Influence of concomitant distant lymph node metastases in metastatic hormone-sensitive prostate cancer patients with bone metastases

Influence of concomitant distant lymph node metastases in metastatic hormone-sensitive prostate cancer patients with bone metastases | 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 Influence of concomitant distant lymph node metastases in metastatic hormone-sensitive prostate cancer patients with bone metastases Mike Wenzel, Benedikt Lauer, Vincenzo Giuseppe Mühlthaler, Maxilimian Filzmayer, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8137517/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Mar, 2026 Read the published version in World Journal of Urology → Version 1 posted 8 You are reading this latest preprint version Abstract Introduction: Most patients with metastatic hormone-sensitive prostate cancer (mHSPC) are burdened by bone metastases. However, the impact of concomitant distant lymph node metastases at diagnosis in these patients is unknown. Materials and methods: We relied on the FRAMCAP database (FRAnkfurt Metastatic Cancer database of the Prostate) to compare time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) between M1b vs. M1a+b mHSPC patients. Univariable and multivariable Cox regression models were applied. Results: Among 432 patients, 64% harbored M1b vs. 36% M1a+b mHSPC. PSA was significantly higher in M1a+b vs. M1b patients (81 vs. 44 ng/ml, p<0.05), as well as rates of LATITUDE high-risk (76% vs. 55%) and CHAARTED high-volume disease (70% vs. 50%) (both p<0.001). Regarding time to mCRPC, median time to CRPC was 26 vs. 16 months for M1b vs. M1a+b patients (hazard ratio [HR]: 1.6, p<0.01). Regarding OS, median OS was not significantly different, with median OS of 53 vs. 47 months for M1b vs. M1a+b patients (p=0.9). After controlling for patient and tumor characteristics in multivariable Cox regression analyses, concomitant lymph node metastases were not an independent risk for shorter time to CRPC or OS in patients with bone metastases (both p>0.15). Conclusion: Patients with concomitant distant lymph node metastases in mHSPC with bone metastases (M1a+b) harbor more unfavorable baseline cancer characteristics relative to M1b without lymph node metastases, translating into significantly shorter time to mCRPC. However, after controlling for patient and tumor characteristics, neither time to mCRCP nor OS seems not be affected by concomitant lymph node metastases. Survival rate mHSPC metastasic burden Figures Figure 1 Figure 2 Introduction Prostate cancer is the second most common malignancy among men worldwide and remains a leading cause of cancer-related mortality [1, 2]. Bone metastases represent the predominant site of spread in metastatic hormone-sensitive prostate cancer (mHSPC), with 69–84% of all mHSPC patients present with bone metastases at diagnosis [3]. To better define prognosis and guide treatment strategies, mHSPC is classified based on tumor volume and tumor risk using two widely established criteria. The CHAARTED criteria differentiate between high-volume and low-volume disease and the LATITUDE criteria classify patients into high-risk and low-risk groups [4–7]. According to the CHAARTED criteria, high-volume disease is defined as the presence of visceral metastases and/or ≥4 bone metastases, with at least one located outside the spine or pelvis [6]. LATITUDE high-risk is classified as at least two of the following three criteria: Gleason score ≥8, ≥3 bone metastases, or the presence of visceral metastases [5]. Nevertheless, in these classifications the presence and extent of concomitant distant lymph nodes are not considered. Several prognostic factors influence outcomes in mHSPC, including patient-related factors such as ECOG performance status, initial PSA level, and Gleason score [4]. The TNM classification distinguishes distant lymph node metastases (M1a) from bone metastases (M1b) regarding its prognostic effect, however both metastatic sides may occur similarly in several patients [4, 8]. Recent publications did report discrepant results concerning the oncologic outcome of patients with M1a, M1b or M1a+b [9, 10]. Additionally, current guidelines provide limited guidance on the specific management and prognostic implications of patients with distant lymph node metastases within the M1b mHSPC population, and the clinical relevance of this subgroup remains an area of ongoing discussion [4, 11] This study aims to evaluate the additional impact of distant lymph node metastases on time to castration-resistant prostate cancer (ttCRPC) and overall survival (OS) in M1b mHSPC patients. To address this knowledge gap, we conducted the current analysis using data from the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) [12, 13]. We hypothesize that patients with concomitant distant lymph node metastases (M1a+b) exhibit a distinct progression and survival profile compared to patients with solely M1b mHSPC disease. Material and Methods Study population Patient data were provided by the FRAMCAP database after obtaining approval from the local ethics committee (reference number: SUG-4-2024). In accordance with the principles of the Declaration of Helsinki, we conducted the current retrospective analysis of metastatic prostate cancer patients treated at the Department of Urology, between 2014 and 2024. Patients diagnosed with mHSPC with a M1b vs. M1a+b metastatic pattern were included in the study, whereas those with non-metastatic/metastatic castration-resistant prostate cancer (mCRPC) or unknown metastatic sides were excluded. Based on these criteria, a total of 432 patients were enrolled and classified into two subgroups according to their metastatic pattern , as defined by the TNM classification (M1b vs. M1a+b) [8] . Staging was performed using conventional methods, including bone scintigraphy and abdominal computed tomography or prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT). All treatment decisions were made following individuals’ case discussions in a multidisciplinary tumor board. Definition of mCRPC According to the EAU guidelines, mCRPC is defined as disease progression despite ongoing anti-hormonal therapy, with a serum testosterone level of 2 ng/ml, or radiological progression, evidenced by at least two new bone metastases or the presence of a visceral lesion [4, 14]. Statistical analysis Descriptive statistics were used to summarize the data, with categorical variables presented as frequencies and proportions. Continuous variables were reported as medians with interquartile ranges (IQR). The Chi-square test was applied to assess differences in proportions, while the t-test and Kruskal-Wallis test were used to compare distributions of continuous variables. Primary endpoints were time to CRPC (ttCRPC) and overall survival (OS). ttCRPC was defined as the interval from the initiation of treatment for mHSPC to the progression to mCRPC or start of subsequent treatment or death. OS was defined as time interval between initiaation of mHSPC treatment and death due to any cause. Both endpoints were evaluated by using Kaplan-Meier curve analyses and log-rank tests. For all analyses, univariable and multivariable Cox regression models were applied. Multivariable Cox regression models were adjusted to account for potential baseline confounders, including patient-related factors such as age and Eastern Cooperative Oncology Group (ECOG) performance status, as well as tumor characteristics such as Gleason score, high vs. low volume CHAARTED mHSPC, synchronous vs. metachronous mHSPC. Additional adjustment for mHSPC treatment was made for ttCRPC analyses, while the number of applied systemic number was adjusted for in OS analyses. All statistical analyses and visualizations were conducted using the R software environment for statistical computing and graphics (version 3.4.3). Results The total study population included 432 patients with a median age of 69 years (IQR 63–75 years, Table 1) at the time of diagnosis of mHSPC. The ECOG performance score was 0 in 64% of all patients. The median PSA at the time of mHSPC diagnosis 60 ng/ml (IQR 14–280ng/ml). Regarding tumor characteristics, 83% of patients presented with synchronous mHSPC. The majority of patients (74%) had a Gleason score of 8–10. Prior local therapy, including radiotherapy or radical prostatectomy, was documented in 29% of cases. Based on the CHAARTED criteria, 57% mHSPC patients harbored high-volume disease, while 63% met LATITUDE high-risk criteria. The median number of systemic treatment lines was two (IQR 2–3). Baseline characteristics M1a+b vs. M1b Patients were stratified according to their metastatic pattern, with 36% (n=157) classified as M1a+b vs. 64% (n=275) as M1b (Table 1). Median age (67 vs. 68 years, p=0.1) and ECOG performance status (33% vs. 38%, p=0.5) did not significantly differ between both two groups. Conversely, median PSA at the mHSPC diagnosis was higher in the M1a+b group compared to M1b, although no statistical significance was reached (82 vs. 46 ng/ml, p=0.2). When assessing tumor characteristics, the proportion of patients with a Gleason score of 8–10 was significantly higher in the M1a+b group compared to the M1b group (82% vs. 69%, p<0.01). Regarding disease stratification by CHAARTED and LATITUDE criteria, the proportion of patients with high-risk disease was significantly higher in the M1a+b group vs. M1b mHSPC patients (76% vs. 55%; p<0.001). Similarly, high-volume disease was more frequently observed in M1a+b than in M1b (70% vs. 50%, p<0.001). Synchronous mHSPC was balanced between M1a+b vs. M1b mHSPC patients (85% vs. 82%, p=0.4). Time to CRPC: M1b vs. M1a+b In ttCRPC analyses, significant differences between M1b vs. M1a+b group were observed (Figure 1). Specifically, median time to CRPC was 26 vs. 16 months for M1b vs. M1a+b mHSPC patients (hazard ratio [HR]: 1.59, confidence interval (CI): 1.18-2.16, p<0.01). After multivariable adjustment for baseline patient and tumor characteristics in Cox regression models, the M1a+b group showed no significant difference compared to the M1b group (HR: 1.44, CI: 0.87-2.40, p=0.16, Table 2A). OS: M1b vs. M1a+b In OS analyses, no significant differences were observed between M1b and M1a+b patients (Figure 2), with a median survival of 53 vs. 47 months, respectively (HR: 1.03, CI: 0.75-1.42, p=0.9). Similarly, after multivariable adjustment for baseline patient and tumor characteristics in Cox regression models, analyses did not reveal any significant associations (HR: 0.83, CI: 0.54-1.29, p=0.41, Table 2B). Discussion We hypothesized that patients with lymph node metastases in addition to bone metastases exhibit a distinct disease trajectory and therefore differ in baseline characteristics compared to patients with bone-only metastases (M1b). We additionally initially aimed to evaluate the impact of concomitant distant lymph node metastases on ttCRPC and OS in patients with osseous M1b mHSPC. To test these hypothesizes, we relied on data from the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) and were able to identify several important findings. First , we analyzed baseline and tumor characteristics in patients with mHSPC stratified by metastatic pattern M1a+b vs. M1b. Median age at diagnosis (68 vs. 70 years), and ECOG performance status showed no significant difference between the two groups (both p >0.05). The PSA level in our cohort was also numerically higher (82 vs. 46 ng/ml) in the M1a+b group, but the difference did not reach statistical significance (p=0.2). Compared to previously published cohorts, a study by Elewaily et al. (n=129) compared patients with M1a (n=28) and M1b (n=91) disease [15]. In line with our findings, the authors found no significant difference in median age (69.5 vs. 69.7 years, p=0.5). Furthermore, tumor characteristics such as Gleason score and median PSA were not significantly different between the two metastatic patterns in the study by Elewaily et al., however median difference was clinically highly relevant (M1a: 24.7 ng/ml vs. M1b: 118.8 ng/ml; both p>0.10) [24]. This aligns with our findings regarding PSA, which was also higher in the M1a+b group (82 ng/ml vs. 46 ng/ml), but without reaching statistical significance, in both studies probably due to sample size limitations or wide IQRs and ranges due to number of bone metastases or concomitant metastatic lymph nodes. In contrast, Gleason score distribution in our cohort showed a significant difference, with a higher proportion of Gleason 8–10 tumors in the M1a+b group (p=0.007). In line, a study by Miyake et al. including 437 mHSPC patients identified age, Gleason score, and the presence of visceral metastases as significant prognostic factors of OS in univariable analysis [16]. Overall, our data indicate that patients with M1a+b mHSPC harbor more unfavorable baseline tumor characteristics, as evidenced by a significantly higher proportion of Gleason score 8–10 tumors (82% vs. 69%, p<0.01), and a significantly higher rates of patients classified as high-risk (76% vs. 55%) and high-volume (70% vs. 50%) according to LATITUDE and CHAARTED criteria, respectively (both p<0.001). These findings underline the importance of differentiating metastatic patterns when stratifying risk and selecting treatment strategies in mHSPC. Second, we assessed cancer-control outcomes, such as ttCRPC and OS relying on Kaplan-Meier curve and log-rank test analyses. Median ttCRPC was significantly shorter in M1a+b patients compared to M1b patients (16 vs. 26 months, HR: 1.6, p<0.01). In contrast, no significant difference in OS was observed between the two groups, with median survival of 47 vs. 53 months, respectively (HR: 1.03, p=0.9). In multivariable analyses no significant results were found in ttCRPC and OS in comparison between the two groups. (both p>0.16). In contrast to the findings of Miyake et al., who identified shorter ttCRPC as a strong negative prognostic marker for OS (p<0.001), our cohort showed no significant difference in overall survival despite a shorter ttCRPC in univariable analyses. Miyake et al. demonstrated a median OS of 40.8 months in patients with ttCRPC of 0–6 months up to 70.1 months in those with a ttCRPC of more than 18.1 months. However, it is important to note that this study did not distinguish between patients with combined M1a and M1b disease and those with M1b disease alone [16]. Still, these results are in contrast with our findings, where patients with concomitant distant lymph node metastases (M1a+b) demonstrated more unfavorable baseline characteristics and a significantly shorter time to mCRPC, suggesting a more aggressive disease biology despite comparable OS. When analyzing cancer control data in the context of the existing literature, it becomes apparent that the proportion of patients with a high tumor burden—defined by tumor volume according to CHAARTED criteria—is significantly higher in the M1a+b group. This subgroup also exhibits a significantly shorter ttCRPC, indicating a more aggressive disease course. In contrast, OS does not differ significantly between groups. This may suggest that, in the setting of progression during the mHSPC stage, OS is more strongly influenced by the choice of therapy subsequent after progression of mHSPC and the individual response to treatment. Moreover, the presence of visceral metastases may have a greater prognostic impact than lymphatic dissemination. This hypothesis is further supported by an Asian study conducted by Wang et al., in which 870 patients with de novo mHSPC were retrospectively analyzed between 2009 and 2021. Patients were stratified according to their metastatic pattern, and OS was assessed. Those patients presenting with osseous or lymphatic metastases showed significantly better OS compared to patients with visceral metastases, particularly hepatic metastasis [18]Additionally, a study by Halabi et al. investigated the prognostic relevance of metastatic patterns in a cohort of 8,820 patients with mCRPC. Although focused on a later disease stage, the findings similarly demonstrated that patients with visceral metastases had significantly worse overall survival compared to those with lymphatic or osseous metastases [19]. To our knowledge, no study to date has specifically examined ttCRPC and OS in direct comparison between M1a+b vs. M1b metastatic patterns. Our findings therefore provide novel insights into the clinical behavior and risk stratification of mHSPC patients based on metastatic distribution. Clinicians should ideally incorporate these findings in their treatment workflow of mHSPC patients, since M1a+b patients are at higher risk of earlier disease progression. Our study has several limitations. First, its single-center approach, which may limit the generalizability of the findings. Second, due to its retrospective design, the study is subject to inherent biases, including potential selection and information bias. Third, staging imaging was not standardized across all patients, which may have affected the classification of metastatic patterns. Although baseline characteristics were well balanced between groups, the number of patients differed substantially between the M1a+b (n=157) vs. M1b (n=275) cohorts, which may have reduced the statistical power to detect significant differences. Finally, data on comorbidities and PSA kinetics and exact number of lymph node and bone metastases were not available, although these factors are known to influence disease progression and OS. Taken together, mHSPC patients with concomitant distant lymph node metastases in addition to bone metastases (M1a+b) present with more unfavorable baseline cancer characteristics compared to patients with solely M1b mHSPC disease. While this is associated with a significantly shorter ttCRPC in univariable analyses, ttCRPC and OS does not differ significantly between the two groups in multivariable analyses. These findings underscore the importance of considering metastatic pattern for early risk stratification, especially regarding follow-up schedules to may protect progression earlier then in M1b mHSPC patients. Future prospective multicenter studies with standardized imaging protocols and larger, balanced cohorts are warranted to validate our findings and to clarify the prognostic implications of M1b vs. M1a+b metastatic patterns in mHSPC. Declarations Data sharing statement: Data are available for bona fide researchers who request it from the authors Financial disclosures and Conflicts of interest: None Human Ehtics and Consent: The current study was in accordance with the Declaration of Helskini. Local Review of the ethics board was approved. Consent to participate declarations: Human Ethics and Consent to participate declarations: not applicable. Funding statement: The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contribution M Wenzel: Project development, Data collection, Data analysis, Manuscript writingB Lauer: Project development, Data collection, Data analysis, Manuscript writingV. Mühlthaler: Project development, Data collection, Data analysis, Manuscript editingM Filzmayer: Project development, Data collection, Data analysis, Manuscript editingC Siech: Project development, Data collection, Data analysis, Manuscript editingC Le: Project development, Data collection, Data analysis, Manuscript editingC Humke: Project development, Data collection, Data analysis, Manuscript editingM Kosiba: Project development, Data collection, Data analysis, Manuscript editingM Kriegmair: Project development, Data collection, Data analysis, Manuscript editingT Steuber: Project development, Data collection, Data analysis, Manuscript editingF Chun: Manuscript editing, Supervision, ValidationP Mandel: Manuscript editing, Supervision, Validation References Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA: a cancer journal for clinicians , 2019 , 69, 7–34. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. 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Cite Share Download PDF Status: Published Journal Publication published 24 Mar, 2026 Read the published version in World Journal of Urology → Version 1 posted Editorial decision: Revision requested 16 Feb, 2026 Reviews received at journal 04 Feb, 2026 Reviewers agreed at journal 03 Feb, 2026 Reviewers agreed at journal 03 Feb, 2026 Reviewers invited by journal 02 Feb, 2026 Editor assigned by journal 21 Nov, 2025 Submission checks completed at journal 21 Nov, 2025 First submitted to journal 17 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-8137517","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585278520,"identity":"b67c8642-4c07-468b-8dc2-4ec012eb7154","order_by":0,"name":"Mike Wenzel","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Mike","middleName":"","lastName":"Wenzel","suffix":""},{"id":585278521,"identity":"09d365c9-884b-4b2d-9f93-0709fc9cdb5a","order_by":1,"name":"Benedikt Lauer","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":true,"prefix":"","firstName":"Benedikt","middleName":"","lastName":"Lauer","suffix":""},{"id":585278522,"identity":"bfcc4f23-97fa-4724-83e3-e2f0213a5021","order_by":2,"name":"Vincenzo Giuseppe Mühlthaler","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Vincenzo","middleName":"Giuseppe","lastName":"Mühlthaler","suffix":""},{"id":585278523,"identity":"d8d39be2-868c-4bab-8964-ab66f78fe727","order_by":3,"name":"Maxilimian Filzmayer","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Maxilimian","middleName":"","lastName":"Filzmayer","suffix":""},{"id":585278524,"identity":"26179046-568d-4160-a7fd-782ccc00e102","order_by":4,"name":"Carolin Siech","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Carolin","middleName":"","lastName":"Siech","suffix":""},{"id":585278525,"identity":"26b9d516-e1af-4008-a612-d27c65b4a98f","order_by":5,"name":"Chi Le","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Chi","middleName":"","lastName":"Le","suffix":""},{"id":585278526,"identity":"a00f9e3f-36f2-4824-8654-2a4758a790d2","order_by":6,"name":"Clara Humke","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Clara","middleName":"","lastName":"Humke","suffix":""},{"id":585278528,"identity":"8f440050-bc3f-443f-ab12-ad4824833082","order_by":7,"name":"Marina Kosiba","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Marina","middleName":"","lastName":"Kosiba","suffix":""},{"id":585278530,"identity":"f591595e-8333-450c-a092-35ef3741a5a9","order_by":8,"name":"Maximilian Kriegmair","email":"","orcid":"","institution":"Urologische Klinik München Planegg","correspondingAuthor":false,"prefix":"","firstName":"Maximilian","middleName":"","lastName":"Kriegmair","suffix":""},{"id":585278532,"identity":"b66ac9ac-9e06-4930-b7df-a6cf419c8a7e","order_by":9,"name":"Thomas Steuber","email":"","orcid":"","institution":"University Hospital Hamburg-Eppendorf","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Steuber","suffix":""},{"id":585278534,"identity":"ec7045c2-41df-4533-ada5-7fd68202efea","order_by":10,"name":"Felix K. H. Chun","email":"","orcid":"","institution":"University Hospital Frankfurt, Goethe University Frankfurt am Main","correspondingAuthor":false,"prefix":"","firstName":"Felix","middleName":"K. H.","lastName":"Chun","suffix":""},{"id":585278536,"identity":"2ac07bb0-6923-46ae-a93a-0e09c90d818a","order_by":11,"name":"Philipp Mandel","email":"","orcid":"","institution":"University Hospital Hamburg-Eppendorf","correspondingAuthor":false,"prefix":"","firstName":"Philipp","middleName":"","lastName":"Mandel","suffix":""}],"badges":[],"createdAt":"2025-11-17 16:10:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8137517/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8137517/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00345-026-06358-5","type":"published","date":"2026-03-24T16:11:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":101881798,"identity":"5d85c55a-7b2e-44ee-a220-f43af40b6d00","added_by":"auto","created_at":"2026-02-04 15:16:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":67107,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"mHSPCOSttCRPCFigure1final.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137517/v1/d0387ebb8a47e30373aecc2d.jpg"},{"id":101863345,"identity":"6c0177e8-96e8-4a73-bb5c-4c9bc77d553f","added_by":"auto","created_at":"2026-02-04 12:06:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":71009,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"mHSPCOSttCRPCFigure2final.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8137517/v1/911e2fd9e83fb4834907d6a1.jpg"},{"id":105755139,"identity":"5abdefd1-2964-4e10-a901-9c86f5c3c3cf","added_by":"auto","created_at":"2026-03-30 16:25:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":804517,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8137517/v1/98f757fb-2a43-4aa9-bdf1-3d50d90576d3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Influence of concomitant distant lymph node metastases in metastatic hormone-sensitive prostate cancer patients with bone metastases","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer is the\u0026nbsp;\u003cstrong\u003esecond most common malignancy among men worldwide\u003c/strong\u003e and remains a leading cause of cancer-related mortality [1, 2]. Bone metastases represent the predominant site of spread in metastatic hormone-sensitive prostate cancer (mHSPC), with 69\u0026ndash;84% of all mHSPC patients present with bone metastases at diagnosis [3].\u003c/p\u003e\n\u003cp\u003eTo better define prognosis and guide treatment strategies, mHSPC is classified based on tumor volume and tumor risk using two widely established criteria. The CHAARTED criteria differentiate between high-volume and low-volume disease and the LATITUDE criteria classify patients into high-risk and low-risk groups [4\u0026ndash;7]. According to the CHAARTED criteria, high-volume disease is defined as the presence of visceral metastases and/or \u0026ge;4 bone metastases, with at least one located outside the spine or pelvis\u0026nbsp;[6]. LATITUDE high-risk is classified as at least two of the following three criteria: Gleason score \u0026ge;8, \u0026ge;3 bone metastases, or the presence of visceral metastases [5]. Nevertheless, in these classifications the presence and extent of concomitant distant lymph nodes are not considered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral prognostic factors influence outcomes in mHSPC, including patient-related factors such as ECOG performance status, initial PSA level, and Gleason score [4]. The TNM classification distinguishes distant lymph node metastases (M1a) from bone metastases (M1b) regarding its prognostic effect, however both metastatic sides may occur similarly in several patients [4, 8]. Recent publications did report discrepant results concerning the oncologic outcome of patients with M1a, M1b or M1a+b [9, 10]. Additionally, current guidelines provide limited guidance on the specific management and prognostic implications of patients with distant lymph node metastases within the M1b mHSPC population, and the clinical relevance of this subgroup remains an area of ongoing discussion [4, 11]\u003c/p\u003e\n\u003cp\u003eThis study aims to evaluate the additional impact of distant lymph node metastases on time to castration-resistant prostate cancer (ttCRPC) and overall survival (OS) in M1b mHSPC patients. To address this knowledge gap, we conducted the current analysis using data from the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) [12, 13]. We hypothesize that patients with concomitant distant lymph node metastases (M1a+b) exhibit a distinct progression and survival profile compared to patients with solely M1b mHSPC disease.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient data were provided by the\u0026nbsp;FRAMCAP database after obtaining approval from the local ethics committee (reference number: SUG-4-2024).\u0026nbsp;In accordance with the principles of the Declaration of Helsinki, we conducted the current retrospective analysis of metastatic prostate cancer patients treated at the Department of Urology, between 2014 and 2024. Patients diagnosed with\u0026nbsp;\u003cstrong\u003emHSPC\u003c/strong\u003e with a M1b vs. M1a+b metastatic pattern were included in the study, whereas those with non-metastatic/metastatic\u0026nbsp;\u003cstrong\u003ecastration-resistant prostate cancer (mCRPC)\u003c/strong\u003e or unknown metastatic sides were excluded. Based on these criteria, a\u0026nbsp;\u003cstrong\u003etotal of 432 patients\u003c/strong\u003ewere enrolled and classified into two\u0026nbsp;\u003cstrong\u003esubgroups\u003c/strong\u003eaccording to their\u0026nbsp;\u003cstrong\u003emetastatic pattern\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e as defined by the\u0026nbsp;\u003cstrong\u003eTNM classification (M1b vs. M1a+b)\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u003cstrong\u003e[8]\u003c/strong\u003e\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e Staging was performed using conventional methods, including bone scintigraphy and abdominal computed tomography or prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT). All treatment decisions were made following individuals’ case discussions in a multidisciplinary tumor board.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of mCRPC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the EAU guidelines, mCRPC is defined as disease progression despite ongoing anti-hormonal therapy, with a serum testosterone level of \u0026lt;50 ng/dl (1.7 nmol/l), along with at least one of the following criteria: biochemical progression, defined as three consecutive PSA increases of at least 50% above the PSA nadir and a PSA level \u0026gt;2 ng/ml, or radiological progression, evidenced by at least two new bone metastases or the presence of a visceral lesion [4, 14].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDescriptive statistics were used to summarize the data, with categorical variables presented as frequencies and proportions. Continuous variables were reported as medians with interquartile ranges (IQR). The Chi-square test was applied to assess differences in proportions, while the t-test and Kruskal-Wallis test were used to compare distributions of continuous variables.\u003c/p\u003e\n\u003cp\u003ePrimary endpoints were time to CRPC (ttCRPC) and overall survival (OS). ttCRPC was defined as the interval from the initiation of treatment for mHSPC to the progression to mCRPC or start of subsequent treatment or death. OS was defined as time interval between initiaation of mHSPC treatment and death due to any cause. Both endpoints were evaluated by using Kaplan-Meier curve analyses and log-rank tests.\u003c/p\u003e\n\u003cp\u003eFor all analyses, univariable and multivariable Cox regression models were applied. Multivariable Cox regression models were adjusted to account for potential baseline confounders, including patient-related factors such as age and Eastern Cooperative Oncology Group (ECOG) performance status, as well as tumor characteristics such as Gleason score, high vs. low volume CHAARTED mHSPC, synchronous vs. metachronous mHSPC. Additional adjustment for mHSPC treatment was made for ttCRPC analyses, while the number of applied systemic number was adjusted for in OS analyses. All statistical analyses and visualizations were conducted using the R software environment for statistical computing and graphics (version 3.4.3).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe total study population included 432 patients with a median age of 69 years (IQR 63\u0026ndash;75 years, Table 1) at the time of diagnosis of mHSPC. The ECOG performance score was 0 in 64% of all patients. The median PSA at the time of mHSPC diagnosis 60 ng/ml (IQR 14\u0026ndash;280ng/ml). Regarding tumor characteristics, 83% of patients presented with synchronous mHSPC. The majority of patients (74%) had a Gleason score of 8\u0026ndash;10. Prior local therapy, including radiotherapy or radical prostatectomy, was documented in 29% of cases. Based on the CHAARTED criteria, 57% mHSPC patients harbored high-volume disease, while 63% met LATITUDE high-risk criteria. The median number of systemic treatment lines was two (IQR 2\u0026ndash;3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline characteristics M1a+b vs. M1b\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were stratified according to their metastatic pattern, with 36% (n=157) classified as M1a+b vs. 64% (n=275) as M1b (Table 1). Median age (67 vs. 68 years, p=0.1) and ECOG performance status (33% vs. 38%, p=0.5) did not significantly differ between both two groups. Conversely, median PSA at the mHSPC diagnosis was higher in the M1a+b group compared to M1b, although no statistical significance was reached (82 vs. 46 ng/ml, p=0.2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen assessing tumor characteristics, the proportion of patients with a Gleason score of 8\u0026ndash;10 was significantly higher in the M1a+b group compared to the M1b group (82% vs. 69%, p\u0026lt;0.01). Regarding disease stratification by CHAARTED and LATITUDE criteria, the proportion of patients with high-risk disease was significantly higher in the M1a+b group vs. M1b mHSPC patients (76% vs. 55%; p\u0026lt;0.001). Similarly, high-volume disease was more frequently observed in M1a+b than in M1b (70% vs. 50%, p\u0026lt;0.001). Synchronous mHSPC was balanced between M1a+b vs. M1b mHSPC patients (85% vs. 82%, p=0.4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTime to CRPC: M1b vs. M1a+b\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn ttCRPC analyses, significant differences between M1b vs. M1a+b group were observed (Figure 1). Specifically, median time to CRPC was 26 vs. 16 months for M1b vs. M1a+b mHSPC patients (hazard ratio [HR]: 1.59, confidence interval (CI): 1.18-2.16, p\u0026lt;0.01). After multivariable adjustment for baseline patient and tumor characteristics in Cox regression models, the M1a+b group showed no significant difference compared to the M1b group (HR: 1.44, CI: 0.87-2.40, p=0.16, Table 2A).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOS: M1b vs. M1a+b\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn OS analyses, no significant differences were observed between M1b and M1a+b patients (Figure 2), with a median survival of 53 vs. 47 months, respectively (HR: 1.03, CI: 0.75-1.42, p=0.9). Similarly, after multivariable adjustment for baseline patient and tumor characteristics in Cox regression models, analyses did not reveal any significant associations (HR: 0.83, CI: 0.54-1.29, p=0.41, Table 2B).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe hypothesized that patients with lymph node metastases in addition to bone metastases exhibit a distinct disease trajectory and therefore differ in baseline characteristics compared to patients with bone-only metastases (M1b). We additionally initially aimed to evaluate the impact of concomitant distant lymph node metastases on ttCRPC and OS in patients with osseous M1b mHSPC. To test these hypothesizes, we relied on data from the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) and were able to identify several important findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFirst\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e we analyzed baseline and tumor characteristics in patients with mHSPC stratified by metastatic pattern M1a+b vs. M1b. Median age at diagnosis (68 vs. 70 years), and ECOG performance status showed no significant difference between the two groups (both p \u0026gt;0.05). The PSA level in our cohort was also numerically higher (82 vs. 46 ng/ml) in the M1a+b group, but the difference did not reach statistical significance (p=0.2). Compared to previously published cohorts, a study by Elewaily et al. (n=129) compared patients with M1a (n=28) and M1b (n=91) disease [15]. In line with our findings, the authors found no significant difference in median age (69.5 vs. 69.7 years, p=0.5). Furthermore, tumor characteristics such as Gleason score and median PSA were not significantly different between the two metastatic patterns in the study by Elewaily et al., however median difference was clinically highly relevant (M1a: 24.7 ng/ml vs. M1b: 118.8 ng/ml; both p\u0026gt;0.10) [24]. This aligns with our findings regarding PSA, which was also higher in the M1a+b group (82 ng/ml vs. 46 ng/ml), but without reaching statistical significance, in both studies probably due to sample size limitations or wide IQRs and ranges due to number of bone metastases or concomitant metastatic lymph nodes. In contrast, Gleason score distribution in our cohort showed a significant difference, with a higher proportion of Gleason 8–10 tumors in the M1a+b group (p=0.007). In line, a study by Miyake et al. including 437 mHSPC patients identified age, Gleason score, and the presence of visceral metastases as significant prognostic factors of OS in univariable analysis [16]. Overall, our data indicate that patients with M1a+b mHSPC harbor more unfavorable baseline tumor characteristics, as evidenced by a significantly higher proportion of Gleason score 8–10 tumors (82% vs. 69%, p\u0026lt;0.01), and a significantly higher rates of patients classified as high-risk (76% vs. 55%) and high-volume (70% vs. 50%) according to LATITUDE and CHAARTED criteria, respectively (both p\u0026lt;0.001). These findings underline the importance of differentiating metastatic patterns when stratifying risk and selecting treatment strategies in mHSPC.\u003c/p\u003e\n\u003cp\u003eSecond, we assessed cancer-control outcomes, such as ttCRPC and OS relying on Kaplan-Meier curve and log-rank test analyses. Median ttCRPC was significantly shorter in M1a+b patients compared to M1b patients (16 vs. 26 months, HR: 1.6, p\u0026lt;0.01). In contrast, no significant difference in OS was observed between the two groups, with median survival of 47 vs. 53 months, respectively (HR: 1.03, p=0.9). In multivariable analyses no significant results were found in ttCRPC and OS in comparison between the two groups. (both p\u0026gt;0.16). In contrast to the findings of Miyake et al., who identified shorter ttCRPC as a strong negative prognostic marker for OS (p\u0026lt;0.001), our cohort showed no significant difference in overall survival despite a shorter ttCRPC in univariable analyses. Miyake et al. demonstrated a median OS of 40.8 months in patients with ttCRPC of 0–6 months up to 70.1 months in those with a ttCRPC of more than 18.1 months. However, it is important to note that this study did not distinguish between patients with combined M1a and M1b disease and those with M1b disease alone [16]. Still, these results are in contrast with our findings, where patients with concomitant distant lymph node metastases (M1a+b) demonstrated more unfavorable baseline characteristics and a significantly shorter time to mCRPC, suggesting a more aggressive disease biology despite comparable OS.\u003cbr\u003e\u0026nbsp;When analyzing cancer control data in the context of the existing literature, it becomes apparent that the proportion of patients with a high tumor burden—defined by tumor volume according to CHAARTED criteria—is significantly higher in the M1a+b group. This subgroup also exhibits a significantly shorter ttCRPC, indicating a more aggressive disease course. In contrast, OS does not differ significantly between groups. This may suggest that, in the setting of progression during the mHSPC stage, OS is more strongly influenced by the choice of therapy subsequent after progression of mHSPC and the individual response to treatment. Moreover, the presence of visceral metastases may have a greater prognostic impact than lymphatic dissemination. This hypothesis is further supported by an Asian study conducted by Wang et al., in which 870 patients with de novo mHSPC were retrospectively analyzed between 2009 and 2021. Patients were stratified according to their metastatic pattern, and OS was assessed. Those patients presenting with osseous or lymphatic metastases showed significantly better OS compared to patients with visceral metastases, particularly hepatic metastasis\u0026nbsp;[18]Additionally, a study by Halabi et al. investigated the prognostic relevance of metastatic patterns in a cohort of 8,820 patients with mCRPC. Although focused on a later disease stage, the findings similarly demonstrated that patients with visceral metastases had significantly worse overall survival compared to those with lymphatic or osseous metastases [19]. To our knowledge, no study to date has specifically examined ttCRPC and OS in direct comparison between M1a+b vs. M1b metastatic patterns. Our findings therefore provide novel insights into the clinical behavior and risk stratification of mHSPC patients based on metastatic distribution.\u0026nbsp;Clinicians should ideally incorporate these findings in their treatment workflow of mHSPC patients, since M1a+b patients are at higher risk of earlier disease progression.\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. First, its single-center approach, which may limit the generalizability of the findings. Second, due to its retrospective design, the study is subject to inherent biases, including potential selection and information bias. Third, staging imaging was not standardized across all patients, which may have affected the classification of metastatic patterns. Although baseline characteristics were well balanced between groups, the number of patients differed substantially between the M1a+b (n=157) vs. M1b (n=275) cohorts, which may have reduced the statistical power to detect significant differences. Finally, data on comorbidities and PSA kinetics and exact number of lymph node and bone metastases were not available, although these factors are known to influence disease progression and OS.\u003c/p\u003e\n\u003cp\u003eTaken together, mHSPC patients with concomitant distant lymph node metastases in addition to bone metastases (M1a+b) present with more unfavorable baseline cancer characteristics compared to patients with solely M1b mHSPC disease. While this is associated with a significantly shorter ttCRPC in univariable analyses, ttCRPC and OS does not differ significantly between the two groups in multivariable analyses. These findings underscore the importance of considering metastatic pattern for early risk stratification, especially regarding follow-up schedules to may protect progression earlier then in M1b mHSPC patients. Future prospective multicenter studies with standardized imaging protocols and larger, balanced cohorts are warranted to validate our findings and to clarify the prognostic implications of M1b vs. M1a+b metastatic patterns in mHSPC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData sharing statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available for bona fide researchers who request it from the authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial disclosures and Conflicts of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ehtics and Consent:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe current study was in accordance with the Declaration of Helskini. Local Review of the ethics board was approved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate declarations:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuman Ethics and Consent to participate declarations: not applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding statement:\u003c/h2\u003e \u003cp\u003eThe research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM Wenzel: Project development, Data collection, Data analysis, Manuscript writingB Lauer: Project development, Data collection, Data analysis, Manuscript writingV. M\u0026uuml;hlthaler: Project development, Data collection, Data analysis, Manuscript editingM Filzmayer: Project development, Data collection, Data analysis, Manuscript editingC Siech: Project development, Data collection, Data analysis, Manuscript editingC Le: Project development, Data collection, Data analysis, Manuscript editingC Humke: Project development, Data collection, Data analysis, Manuscript editingM Kosiba: Project development, Data collection, Data analysis, Manuscript editingM Kriegmair: Project development, Data collection, Data analysis, Manuscript editingT Steuber: Project development, Data collection, Data analysis, Manuscript editingF Chun: Manuscript editing, Supervision, ValidationP Mandel: Manuscript editing, Supervision, Validation\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel, R.L.; Miller, K.D.; Jemal, A. 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Regional location of lymph node metastases predicts survival in patients with de novo metastatic prostate cancer. \u003cem\u003eAsian journal of andrology\u003c/em\u003e, \u003cstrong\u003e2023\u003c/strong\u003e, \u003cem\u003e25, \u003c/em\u003e462\u0026ndash;467.\u003c/li\u003e\n\u003cli\u003eHalabi, S.; Kelly, W.K.; Ma, H.; Zhou, H.; Solomon, N.C.; Fizazi, K.; Tangen, C.M.; Rosenthal, M.; Petrylak, D.P.; Hussain, M.; Vogelzang, N.J.; Thompson, I.M.; Chi, K.N.; Bono, J. de; Armstrong, A.J.; Eisenberger, M.A.; Fandi, A.; Li, S.; Araujo, J.C.; Logothetis, C.J.; Quinn, D.I.; Morris, M.J.; Higano, C.S.; Tannock, I.F.; Small, E.J. Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer. \u003cem\u003eJCO\u003c/em\u003e, \u003cstrong\u003e2016\u003c/strong\u003e, \u003cem\u003e34, \u003c/em\u003e1652\u0026ndash;1659.\u003c/li\u003e\n\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":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Survival rate, mHSPC, metastasic burden","lastPublishedDoi":"10.21203/rs.3.rs-8137517/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8137517/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMost patients with metastatic hormone-sensitive prostate cancer (mHSPC) are burdened by bone metastases. However, the impact of concomitant distant lymph node metastases at diagnosis in these patients is unknown.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and methods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe relied on the FRAMCAP database (FRAnkfurt Metastatic Cancer database of the Prostate) to compare time to metastatic castration-resistant prostate cancer (mCRPC) and overall survival (OS) between M1b vs. M1a+b mHSPC patients. Univariable and multivariable Cox regression models were applied.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 432 patients, 64% harbored M1b vs. 36% M1a+b mHSPC. PSA was significantly higher in M1a+b vs. M1b patients (81 vs. 44 ng/ml, p\u0026lt;0.05), as well as rates of LATITUDE high-risk (76% vs. 55%) and CHAARTED high-volume disease (70% vs. 50%) (both p\u0026lt;0.001). Regarding time to mCRPC, median time to CRPC was 26 vs. 16 months for M1b vs. M1a+b patients (hazard ratio [HR]: 1.6, p\u0026lt;0.01). Regarding OS, median OS was not significantly different, with median OS of 53 vs. 47 months for M1b vs. M1a+b patients (p=0.9). After controlling for patient and tumor characteristics in multivariable Cox regression analyses, concomitant lymph node metastases were not an independent risk for shorter time to CRPC or OS in patients with bone metastases (both p\u0026gt;0.15).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with concomitant distant lymph node metastases in mHSPC with bone metastases (M1a+b) harbor more unfavorable baseline cancer characteristics relative to M1b without lymph node metastases, translating into significantly shorter time to mCRPC. However, after controlling for patient and tumor characteristics, neither time to mCRCP nor OS seems not be affected by concomitant lymph node metastases.\u003c/p\u003e","manuscriptTitle":"Influence of concomitant distant lymph node metastases in metastatic hormone-sensitive prostate cancer patients with bone metastases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-04 12:06:10","doi":"10.21203/rs.3.rs-8137517/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-16T15:42:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-05T03:23:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97007549473989495227379619862701524024","date":"2026-02-03T20:44:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198376799326214232304482870025228947565","date":"2026-02-03T09:59:25+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-03T02:27:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-22T00:40:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-21T16:29:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Urology","date":"2025-11-17T16:01:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3b00b987-1c32-40a9-bb9c-bfeb97e20837","owner":[],"postedDate":"February 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:21:40+00:00","versionOfRecord":{"articleIdentity":"rs-8137517","link":"https://doi.org/10.1007/s00345-026-06358-5","journal":{"identity":"world-journal-of-urology","isVorOnly":false,"title":"World Journal of Urology"},"publishedOn":"2026-03-24 16:11:58","publishedOnDateReadable":"March 24th, 2026"},"versionCreatedAt":"2026-02-04 12:06:10","video":"","vorDoi":"10.1007/s00345-026-06358-5","vorDoiUrl":"https://doi.org/10.1007/s00345-026-06358-5","workflowStages":[]},"version":"v1","identity":"rs-8137517","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8137517","identity":"rs-8137517","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}