) Circulating Tumor DNA as a Minimal Residual Disease Assessment and Recurrence Risk in Patients Undergoing Curative-Intent Resection with or without Adjuvant Chemotherapy in Colorectal Cancer: A Systematic Review and Meta-Analysis. Int J Mol Sci 24(12):10230 Li AY, Gaebe K, Zulfiqar A, Lee G, Jerzak KJ, Sahgal A et al (2023) Association of Brain Metastases With Survival in Patients With Limited or Stable Extracranial Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 6(2):e230475 Additional Declarations Competing interest reported. KJJ serves as a consultant and advisory board member for: Amgen, Astra-Zeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Gilead Sciences, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Seagen, Novartis, and Viatris. HC has received speaker's honoraria from Novartis. These organizations had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. No competing interests from other authors of this manuscript. Cite Share Download PDF Status: Published Journal Publication published 04 Oct, 2024 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 28 Aug, 2024 Reviews received at journal 23 Aug, 2024 Reviewers agreed at journal 17 Aug, 2024 Reviews received at journal 15 Aug, 2024 Reviews received at journal 11 Aug, 2024 Reviewers agreed at journal 11 Aug, 2024 Reviewers agreed at journal 09 Aug, 2024 Reviewers agreed at journal 09 Aug, 2024 Reviewers invited by journal 05 Aug, 2024 Editor assigned by journal 03 Aug, 2024 Submission checks completed at journal 03 Aug, 2024 First submitted to journal 02 Aug, 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-4850268","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":339713099,"identity":"04508008-65dd-4f7a-a975-a572c9ac3b86","order_by":0,"name":"Kevin Yijun Fan","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"Yijun","lastName":"Fan","suffix":""},{"id":339713100,"identity":"54d4989a-4402-4c1e-a2e4-9871fcbd0e92","order_by":1,"name":"Katarzyna Joanna Jerzak","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Katarzyna","middleName":"Joanna","lastName":"Jerzak","suffix":""},{"id":339713101,"identity":"9fba8cee-a9fe-4720-9fd8-08318cea550d","order_by":2,"name":"Sudhir Kumar","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Sudhir","middleName":"","lastName":"Kumar","suffix":""},{"id":339713102,"identity":"75976d85-00a2-4bd3-bd8c-f1149b0101e5","order_by":3,"name":"Veronika Moravan","email":"","orcid":"","institution":"VM Stats","correspondingAuthor":false,"prefix":"","firstName":"Veronika","middleName":"","lastName":"Moravan","suffix":""},{"id":339713103,"identity":"c05973a1-8ec4-415b-a060-30773572918c","order_by":4,"name":"Badr Id Said","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Badr","middleName":"Id","lastName":"Said","suffix":""},{"id":339713104,"identity":"85c63f72-f572-4338-8ba1-86e9951e9000","order_by":5,"name":"Sunit Das","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Sunit","middleName":"","lastName":"Das","suffix":""},{"id":339713105,"identity":"38789774-8cd8-4cd5-bba5-e17af714801b","order_by":6,"name":"Alexander V. Louie","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"V.","lastName":"Louie","suffix":""},{"id":339713106,"identity":"da48aad2-afef-4ad7-9f08-e782fcef6acd","order_by":7,"name":"Hany Soliman","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Hany","middleName":"","lastName":"Soliman","suffix":""},{"id":339713107,"identity":"d08c7eab-d417-45b3-98ed-eec9970fe121","order_by":8,"name":"Arjun Sahgal","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Arjun","middleName":"","lastName":"Sahgal","suffix":""},{"id":339713108,"identity":"d86e492b-cc68-4b61-8d41-62210dedfecf","order_by":9,"name":"Hanbo Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYBACAwYGNhCdwMDAfAAmwsDYQJwWtgSStfAYEKfFnP3ssQcfGOzy+KV7Pn/m3XEncbv04YMPZzDYyePSYtmTl244gyG5WHLO2W3SvGeeJe7sS0s23MCQbIjLJoMDOWbSPAwHEjfcyN3GzNt2OHHDGR4zyQcMB3A6zuD8G4iW/TdyHn9G1mKPU8sNmC0SOQzScC0bgCK4tbwxN5xhkJw440aameTctsPGO3vYkkEiybgdlmP24EOFXWL/jOTHH962HZbdzsN88GFPhZ0tLi1QjQimYwO6CEFgT4LaUTAKRsEoGCEAAMyNXJuRoD1eAAAAAElFTkSuQmCC","orcid":"","institution":"University of Toronto","correspondingAuthor":true,"prefix":"","firstName":"Hanbo","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-08-02 19:27:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4850268/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4850268/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-024-04834-9","type":"published","date":"2024-10-04T15:57:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62387637,"identity":"17e47e82-48a4-49f4-a102-8255e0eaad3f","added_by":"auto","created_at":"2024-08-13 15:13:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":262594,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall clinical outcomes: \u003c/strong\u003eA) cumulative incidence of brain metastases (CIBrM), B) progression free survival (PFS), C) overall survival (OS). Abbreviations: OMD (oligometastatic disease).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4850268/v1/2b778dcc5ca35aa2f8d454ea.jpeg"},{"id":62387638,"identity":"b8618120-ef3a-4699-9e10-39861688c0c4","added_by":"auto","created_at":"2024-08-13 15:13:59","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":486245,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier analysis of cumulative incidence of brain metastases \u003c/strong\u003eby A) primary tumour site, B) time from primary cancer diagnosis to oligometastatic disease (OMD) diagnosis, C) total number of metastases, D) location of metastases, E) total planning target volume (PTV). Abbreviations: NSCLC (non-small cell lung cancer).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4850268/v1/45ed2f864d0746d3814cd341.jpeg"},{"id":66096768,"identity":"edd0115f-3e58-4958-a08b-cd775cf63c22","added_by":"auto","created_at":"2024-10-07 16:09:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1908619,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4850268/v1/e8727e6f-23dd-4c6c-8548-b28fc6c23371.pdf"}],"financialInterests":"Competing interest reported. KJJ serves as a consultant and advisory board member for: Amgen, Astra-Zeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Gilead Sciences, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Seagen, Novartis, and Viatris. HC has received speaker's honoraria from Novartis. These organizations had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. No competing interests from other authors of this manuscript.","formattedTitle":"Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOligometastatic disease (OMD) is an intermediate state between localized and polymetastatic disease(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Several recent trials have shown that SBRT (stereotactic body radiation therapy) improves overall survival (OS) and progression-free survival (PFS)(\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) in patients with OMD, supporting the paradigm that such patients can be treated with the intent of long-term disease control or cure.\u003c/p\u003e \u003cp\u003eHowever, despite curative-intent treatment of OMD, a proportion of these patients go on to develop brain metastases (BrM), which is often an unexpected pivotal event associated with significant morbidity and mortality and finite treatment options. Between 10 and 40% of patients with cancer develop BrM, with common primary sites being non-small cell lung cancer (NSCLC), breast cancer, and melanoma(\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The median overall survival of patients with BrM is 7\u0026ndash;12 months(\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), although a small proportion of patients have long term survival(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHence, there is a need to better understand the variables associated with the development of BrM in patients with OMD, in order to individualize treatment decisions and optimize patient selection and surveillance. In a retrospective Canadian cohort of patients with OMD treated with SBRT, we aimed to investigate clinical variables associated with development of BrM.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eWe investigated a retrospective cohort of 415 patients with OMD treated with SBRT between January 2008 and December 2016 at Sunnybrook Odette Cancer Centre (Toronto, Canada), as secondary use of local data originally part of a multi-institutional database that was previously described (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), with additional retrospective data collected on BrM. All patients were 18 years of age or older and had a pathologically confirmed diagnosis of a solid tumour malignancy. Patients with a primary diagnosis of hematological malignancy, primary central nervous system cancer or germ cell cancer, were excluded. All patients had\u0026thinsp;\u0026le;\u0026thinsp;5 cumulative sites of metastatic disease seen on conventional staging investigations. Malignant lymph node(s), as defined by site-specific size criteria or PET avidity, were considered as site(s) of OMD. All patients had at least one site of OMD treated with SBRT. Patients with \u0026ge;\u0026thinsp;1 site treated with conventional radical doses of radiation (\u0026gt;\u0026thinsp;60 Gy) were included as long as at least one site was treated with SBRT. Radiation therapy planning and treatment parameters were previously described(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). All patients underwent complete imaging within 4 months of first SBRT treatment, including either a CT scan of the head, chest, abdomen and pelvis or a full body PET scan, with an MRI of the brain being an acceptable substitute for a head CT. Eleven patients had BrM at the time of OMD diagnosis. These patients were excluded from subsequent analyses below (which will focus on the 404 patients without pre-existing BrM), and will be described separately.\u003c/p\u003e \u003cp\u003eCumulative incidence of brain metastases (CIBrM), overall survival (OS), and progression-free survival (PFS) were examined, starting at the date of diagnosis of OMD, and censored at the most recent follow-up date. Baseline covariates examined included: primary cancer site, time from primary cancer diagnosis to OMD diagnosis (measured as a continuous variable), total number of extracranial metastases, location of extracranial metastases, and total planning target volume (total PTV, defined as the sum of the PTVs of all lesions treated at the time of initial OMD presentation, as a surrogate measure of total disease burden). Kaplan-Meier curves were generated for PFS and OS; the log-rank test was used to ascertain any statistically significant differences between curves. Cox proportional hazards regression was employed to evaluate variables associated with PFS and OS. CIBrM was analysed with death prior to BrM development as a competing risk. Cumulative Incidence Function (CIF) curves were estimated, charted, and visually inspected. The Fine-Gray test was employed to test for differences between CIF curves. The effect of covariates on the CIF was modelled using Fine-Gray subdistribution regression. Modeling the effect of covariates on the CIF allows one to estimate the effect of covariates on the absolute risk of the outcome over time. Multivariable analysis (MVA) for CIBrM, PFS and OS was done using all covariates. Plots of Schoenfeld residuals were used to evaluate the proportional hazard subdistribution assumption.\u003c/p\u003e \u003cp\u003eExtracranial progression was not included as a covariate in the initial MVA as it was a temporal variable, rather than a baseline variable. We used conditional analysis to investigate the association between development of widespread extracranial progression (i.e. development of 5 or more sites of new extracranial disease) or any extracranial progression (i.e. widespread extracranial progression, extracranial oligoprogression, or extracranial local recurrence) within six pre-defined timeframes (i.e. within 6, 12, 24, 48 and 60 months from OMD diagnosis) and the CIBrM, after adjusting for the five baseline variables above. In this conditional analysis, all patients who died, were lost to follow-up, or developed BrM within each timeframe were excluded from that conditional analysis.\u003c/p\u003e \u003cp\u003eAll testing used the traditional significance level of α\u0026thinsp;=\u0026thinsp;.05. Analyses were performed using R software package, version 4.3.1 (R Core Team 2023, R Foundation for Statistical Computing, Vienna, Austria)(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eIn the full cohort of 415 patients, the median age was 71 years (range 32\u0026ndash;94 years). 222 patients (53%) were male, and 193 patients (47%) were female. The five most common primary cancer sites were non-small cell lung cancer (NSCLC) (n\u0026thinsp;=\u0026thinsp;136, 33%), colorectal cancer (n\u0026thinsp;=\u0026thinsp;106, 26%), prostate cancer (n\u0026thinsp;=\u0026thinsp;53, 13%), breast cancer (n\u0026thinsp;=\u0026thinsp;43, 10%), renal cell carcinoma (n\u0026thinsp;=\u0026thinsp;29, 7%). 126 patients (30%) presented with synchronous OMD (i.e. within 6 months of primary cancer diagnosis) and 289 patients (70%) presenting with metachronous OMD (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eBaseline and treatment characteristics.\u003c/b\u003e Abbreviations: BrM (brain metastasis), NSCLC (non-small cell lung cancer), OMD (oligometastatic disease), mets (metastases), SRS (stereotactic radiosurgery).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eNo BrM at diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eBrM at diagnosis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;415\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian (range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (32\u0026ndash;94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71 (32\u0026ndash;94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e58 (46\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e222\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary site\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNSCLC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eColorectal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eProstate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBreast\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKidney\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSkin (melanoma)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndometrium\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStomach\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePancreas\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSkin (non\u0026thinsp;=\u0026thinsp;melanoma)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOropharynx\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThyroid\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNasopharynx\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypopharynx\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCholangiocarcinoma\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnal canal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOther\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary to OMD (months)\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e18 (3.0\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (3.1\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40 (3.0\u0026ndash;96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026le;\u0026thinsp;6 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;6 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal number of mets\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e64%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of BrM at OMD diagnosis\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e91%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLocation of mets\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone only\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLung or liver\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e273\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e55%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOther\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal PTV (cc)\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (25\u0026ndash;112)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51 (24\u0026ndash;109)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e69 (46\u0026ndash;163)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026le;50\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e197\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;50\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e55%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSystemic therapy change after MDT\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e281\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e275\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e55%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment of BrM present at diagnosis\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSRS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCraniotomy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e82%\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 \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical outcomes: Cumulative incidence of BrM, progression-free survival, and overall survival\u003c/h2\u003e \u003cp\u003eMedian follow-up was 49 (interquartile range [IQR]: 26\u0026ndash;88) months. In total, 58 patients (14%) developed brain metastases. CIBrM was 5.3% (95% CI 3.4%-7.8%) at 24 months after OMD diagnosis, 12% (95% CI 9.0%-16%) at 60 months after OMD diagnosis, and 16% (95% CI 12%-21%) at 120 months after OMD diagnosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). 186 patients (46%) died without BrM, and 160 patients (40%) were alive without BrM at the time of last follow-up. Median OS was 70 months (95% CI 59\u0026ndash;85 months) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Median PFS was 25 months (95% CI 22\u0026ndash;28 months) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Among the 265 patients (66%) who had disease progression, 84 (32%) were alive at the time of last followup.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eFine-gray competing risks analysis of CIBrM\u003c/h2\u003e \u003cp\u003ePatients with different primary cancer sites had significantly different incidence of BrM (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with CIBrM at 5 years after OMD diagnosis of 22% (95% CI 11%-36%) in patients with breast cancer, 15% (95% CI 9.5%-22%) in patients with NSCLC, 15% (95% CI 4.6\u0026ndash;32%) in patients with renal cell carcinoma, 5.3% (95% CI 2.0\u0026ndash;11%) in patients with colorectal cancer, 0% in patients with prostate cancer, and 23% (95% CI 9.4\u0026ndash;39%) in patients with other primary sites (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003ePatients with synchronous OMD had a 5-year CIBrM of 15% (95% CI 9.0\u0026ndash;22%) compared to 11% (95% CI 7.4\u0026ndash;15%) in patients with metachronous OMD (p\u0026thinsp;=\u0026thinsp;0.3). Patients with a solitary metastasis had a 5-year CIBrM of 12% (95% CI 7.8\u0026ndash;16%) compared to 13% (95% CI 8.0\u0026ndash;19%) in patients with multiple metastases (p\u0026thinsp;=\u0026thinsp;0.5). Patients with isolated bone metastases had a 5-year CIBrM of 11% (6.0\u0026ndash;19%) compared to 13% (95% CI 13\u0026ndash;24%) in patients with lung or liver metastases, and 7.6% (95% CI 1.2\u0026ndash;22%) in patients with other sites of metastases (p\u0026thinsp;=\u0026thinsp;0.5). Patients with a total PTV of 50 cc or less had a 5-year CIBrM of 7.8% (95% CI 4.6\u0026ndash;12%) compared to 17% (95% CI 13\u0026ndash;25%) in patients with a total PTV above 50 cc (p\u0026thinsp;=\u0026thinsp;0.11) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB-E).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMultivariable analysis of covariates associated with CIBrM\u003c/h2\u003e \u003cp\u003eIn a MVA for the outcome of CIBrM, among the five baseline covariates assessed, primary cancer site was the only variable that was independently associated with CIBrM (Likelihood ratio test (LRT) p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Specifically, patients with colorectal cancer and prostate cancer had a significantly lower hazard ratio (HR) for CIBrM (HR 0.37 (95% CI 0.16\u0026ndash;0.87, p\u0026thinsp;=\u0026thinsp;0.022) and HR 0.00 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), respectively) compared to patients with NSCLC (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNumber of extracranial metastases, location of extracranial metastases, total PTV, and time from primary cancer diagnosis to OMD diagnosis were not significantly associated with CIBrM (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003e\u003cb\u003eVariables associated with cumulative incidence of brain metastases (CIBrM), progression free survival (PFS), and overall survival (OS).\u003c/b\u003e Abbreviations: MVA (multivariate analysis), NSCLC (non-small cell lung cancer), OMD (oligometastatic disease), PTV (planning target volume), mets (metastases), LRT (likelihood ratio test).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eCIBrM MVA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e \u003cp\u003ePFS MVA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c12\" namest=\"c10\"\u003e \u003cp\u003eOS MVA\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLRT p\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLRT p\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eLRT p\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary site\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNSCLC (ref)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eColorectal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34 (0.14,0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.96 (0.71, 1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.60 (0.42, 0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBreast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.8 (0.79, 4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.52 (0.34, 0.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.29 (0.17, 0.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProstate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0 (0.0, 0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.30 (0.18, 0.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.17 (0.090,0.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKidney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.9 (0.82, 4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.48 (0.28, 0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.23 (0.11, 0.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.2 (0.51, 2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.1 (1.4, 3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.5 (1.0, 2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary to OMD (months)\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0 (0.99, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.0 (1.0, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.0 (0.99, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal number of mets\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (ref)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.22 (0.66, 2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.1 (0.86, 1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.0 (0.77, 1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLocation of mets\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBone only (ref)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung or liver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.59, 2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.44 (0.31, 0.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.68 (0.46, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.86 (0.24, 3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.51 (0.30, 0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.39 (0.19, 0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal PTV (cc)\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 \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.00 (1.00, 1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.0 (1.0, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.0 (1.0, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.004\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 \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMultivariable analysis of covariates associated with PFS and OS\u003c/h2\u003e \u003cp\u003eIn a MVA for the outcome of PFS, primary cancer site (LRT p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), location of metastases (LRT p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and total PTV (LRT p\u0026thinsp;=\u0026thinsp;0.042) were independently associated with PFS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn a MVA for the outcome of OS, primary cancer site (LRT p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), location of metastases (LRT p\u0026thinsp;=\u0026thinsp;0.02), total PTV (LRT p\u0026thinsp;=\u0026thinsp;0.004) and time from primary cancer diagnosis to OMD (LRT p\u0026thinsp;=\u0026thinsp;0.013) were independently associated with OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eConditional analysis of association between extracranial progression and CIBrM\u003c/h2\u003e \u003cp\u003eDevelopment of widespread extracranial progression (i.e. five or more sites of new extracranial disease) within four of the six pre-defined time intervals, i.e. within 24, 36, 48 and 60 months of OMD diagnosis, was independently associated with higher CIBrM after that time interval, after adjusting for the five baseline covariates above (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDevelopment of any extracranial progression (i.e. widespread extracranial progression, extracranial oligoprogression, or extracranial local recurrence) within 48 months of OMD diagnosis, but not within any of the other five timepoints investigated, was independently associated with higher CIBrM after that time interval, after adjusting for the five baseline covariates (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eConditional analysis of cumulative incidence of brain metastases, based on ECP (extracranial progression) and WSP (widespread progression) within various time intervals.\u003c/b\u003e Abbreviations: MVA (multivariate analysis), LRT (likelihood ratio test). All time intervals are relative to date of diagnosis of oligometastatic disease. MVA adjusts for the five baseline variables investigated in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\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\u003eECP or WSP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo ECP or WSP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUVA HR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLRT p\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMVA HR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLRT p\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECP within 6 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e373\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.7(0.65\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.4(0.43\u0026ndash;4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECP within 12 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.6 (0.85-3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.7(0.84\u0026ndash;3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECP within 24 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.2(0.59\u0026ndash;2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.3(0.62\u0026ndash;2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECP within 36 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.6(0.76\u0026ndash;3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.8(0.76\u0026ndash;4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECP within 48 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.8(1.2\u0026ndash;6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.0(1.6\u0026ndash;9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.0041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECP within 60 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.7(0.60-5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.0(1.1\u0026ndash;8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWSP within 6 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.6(0.48\u0026ndash;5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.3(0.32\u0026ndash;5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWSP within 12 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.1(0.93\u0026ndash;4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.6(0.96\u0026ndash;7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWSP within 24 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e268\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.1(1.5\u0026ndash;6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.1(1.5\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.0041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWSP within 36 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0(1.3\u0026ndash;6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.7(1.3\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWSP within 48 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.4(0.88\u0026ndash;6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.9(1.7\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.0094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWSP within 60 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.2(0.47-10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e23(1.6\u0026ndash;340)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.017\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 \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics and outcomes of patients with pre-existing BrM\u003c/h2\u003e \u003cp\u003eIn total, eleven patients had pre-existing BrM at the time of OMD diagnosis. Among these patients, ten had a single BrM, and one had two BrM. All patients had more than one site of OMD, and 4 patients had synchronous OMD. 5 patients had NSCLC, 2 had colorectal cancer, 2 had melanoma, 1 had breast cancer, and 1 had renal cell carcinoma. 9 patients underwent craniotomy: 4 underwent adjuvant whole brain radiotherapy, and 5 underwent adjuvant intensity modulated radiotherapy to the surgical cavity. Two patients were treated with stereotactic radiosurgery alone without surgery (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These eleven patients had poor prognosis, with median intracranial PFS of 6.2 months, median extracranial PFS of 13 months, and median OS of 23 months. Only two patients did not have intracranial progression, and they were also the only two patients alive at the time of last followup.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first study to identify variables associated with development of BrM in a population consisting exclusively of patients with OMD treated with SBRT. We found that variables associated with baseline burden and distribution of extracranial disease were not associated with CIBrM. We also found primary cancer site and extracranial progression were independently associated with CIBrM.\u003c/p\u003e \u003cp\u003eWe investigated several variables related to baseline metastatic burden and distribution at the time of OMD diagnosis, including: total number of metastases, total PTV (i.e. a surrogate measure of total metastatic burden), and location of extracranial metastases. While many of these variables were independently associated with PFS and OS, none of them were associated with CIBrM on univariable and multivariable analysis. These findings suggest that different underlying variables predict extracranial and intracranial progression. This calls for a need to investigate additional variables associated with the risk of developing BrM in this population. It is important to recognize that there were fewer events (n\u0026thinsp;=\u0026thinsp;58) in the CIBrM analysis compared to the PFS and OS analyses, which reduced statistical power.\u003c/p\u003e \u003cp\u003eIt is well known that the incidence of BrM varies greatly depending on primary tumor site, and we demonstrate that this holds true in the setting of oligometastatic disease. In a population-based study of over 16,000 patients, Barnholtz-Sloan et al(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) observed that the incidence of BrM was 9.6% for patients across all primary tumor sites, and highest among patients with lung cancer (19.9%), followed by melanoma (6.9%), renal cell carcinoma (6.5%), breast cancer (5.1%), and lowest among patients with colorectal (1.8%) cancer. Furthermore, is it known that patients with prostate cancer have an extremely low incidence of BrM (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Our finding that patients with colorectal and prostate cancer had a significantly lower CIBrM compared to patients with NSCLC is consistent with what is known about these cancer types. Future studies will need to investigate variables associated with BrM development in individual cancer types by integrating histology-specific variables, such as receptor status and Ki67 index in breast cancer(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), pathological subtype in lung cancer(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), and primary location and mitotic rate in melanoma(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), in order to provide more accurate prognostication.\u003c/p\u003e \u003cp\u003eWe observed that extracranial progression, particularly widespread extracranial progression (i.e. 5 or more sites of disease), was independently associated with CIBrM. A recent retrospective study had also identified an association between development of BrM and oligometastic-to-polymetastatic transition (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Biologically, many of these cancers may exhibit an aggressive phenotype with a greater propensity to metastasize. Furthermore, these cancers may harbour more resistant clones to ongoing systemic therapies, or alternatively, the patient may no longer be actively receiving systemic therapy to control their disease. This calls for a need to investigate additional temporally dynamic variables when estimating the risk of developing BrM in patients with OMD. An example of a non-invasive dynamic variable is circulating tumour DNA (ctDNA), which has been shown to predict recurrence-free survival after curative-intent resection in oligometastatic colorectal cancer in a metanalysis of 23 studies(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), and further studies are underway to investigate the utility of ctDNA in patients with various cancer types treated with SBRT for OMD(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough our cohort only included 11 patients with pre-existing BrM, it is important to consider the very short median intracranial PFS and OS of this subgroup. In a meta-analysis of 68 studies, Li et al(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) observed that patients with BrM with stable extracranial disease had a longer intracranial PFS compared to patients with disseminated or uncontrolled extracranial disease. In addition, in patients with oligometastatic NSCLC, Iyengar et al(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) observed that SBRT to extracranial sites was associated with a numerically lower rate of intracranial progression. There is a complex association between the dynamics of extracranial and intracranial disease, involving the intrinsic metastatic potential of the tumour and the timing and choice of systemic therapies. It is important for future trials regarding OMD to include patients with BrM, in order to identify substrates necessary for long term intracranial control.\u003c/p\u003e \u003cp\u003eOur study has a number of limitations. It is a single centre retrospective study, and the infrequent occurrence of BrM limited our statistical power. In addition, we chose to define temporal clinical outcomes in relation to the date of diagnosis of OMD rather than the end date of SBRT, as our primary objective was to investigate variables associated with development of BrM in patients with OMD, rather than to investigate the effect of SBRT on outcomes. When generalizing our findings, readers will need to be cognizant that all patients in our cohort received SBRT at some point.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn patients treated with SBRT for OMD, it is crucial to identify and integrate biomarkers to predict an individual patient\u0026rsquo;s risk of developing BrM, which are associated with significant morbidity and mortality. Our study shows that although variables related to baseline burden and distribution of extracranial disease are associated with extracranial progression, they are not associated with intracranial progression. Furthermore, as expected, primary cancer site and extracranial progression are independently associated with the development of BrM. This calls for a need to explore beyond traditional clinical variables and to investigate histology-specific and/or dynamic biomarkers that better reflect the underlying biology of intracranial metastogenesis, in order to identify patients with OMD at high risk of developing BrM who may benefit from screening and preventative treatment.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthics approval and consent to participate:\u003c/h2\u003e \u003cp\u003e Ethics approval was obtained from the Sunnybrook Research Institute (REB SUN-5942). This study was performed in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003e KJJ serves as a consultant and advisory board member for: Amgen, Astra-Zeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Gilead Sciences, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Seagen, Novartis, and Viatris. HC has received speaker's honoraria from Novartis. These organizations had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. No competing interests from other authors of this manuscript.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding information:\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKYF and KJJ contributed equally and are co-first authors of this manuscript. KYF, KJJ and HC conceptualized the study. KYF, and VM contributed to software development and implementation. Analyses were performed by KYF, KJJ, VM and HC. Data were collected by KYF, SK and BIS. Curation of data was conducted by KYF, KJJ, SK, VM and HC. The original draft was written by KYF, KJJ and HC. Reviewing and editing of the manuscript was performed by KYF, KJJ, SK, VM, BIS, SD, AVL, HS, AS and HC. Data visualization was conducted by KYF and VM. Project management and coordination was performed by KYF, KJJ and HC.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe acknowledge Hold\u0026rsquo;em for Life Oncology Fellowships for trainee support.\u003c/p\u003e\u003ch2\u003eData availability:\u003c/h2\u003e \u003cp\u003eThe datasets analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHellman S, Weichselbaum RR, Oligometastases (1995) J Clin Oncol Off J Am Soc Clin Oncol 13(1):8\u0026ndash;10\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeckham TH, Yang TJ, Gomez D, Tsai CJ (2021) Metastasis-directed therapy for oligometastasis and beyond. Br J Cancer 124(1):136\u0026ndash;141\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuckenberger M, Lievens Y, Bouma AB, Collette L, Dekker A, deSouza NM et al (2020) Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol 21(1):e18\u0026ndash;28\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C et al (2020) Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 38(25):2830\u0026ndash;2838\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGomez DR, Tang C, Zhang J, Blumenschein GR, Hernandez M, Lee JJ et al (2019) Local Consolidative Therapy Vs. 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JAMA Netw Open 6(2):e230475\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":"","lastPublishedDoi":"10.21203/rs.3.rs-4850268/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4850268/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose:\u003c/h2\u003e \u003cp\u003eIn patients with oligometastatic disease (OMD) treated with stereotactic body radiation therapy (SBRT), those who develop brain metastases (BrM) may have poor outcomes. We aimed to investigate variables associated with BrM development in this population.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003ePatients with \u0026le;\u0026thinsp;5 extracranial metastases from solid tumors treated with SBRT from 2008\u0026ndash;2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between extracranial progression and CIBrM using time-based conditional analysis.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eAmong 404 patients, the most common primary sites were lung, colorectal, prostate, breast and kidney. Median follow-up was 49 months. Median PFS was 25 months. Median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. On multivariable analysis, number of extracranial metastases, location of metastases, total planning target volume (PTV), and time from primary diagnosis to OMD were not associated with CIBrM, although several of these variables were associated with extracranial PFS and OS. Primary site was associated with CIBrM, with colorectal and prostate cancer associated with lower CIBrM compared to lung cancer. Widespread extracranial progression (\u0026ge;\u0026thinsp;5 sites) within 24, 36, 48 and 60 months of OMD diagnosis was independently associated with higher CIBrM.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eIn patients with OMD treated with SBRT, baseline variables related to extracranial disease burden and distribution were not associated with BrM development, while primary site and widespread extracranial progression were associated with BrM development.\u003c/p\u003e","manuscriptTitle":"Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-13 15:13:54","doi":"10.21203/rs.3.rs-4850268/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-28T23:36:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-23T09:12:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"155933485947948948799951745198237986364","date":"2024-08-17T20:41:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-16T00:50:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-11T18:18:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"224856291747244852707618690211734819378","date":"2024-08-11T15:36:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"64663255690631296998728438181995525840","date":"2024-08-10T01:58:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"233510204756798811616083201467562663367","date":"2024-08-09T11:58:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-05T11:26:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-04T00:55:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-04T00:54:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2024-08-02T19:26:17+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":"aa2e74d8-da7f-4006-9b34-423d221507f8","owner":[],"postedDate":"August 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-07T16:00:43+00:00","versionOfRecord":{"articleIdentity":"rs-4850268","link":"https://doi.org/10.1007/s11060-024-04834-9","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2024-10-04 15:57:22","publishedOnDateReadable":"October 4th, 2024"},"versionCreatedAt":"2024-08-13 15:13:54","video":"","vorDoi":"10.1007/s11060-024-04834-9","vorDoiUrl":"https://doi.org/10.1007/s11060-024-04834-9","workflowStages":[]},"version":"v1","identity":"rs-4850268","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4850268","identity":"rs-4850268","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}