Metastatic pattern with mild prognostic impact in high-volume castration-sensitive prostate cancer

Metastatic pattern with mild prognostic impact in high-volume castration-sensitive prostate cancer | 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 Article Metastatic pattern with mild prognostic impact in high-volume castration-sensitive prostate cancer Dai Koguchi, Hideyasu Tsumura, Ken-ichi Tabata, Shuhei Hirano, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6006181/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract We aimed to investigate the prognostic impact of the extent of bone metastasis (BM) and lung metastasis (LM) in patients with high-volume (HV) castration-sensitive prostate cancer (CSPC). We retrospectively reviewed 379 patients with synchronous metastatic CSPC, focusing on BM patterns, with and without LM. According to the CHAARTED criteria, 115 and 264 patients were respectively classified as having low-volume (LV) disease with BM of extent of disease 1 (LV-EOD1) and HV disease with BM of EOD 1 to 4 (HV-EOD1-4; 197 with BM alone and 67 with BM plus LM). We compared overall survival (OS) between the LV-EOD1 and HV-EOD1-4 groups after propensity score matching (PSM). We used multivariate Cox regression analysis to assess the risk factors for OS in HV-EOD1-4 patients. There was no significant difference in the OS between LV-EOD1 group and HV-EOD ≤ 2 group (in patients with BM alone or after adding patients with BM plus LM) after PSM. A multivariate analysis for OS in HV-EOD1-4, including LM, demonstrated that EOD ≥ 3 and Gleason score ≥ 9 were independent risk factors, and LM had no significant role. Therefore, HV-EOD ≤ 2, regardless of LM, has a prognostic impact comparable to that of LV-EOD1. Health sciences/Oncology Health sciences/Urology prostate cancer treatment prognosis high-volume disease metastatic pattern extent of disease Figures Figure 1 Figure 2 Figure 3 1. Introduction Risk stratification in cancer treatment is critical for determining the severity of the disease and developing treatment strategies. Most guidelines for metastatic castration-sensitive prostate cancer (mCSPC) recommend treatment strategies according to CHAARTED criteria, which has a high diagnostic potential to discern aggressive tumor characters based on tumor volume [ 1 – 4 ]. Based on the CHAARTED criteria, mCSPC is divided into two subcategories, and high-volume (HV) disease is considered as formidable status. The Phase 3 TITAN trial in fact showed apalutamide plus androgen deprivation therapy (ADT) provided a less than one-year median castration resistant-free survival (CFS) for HV disease, which was half as long as that for low-volume (LV) disease (8.3 vs. 16.6 months) [ 5 ]. Subsequently, results from two recent network meta-analyses of HV disease showed that triplet therapy (TP), including darolutamide plus docetaxel (DTX) and ADT, ranked first, followed by doublet therapy (DT) [ 6 , 7 ]. However, this intensified systemic therapy (TP) involves up to approximately 50% risk of grade ≥ 3 adverse events mostly derived from DTX, such as neutropenic fever, peripheral neuropathy, and fluid retention [ 8 – 10 ]. Given the deterioration in patients’ quality of life (QOL) following TP, current guidelines for HV disease have not yet resolved outstanding questions as to which patients will likely benefit most from TP or DT, including androgen receptor pathway inhibitor (ARPI) plus ADT. A solution to solving the unmet needs for the optimal treatment choice for HV-mCSPC may be its subcategorization. HV is defined as having four or more bone metastases with at least one outside the spine and pelvis or having visceral metastases (VM) [ 1 ]. In other words, it includes heterogeneous metastatic types covering bone metastasis (BM) with the extent of disease (EOD) 1 to 4, or VM with or without BM [ 1 , 11 ]. Therefore, we hypothesized that the subcategorization of such a heterogeneous disease would enable the identification of some metastatic patterns with mild prognostic impact, leading to better oncological management with both long-term survival and stable QOL by the avoidance of TP. We aimed to explore metastatic patterns with mild prognostic impact in synchronous HV-mCSPC by comparing survival outcomes between LV disease with BM of EOD1 (LV-EOD1) and HV diseases with BM of EOD1 to 4 (HV-EOD1-4) including lung metastasis (LM). 2. Methods 2.1. Study population We retrospectively reviewed the clinical data of 451 patients who received ADT or DT of ARPI or DTX plus ADT for mCSPC at Kitasato University Hospital between April 2004 and September 2023. Of the 145 patients with LV disease and 306 with HV disease, we focused on patients who had BM with and without LM, irrespective of the presence of distal lymph node metastasis. Patients with metachronous mCSPC, LV disease with an EOD2 or VM, except for LM alone, were excluded from the present study. Initial diagnosis of prostate cancer (PCa) was histologically confirmed in all cases. Data on patient characteristics were collected from medical charts. They included demographic data, Charlson Comorbidity Index [ 12 ], disease volume classified as HV or LV per CHAARTED criteria [ 1 ], EOD classified via bone scintigraphy [ 11 ], and prognostic variables including radiographic progression, castration-resistant prostate cancer (CRPC)-free survival (CFS) and overall survival (OS). All patients initially received ADT consisting of orchiectomy or luteinizing hormone-releasing agonists/antagonists, or ADT in combination with nonsteroidal antiandrogen. This study was approved by the Institutional Review Board of Kitasato University School of Medicine and Kitasato University Hospital (Kanagawa, Japan) and was conducted in accordance with the Declaration of Helsinki, including the request to waive documentation of informed consent (B23-106, B22-102 and B24-120). 2.2. Definition of endpoints The primary endpoint was OS, defined as the interval from the date of initiation of treatment for mCSPC to the date of death from any cause. The secondary endpoint was CFS, and CRPC was defined as PSA failure or radiographic progression; the former required a 25% and > 2 ng/mL rise in PSA four weeks apart from the nadir, regardless of the serum castration level according to the JUA guidelines [ 4 ]. Radiographic progression was determined based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. via CT or the appearance of one or more new BM via technetium-99 bone scanning [ 1 ]. 2.3. Statistical analysis Kaplan–Meier analysis was performed to evaluate OS and CFS for the overall cohort by tumor volume and EOD. Propensity score matching (PSM) was used to match potential covariates by a 1:1 matching ratio between LV-EOD1 and HV-EOD1-4 or HV-EOD ≤ 2, including LM. The matched clinicopathological features involved age, initial PSA levels, Gleason score (GS), clinical T-stage, clinical N-stage, clinical M1a status, and type of initial treatment and radiation therapy (RT) for mCSPC. In cases with BM alone, OS was compared via the Kaplan–Meier method between LV-EOD1 and HV-EOD ≤ 4, and CFS was compared between LV-EOD1 and HV-EOD ≤ 2 disease. In cases with BM and LM, comparative analyses for the prognoses between LV-EOD1 and HV-EOD ≤ 2, including LM, were performed. The prognostic impact of HV-EOD ≥ 3, including LM, was not evaluated because we had speculated that the prognostic impact of LM would not have been conclusive given the preexistence of some extent of prognostic difference between LV-EOD1 and HV-EOD ≥ 3 without LM (Supplementary Fig. S1 ). With a focus on patients with BM plus LM, rPFS for LM was compared with CFS for the overall cohort via the Kaplan–Meier method. Multivariate Cox regression analyses were performed to investigate the prognostic value of clinicopathological factors, including BM and LM in HV-mCSPC. Patient characteristics were compared using the chi-squared test (or Fisher’s exact test, if appropriate) for categorical variables and the Mann–Whitney U test for continuous variables. All statistical analyses were performed using Stata 14 for Windows (Stata, Chicago, IL, USA). All P values were two-sided, and P < 0.05 was considered statistically significant. 3. Results 3.1. Patient characteristics Of the 451 included patients, 379 met the inclusion criteria. Table 1 shows the characteristics of 115 patients with LV-EOD1 and 264 with HV-EOD1-4, including LM. Among those with HV disease, 197 (74.6%) had BM alone, and 67 (25.4%) had BM plus LM. Among those with LM, 19 (46.3%), 12 (17.1%), 19 (25.3%), and 17 (21.8%) had an EOD 1, 2, 3, and 4, respectively. In comparison with LV-EOD1, HV disease had significantly higher initial PSA levels, significantly greater proportions of GS ≥ 9, clinical T ≥ 3b, clinical N1 and clinical M1a, and a significantly lower proportion of prostate-directed RTx (PDRT) for mCSPC (17.8% vs. 40.9%, P < 0.001). PDRT for HV-EOD1-4 was seen in 31.7% (n = 13), 20.0% (n = 14), 16.0% (n = 12) and 10.3% (n = 8) patients, respectively. Proportions of patients with ARPI or DTX for mCSPC in HV and LV diseases were similar (HV disease, n= 57, 21.6% vs. LV disease, n = 19, 16.5%, P = 0.33); each proportion of the intensified ADT in HV-EOD1-4 accounted for 17.1% (n = 7), 24.3% (n = 17), 26.7% (n = 20) and 16.7% (n = 13), respectively, and 5.3% (n = 3) of the patients with the intensified ADT for mCSPC received DTX for HV disease. In the PSM analysis, there were no major differences in patient demographics between the PSM cohort except for a significantly lower proportion of patients with RT and PDRT in HV-EOD ≥ 2 (Table 2 and Supplementary Table S1). First subsequent systemic treatments for CRPC in the PSM cohort are shown in Supplementary Table S2. The proportions of patients with ARPI or DTX for CRPC were similar among HV-EOD ≤ 2, including LM and LV-EOD1. 3.2 Survival outcomes in the overall cohort The median follow-up of patients with LV-EOD1 and HV-EOD1-4 was 53 and 30 months, respectively. In the overall cohort, Kaplan–Meier analyses showed a significant difference in OS and CFS during these follow-up periods (Fig. 1 and Supplementary Fig. S2). The median OS and CFS for LV-EOD1 were 105 and 52.3 months, while those for HV-EOD1-4, including LM were 120 and 28.1, 89.6 and 25.9, 40.9 and 16.1, and 38.9 and 9.2 months, respectively (P < 0.001). No significant differences were seen in the OS and CFS between HV-EOD1 and LV-EOD1 (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.37-2.05, P = 0.81, and HR: 1.44, 95% CI: 0.77-2.71, P = 0.25, respectively). Moreover, no significant differences were seen in the OS between HV-EOD2 and LV-EOD1 (HR: 1.48, 95% CI: 0.87-2.54, P = 0.15), whereas HV-EOD2 had better CFS compared with LV-EOD1 (HR: 1.85, 95% CI: 1.19-2.88, P = 0.006). In patients with HV-EOD2, the number of BM ≤ 10 was associated with better survival outcomes compared to BM ≥ 11 with a median OS of 96.2 vs. 59.1 months (HR: 0.65, 95% CI: 0.35-2.12, P = 0.43) and CFS of 30.6 vs. 16.1 months (HR: 0.33, 95% CI: 0.13-081, P = 0.025) (Supplementary Fig. S3). 3.3 Survival outcomes in the PSM cohort In terms of BM alone, median follow-up of EOD1-4 for HV and LV were 46.2 and 55.3, 38.1 and 40.6, 29.7 and 49.4, and 27.2 and 49.8 months, respectively. Kaplan–Meier analyses showed that HV-EOD 1 had no significant impact on OS and CFS compared with LV-EOD1 (HR: 0.79, 95% CI: 0.27-2.28, P = 0.35, and HR: 0.81, 95% CI: 0.39-2.41, P = 0.83, respectively). Similar trends were seen with HV-EOD2 (HR: 0.94, 95% CI: 0.50-1.44, P = 0.52, and HR: 1.07, 95% CI: 0.65-1.77, P = 0.58, respectively) (Fig. 2 and Supplementary Fig. S4). In contrast, significantly worse OS was associated with HV-EOD3 (HR: 2.26, 95% CI: 1.20-4.25, P < 0.001) and HV-EOD4 (HR: 2.32, 95% CI: 1.40-3.83, P < 0.001) compared with LV-EOD1 (Supplementary Fig. S5). In patients with BM and LM, the median follow-up for HV and LV were 32.9 and 31.1 months in patients with EOD1 and 38.8 and 39.9 months in those with EOD2. LM accounted for 45% (n = 18) in HV-EOD1 and 16.7% (n = 11) in HV-EOD2. Kaplan–Meier analyses showed no significant impact of HV-EOD1, including LM, on OS and CFS compared with LV-EOD1 (HR: 0.54, 95% CI: 0.23-1.25, P = 0.20, and HR: 0.77, 95% CI: 0.41-1.43, P = 0.44, respectively). Similar results were seen for HV-EOD2, including LM (HR: 1.02, 95% CI: 0.58-1.80, P = 0.94, and HR: 1.13, 95% CI: 0.71-1.77, P = 0.64, respectively) (Fig. 3 and Supplementary Fig. S6). 3.4 LM- specific survival outcomes Of the 67 patients with BM plus LM, 8 (11.9%) had the radiographic progression of LM, whereas 42 (62.7%) developed progression to CRPC for any reason with HR of 0.12 (95% CI: 0.09-0.28, P < 0.001) (Supplementary Table S3). The proportions of site-specific radiographic progression to CRPC significantly differed between BM (n = 20, 29.9%) and LM (n = 4, 6.0%) (P < 0.001), and the number of LM did not correlate with the progression to CRPC (solitary, n = 1, 1.5%; 2-10, n = 1, 1.5% and ≥ 11, n = 2, 3.0%; P = 0.62). 3.5 Multivariate Cox regression analyses for survival outcomes in HV disease Multivariate analysis for OS demonstrated that EOD ≥ 3 (HR: 2.03, 95% CI: 1.32-3.11, P = 0.001), GS ≥ 9 (HR: 1.69, 95% CI: 1.12-2.53, P = 0.001) and ARPI or DTX plus ADT (HR: 0.39, 95% CI: 0.22-0.72, P = 0.002) were independent prognostic factors (Table 3). The analysis for CFS revealed EOD ≥ 3 (HR: 2.64, 95% CI: 1.87-3.71, P < 0.001), GS ≥ 9 (HR: 1.48, 95% CI: 1.05-2.10, P = 0.026) and T ≥ 3b (HR: 1.57, 95% CI: 1.08-2.27, P = 0.018) and ARPI or DTX plus ADT (HR: 0.21, 95% CI: 0.12-0.36, P < 0.001,) as independent prognostic factors (Supplementary Table S4). LM did not have a significant impact on OS (HR: 1.20, 95% CI: 0.82-1.75, P = 0.35) and CFS (HR: 1.22, 95% CI: 0.76-1.95, P = 0.41). 4. Discussion Since the advent of TP for mCSPC, optimal treatment intensity for HV disease has been a clinical dilemma. This study focused on patients who had BM with and without LM and found some metastatic patterns in HV disease that had a survival impact comparable to that in LV-EOD1. First, in cases with BM alone, PSM analysis revealed no significant difference in OS and CFS between LV-EOD1 and HV-EOD ≤ 2. In HV-EOD2, BM ≤ 10 was associated with better outcomes compared to BM ≥ 11 in the unadjusted cohort. Second, PSM analysis also showed that in spite of being a VM, LM, along with BM, had no significant impact on OS and CFS compared with LV-EOD1. The multivariate analysis confirmed this potential mild aggressive behavior of LM. Patients with HV-EOD ≤ 2, including LM, accounted for 36.3% (111/306) of the entire present cohort of HV-mCSPC. BM without VM comprises the most frequent metastatic pattern, accounting for approximately 85% of mCSPC, as seen in the Surveillance, Epidemiology, and End Results (SEER) and TITAN databases [ 5 , 13 , 14 ]. Hence, we assumed that subclassification of this dominant pattern of BM alone would reveal a range of oncological characters. The present PSM analysis notably indicates that HV-EOD ≤ 2 should be prognostically distinguished from HV-EOD ≥ 3. In comparison with LV-EOD1, HV-EOD ≤ 2 had no significant impact on OS and CFS, whereas HV-EOD ≥ 3 had significantly worse OS (HV-EOD3, HR: 2.26, 95% CI: 1.20–4.25 and HV-EOD4, HR: 2.32, 95% CI: 1.40–3.83). This mild aggressive potential of HV-EOD ≤ 2 will likely enhance its validity given the similar proportion of the first subsequent treatment of ARPI and DTX for CRPC among the cohorts. Moreover, the comparable survival outcomes for HV-EOD1 and LV-EOD1 appear logical according to robust evidence of favorable prognosis for oligometastatic PCa, which covers only the number of metastases irrespective of the metastatic site [ 15 ]. In contrast, the HV-EOD2 prognosis may need to be considered with caution because of the wide range of BM (6–20) in EOD2. The limited data on EOD-based analysis reported significantly worse OS for non-subclassified EOD2 than that for EOD1 in mCSPC initially treated with ADT (P = 0.013) [ 11 ]. In other words, as the present study found that BM ≤ 10 was associated with a better prognosis, especially with CFS, EOD2 potentially represents the bifacial biology of oligometastatic or widespread PCa. Therefore, TP will likely pose a risk of over-treatment for HV-EOD2 consisting of BM ≤ 10 in particular. LM is most commonly seen with BM, accounting for 35% of mCSPC based on the nationwide study [ 13 ]. Another intriguing finding of the present study is that LM can be interpreted separately from the aggressive behavior of VM. For example, PSM analysis showed that OS and CFS in HV-EOD1, including LM, did not significantly differ from those in LV-EOD1 in spite of as much as 45% of LM in HV-EOD1. Moreover, LM infrequently progressed to CRPC compared with BM (6.0% vs. 29.9%, P < 0.001). Although literature has dominantly referred to the prognostic impact of solitary LM as a case report, some clinical research previously reported consistent results with the present study [ 14 , 16 , 17 ]; one of the largest studies based on the SEER database including 16,643 synchronous mCSPC patients demonstrated comparable five-year survival of BM plus LM (22.1%) vs. BM alone (24.2%). A rationale for such a mild prognostic impact of LM potentially relies on two mechanisms. First, LM may have a typical genomic landscape of nonmetastatic PCa, as shown in a retrospective study for metachronous mCSPC, wherein PTEN, SPOP, and chromosome 8p alterations were frequently observed, whereas TP53 and DNA damage repair gene mutations were absent [ 18 ]. Second, LM, irrespective of primary tumor origin, may have a high immunogenic status based on a clustering analysis that showed high infiltration of myeloid dendritic cells and cytotoxic lymphocytes into the cancer cell and the LM stroma, compared to other metastatic sites, such as liver, brain, and bone [ 19 ]. The myeloid dendritic cells and cytotoxic lymphocytes are essential partners for the initial antitumor step. Hence, based on our clinical findings and the available data, during treatment decision-making for HV-mCSPC, the mere presence of LM does not qualify for TP. Androgen receptor (AR)-independence is a key indicator of the inclusion of DTX in the treatment of mCSPC because DTX is classified as taxane-based cytotoxic chemotherapy. Transcriptional analysis showed that DTX or RT provided additional OS benefits compared to ADT alone for the synchronous pattern (HR: 0.47, 95% CI: 0.30–0.72), which had significantly lower hallmark androgen response compared with the metachronous pattern (3.15 vs. 3.32; P < 0.01). In contrast, the metachronous pattern did not correlate with the additional effect of DTX or RT, and yet, ARPI plus ADT favored more than ADT alone in the metachronous-LV disease [ 5 , 20 , 21 ]. Exploring clinical features with some extent of AR independence may help identify patients who would benefit from a DTX-included regimen, and such candidates, besides the synchronous pattern, may correspond to advanced clinicopathological features. For example, GS ≥ 9 harbored approximately twice as much low-AR activity as GS ≤ 7 (22% vs. 10%) even in treatment-naïve primary PCa, and seminal vesicle invasion in prostatectomy specimen correlated with ETS family, which could activate AR independent of the ligand (odds ratio: 2.27 vs. negative ETS member, P = 0.004) [ 22 , 23 ]. From the perspectives of clinical data, significant additional OS benefit of DTX to ADT alone was found for GS ≥ 8 (HR: 0.68, 95% CI: 0.53–0.87) in a subgroup analysis of the CHAARTED trial with mature follow-up, and that more favorable HR was demonstrated for a metastatic pattern of HV and T4 in a systematic review and meta-analysis based on STOPCAP program (HR: 0.38, 95% CI: 0.26–0.53) [ 1 , 24 ]. Hence, AR independence explains independent worse prognostic values of GS ≥ 9, EOD ≥ 3, and T ≥ 3b, as shown in the present multivariate analysis, which included only a limited proportion of patients with DTX (5.3%). DTX should thus be considered for HV-mCSPC with aggressive characteristics, and the recent evidence currently favored TP among the DTX-inclusive regimen [ 6 , 7 , 25 ]. In other words, our findings show that EOD ≤ 2, especially without high GS and advanced T-stage, qualifies for DT with ARPI irrespective of the presence of LM. Our study had some limitations. First, the present retrospective design might have introduced bias into the process of patient selection. Second, the proportions of RT and PSA ≥ 100 ng/ml were not closely matched via PSM analysis between HV-EOD ≥ 2 and LV-EOD1. In part, this was because of the preexistence of significantly greater proportions of the two variables for HV-EOD1-4 than LV-EOD1 in the unadjusted cohort. This tendency may reflect the promising results of PDRT for LV-mCSPC as shown in the STAMPEDE trial and the positive correlation between tumor volume and PSA levels, thereby endorsing our findings of potential mild prognostic impact of HV-EOD2 [ 26 ]. Third, the definition of CRPC in this study differs from that proposed in EAU guidelines, leading to relatively short periods of CFS when PSA failure alone occurred. Thus, in this study, we set the primary endpoint as OS, which has the same definition per any guideline. 5. Conclusions Our findings show that EOD ≤ 2, irrespective of the presence of LM, even though classified as HV disease, has a survival impact comparable to LV-EOD1, accounting for approximately 35% of the entire HV disease cohort. Hence, among factors considered during decision-making, such as physical and social factors, clinicians should focus not only on tumor volume but also on the details of the tumor characteristics. Specifically, EOD ≤ 2, especially without high GS and advanced T-stage, irrespective of the presence of LM, will be well qualified for DT, sparing DTX for the more formidable CRPC. Randomized trials are needed to validate our findings. Declarations Competing Interests: All authors have no competing interests to disclose. Author Contribution Conceptualization, D.K.; Data curation, D.K.; Formal analysis, D.K.; Investigation, T.H., K.T., S.H., S.S., T.S., M.I.; Methodology, D.K., H.T.; Writing-original draft, D.K., H.T.; Writing-review & editing, D.K., H.T.; Supervision, K.M. All authors reviewed the manuscript. Acknowledgements: Not applicable Data Availability The data sets generated and analyzed during the current study are available from the corresponding author on reasonable request. References Kyriakopoulos, C. E. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized Phase III E3805 CHAARTED trial. J. Clin. Oncol. 36 , 1080–1087 (2018). American Urological Association. Advanced Prostate Cancer: AUA/SUO Guideline. https://www.auanet.org/guidelines-and-quality/guidelines/advanced-prostate-cancer (2023). European Association of Urology. 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Characteristics of patients at baseline Variables HV LV-E OD1 P value n = 264 n = 115 Age, median, yr 73 (46-91) 72 (45-92) 0.71 Charlson Comorbidity Index ≥ 1, n (%) 88 (33.3) 35 (30.4) 0.58 PSA, median, range (ng/ml) 443 (2-13042) 96 (5-6503) 0.04 Gleason score ≥ 9, n (%) 156 (59.1) 50 (43.5) 0.005 Clinical T ≥ 3b, n (%) 186 (70.5) 68 (59.1) 0.033 Clinical N1, n (%) 159 (60.2) 56 (48.6) 0.004 Metastatic status, n (%) Lymph node metastasis 74 (26.4) 14 (12.2) < 0.001 Lung metastasis 67 (25.4) 0 < 0.001 Bone metastasis 264 (100) 115 (100) < 0.001 EOD1 41 (15.5) 115 (100) EOD2 70 (26.5) EOD3 75 (28.4) EOD4 78 (29.5) Treatment for CSPC ADT or CAB 207 (78.4) 96 (83.5) 0.33 ARPI or DTX 57 (21.6) 19 (16.5) Radiation therapy for CSPC, n (%) 51 (19.3) 51 (44.3) < 0.001 Prostate-directed radiation therapy, n (%) 47 (17.8) 47 (40.9) < 0.001 Castration-resistant prostate cancer, n (%) 179 (67.0) 51 (44.3) < 0.001 Death, n (%) 129 (48.9) 39 (33.9) 0.007 Abbreviation: HV, high-volume; LV, low-volume; EOD, extent of disease; PSA, prostate-specific antigen; CSPC, castration-sensitive prostate cancer; ADT, androgen-deprivation therapy; CAB, combined androgen blockade; ARPI, androgen receptor pathway inhibitor; DTX, docetaxel. Table 2. Patient background after propensity score matching between HV-EOD1-4 and LV-EOD1 Variables, n (%) HV-EOD1 (n = 22) LV-EO D1 (n = 22) P value HV-EOD2 (n = 57) LV-EO D1 (n = 57) P value HV-EO D3 (n = 53) LV-EOD1 (n = 53) P value HV-EO D4 (n = 56) LV-EOD1 (n = 56) P value Age ≥ 75, yr 6 (27.2) 5 (22.7) 0.73 19 (33.3) 19 (33.3) - 28 (52.8) 29 (54.7) 0.85 25 (44.6) 27 (48.2) 0.70 Charlson Comorbidity Index ≥ 1 6 (27.2) 4 (18.2) 0.72 18 (31.6) 19 (33.3) 0.84 18 (34.0) 17 (32.1) 0.84 17 (30.4) 19 (33.9) 0.68 PSA ≥ 100 ng/ml at baseline 16 (72.7) 14 (63.6) 0.75 41 (71.9) 34 (59.7) 0.17 46 (86.8) 35 (66.0) 0.012 49 (87.5) 36 (64.3) 0.001 Gleason score ≥ 9 14 (63.6) 15 (68.2) 0.75 30 (52.6) 30 (52.6) 0.33 37 (69.8) 35 (66.0) 0.68 41 (73.2) 38 (67.9) 0.50 Clinical T ≥ 3b 14 (63.6) 14 (63.6) - 38 (66.7) 38 (66.7) - 40 (75.5) 37 (69.8) 0.51 38 (67.9) 39 (69.6) 0.83 Clinical N1 11 (50.0) 12 (54.5) 0.75 29 (50.9) 30 (52.6) 0.85 29 (54.7) 29 (54.7) - 30 (53.6) 31(45.6) 0.84 Metastatic status Lymph node metastasis 3 (13.6) 3 (13.6) - 11 (19.3) 9 (15.8) 0.62 8 (12.5) 7 (17.5) 0.78 10 (17.9) 11(19.6) 0.81 Bone metastasis 22 (100) 22 (100) - 57 (100) 57 (100) - 53 (100) 53 (100) - 56 (100) 56 (100) - Treatment for CSPC 0 0 - 0 0 - ADT or CAB 20 (90.9) 21 (95.5) 0.86 43 (75.5) 43 (75.5) - 38 (71.7) 40 (75.5) 0.66 46 (82.1) 45 (80.4) 0.73 ARPI or DTX 2 (9.1) 1 (4.5) 14 (24.5) 14 (24.5) 15 (28.3) 13 (24.5) 10 (17.9) 11 (19.6) Radiation therapy for CSPC 10 (45.5) 9 (40.9) 0.76 11 (19.3) 25 (43.8) 0.005 11 (20.8) 35 (66.0) < 0.001 7 (12.5) 33 (58.9) < 0.001 Prostate-directed radiation therapy 9 (40.9) 8 (36.4) 0.76 11 (19.3) 24 (42.1) 0.008 10 (18.9) 33 (62.3) < 0.001 7 (12.5) 33 (58.9) < 0.001 CRPC, n (%) 9 (40.9) 9 (40.9) - 34 (59.6) 30 (52.6) 0.57 26 (49.1) 22 (41.4) 0.56 47 (83.9) 31 (55.4) 0.002 Death, n (%) 6 (27.3) 8 (36.3) 0.75 21 (36.8) 17 (29.8) 0.55 39 (73.6) 15 (28.3) < 0.001 39 (69.6) 26 (46.4) 0.021 Abbreviation: HV, high-volume; LV, low-volume; EOD, extent of disease; PSA, prostate-specific antigen; CSPC, castration-sensitive prostate cancer; ADT, androgen-deprivation therapy; CAB, combined androgen blockade; ARPI, androgen receptor pathway inhibitor; DTX, docetaxel; CRPC, castration-resistant prostate cancer. Table 3. A multivariate COX analysis of overall survival in patients with HV disease Variable Reference HR 95%CI P value EOD ≥ 3 EOD ≤ 2 2.03 1.32-3.11 0.001 Age ≥ 75 Age ≤ 74 1.08 0.74-1.57 0.70 PSA at baseline ≥ 100 g/ml PSA < 100 ng/ml 0.63 0.39-1.03 0.062 Gleason score ≥ 9 Gleason score ≤ 8 1.69 1.12-2.53 0.012 Clinical T ≥ 3b Clinical T ≤ 3a 1.18 0.77-1.80 0.49 Clinical N1 Clinical N0 1.01 0.60-1.32 0.56 Clinical M1a Absence 1.44 0.92-2.26 0.11 Lung metastasis Absence 1.22 0.76-1.95 0.41 ARPI or DTX for CSPC ADT or CAB for CSPC 0.39 0.22-0.72 0.002 Radiation therapy for CSPC None 0.79 0.58-1.09 0.16 Abbreviation: HV, high-volume; HR, hazard ratio; CI, confidence interval; EOD, extent of disease; PSA, prostate-specific antigen; CSPC, castration-sensitive prostate cancer; ARPI, androgen receptor pathway inhibitor; DTX, docetaxel; ADT, androgen-deprivation therapy; CAB, combined androgen blockade. Additional Declarations No competing interests reported. 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Koguchi","email":"data:image/png;base64,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","orcid":"","institution":"Kitasato University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Dai","middleName":"","lastName":"Koguchi","suffix":""},{"id":415066802,"identity":"cc59aa37-17bd-43c3-a5fa-4d2c07463a63","order_by":1,"name":"Hideyasu Tsumura","email":"","orcid":"","institution":"Kitasato University School of 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Ishii","suffix":""},{"id":415066809,"identity":"345d4fd6-00d3-4c44-9ec2-e13fee8d327a","order_by":8,"name":"Kazumasa Matsumoto","email":"","orcid":"","institution":"Kitasato University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kazumasa","middleName":"","lastName":"Matsumoto","suffix":""}],"badges":[],"createdAt":"2025-02-11 10:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6006181/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6006181/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76284181,"identity":"922ddf51-1fca-497f-974f-e375d9265cb0","added_by":"auto","created_at":"2025-02-14 10:54:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":123184,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier analysis of overall survival in the total cohort by tumor volume and extent of disease\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6006181/v1/d57f1119e7a96045dc5f6e5a.png"},{"id":76284179,"identity":"4ba700e2-5698-49af-8da2-4e8ab2b23fce","added_by":"auto","created_at":"2025-02-14 10:54:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":162117,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier analysis of overall survival in HV-EOD ≤ 2 and LV-EOD1 after propensity score matching\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6006181/v1/5a8c7680b7f50d89a0bfbab0.png"},{"id":76284194,"identity":"c0f39be9-c123-4475-b164-89f811710e85","added_by":"auto","created_at":"2025-02-14 10:54:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":159742,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier analysis of overall survival in HV-EOD ≤ 2, including lung metastasis and LV-EOD1 after propensity score matching\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6006181/v1/e9679f56bb6fbe83eff82eae.png"},{"id":76285922,"identity":"b193db15-6bf0-4c65-900a-7438dd58074f","added_by":"auto","created_at":"2025-02-14 11:10:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1287371,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6006181/v1/cabea010-c9eb-4e76-a47c-5afb60fd13d5.pdf"},{"id":76284188,"identity":"94dde834-0929-4e7a-8027-a2133ccf8c54","added_by":"auto","created_at":"2025-02-14 10:54:20","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":29784,"visible":true,"origin":"","legend":"","description":"","filename":"TableSupple.docx","url":"https://assets-eu.researchsquare.com/files/rs-6006181/v1/345a4859111c338137511171.docx"},{"id":76284203,"identity":"f4a64efc-4d40-499c-a6f0-432bde642672","added_by":"auto","created_at":"2025-02-14 10:54:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":38972111,"visible":true,"origin":"","legend":"","description":"","filename":"FigureSupple.docx","url":"https://assets-eu.researchsquare.com/files/rs-6006181/v1/4d6d8955b2a5ca89c1211915.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Metastatic pattern with mild prognostic impact in high-volume castration-sensitive prostate cancer","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eRisk stratification in cancer treatment is critical for determining the severity of the disease and developing treatment strategies. Most guidelines for metastatic castration-sensitive prostate cancer (mCSPC) recommend treatment strategies according to CHAARTED criteria, which has a high diagnostic potential to discern aggressive tumor characters based on tumor volume [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on the CHAARTED criteria, mCSPC is divided into two subcategories, and high-volume (HV) disease is considered as formidable status. The Phase 3 TITAN trial in fact showed apalutamide plus androgen deprivation therapy (ADT) provided a less than one-year median castration resistant-free survival (CFS) for HV disease, which was half as long as that for low-volume (LV) disease (8.3 vs. 16.6 months) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Subsequently, results from two recent network meta-analyses of HV disease showed that triplet therapy (TP), including darolutamide plus docetaxel (DTX) and ADT, ranked first, followed by doublet therapy (DT) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, this intensified systemic therapy (TP) involves up to approximately 50% risk of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events mostly derived from DTX, such as neutropenic fever, peripheral neuropathy, and fluid retention [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Given the deterioration in patients\u0026rsquo; quality of life (QOL) following TP, current guidelines for HV disease have not yet resolved outstanding questions as to which patients will likely benefit most from TP or DT, including androgen receptor pathway inhibitor (ARPI) plus ADT.\u003c/p\u003e \u003cp\u003eA solution to solving the unmet needs for the optimal treatment choice for HV-mCSPC may be its subcategorization. HV is defined as having four or more bone metastases with at least one outside the spine and pelvis or having visceral metastases (VM) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In other words, it includes heterogeneous metastatic types covering bone metastasis (BM) with the extent of disease (EOD) 1 to 4, or VM with or without BM [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, we hypothesized that the subcategorization of such a heterogeneous disease would enable the identification of some metastatic patterns with mild prognostic impact, leading to better oncological management with both long-term survival and stable QOL by the avoidance of TP. We aimed to explore metastatic patterns with mild prognostic impact in synchronous HV-mCSPC by comparing survival outcomes between LV disease with BM of EOD1 (LV-EOD1) and HV diseases with BM of EOD1 to 4 (HV-EOD1-4) including lung metastasis (LM).\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study population\u003c/h2\u003e \u003cp\u003e We retrospectively reviewed the clinical data of 451 patients who received ADT or DT of ARPI or DTX plus ADT for mCSPC at Kitasato University Hospital between April 2004 and September 2023. Of the 145 patients with LV disease and 306 with HV disease, we focused on patients who had BM with and without LM, irrespective of the presence of distal lymph node metastasis. Patients with metachronous mCSPC, LV disease with an EOD2 or VM, except for LM alone, were excluded from the present study. Initial diagnosis of prostate cancer (PCa) was histologically confirmed in all cases.\u003c/p\u003e \u003cp\u003eData on patient characteristics were collected from medical charts. They included demographic data, Charlson Comorbidity Index [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], disease volume classified as HV or LV per CHAARTED criteria [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], EOD classified via bone scintigraphy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and prognostic variables including radiographic progression, castration-resistant prostate cancer (CRPC)-free survival (CFS) and overall survival (OS). All patients initially received ADT consisting of orchiectomy or luteinizing hormone-releasing agonists/antagonists, or ADT in combination with nonsteroidal antiandrogen.\u003c/p\u003e \u003cp\u003e This study was approved by the Institutional Review Board of Kitasato University School of Medicine and Kitasato University Hospital (Kanagawa, Japan) and was conducted in accordance with the Declaration of Helsinki, including the request to waive documentation of informed consent (B23-106, B22-102 and B24-120).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Definition of endpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint was OS, defined as the interval from the date of initiation of treatment for mCSPC to the date of death from any cause. The secondary endpoint was CFS, and CRPC was defined as PSA failure or radiographic progression; the former required a 25% and \u0026gt;\u0026thinsp;2 ng/mL rise in PSA four weeks apart from the nadir, regardless of the serum castration level according to the JUA guidelines [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Radiographic progression was determined based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. via CT or the appearance of one or more new BM via technetium-99 bone scanning [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e \u003cp\u003eKaplan\u0026ndash;Meier analysis was performed to evaluate OS and CFS for the overall cohort by tumor volume and EOD. Propensity score matching (PSM) was used to match potential covariates by a 1:1 matching ratio between LV-EOD1 and HV-EOD1-4 or HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2, including LM. The matched clinicopathological features involved age, initial PSA levels, Gleason score (GS), clinical T-stage, clinical N-stage, clinical M1a status, and type of initial treatment and radiation therapy (RT) for mCSPC. In cases with BM alone, OS was compared via the Kaplan\u0026ndash;Meier method between LV-EOD1 and HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;4, and CFS was compared between LV-EOD1 and HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2 disease. In cases with BM and LM, comparative analyses for the prognoses between LV-EOD1 and HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2, including LM, were performed. The prognostic impact of HV-EOD\u0026thinsp;\u0026ge;\u0026thinsp;3, including LM, was not evaluated because we had speculated that the prognostic impact of LM would not have been conclusive given the preexistence of some extent of prognostic difference between LV-EOD1 and HV-EOD\u0026thinsp;\u0026ge;\u0026thinsp;3 without LM (Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). With a focus on patients with BM plus LM, rPFS for LM was compared with CFS for the overall cohort via the Kaplan\u0026ndash;Meier method. Multivariate Cox regression analyses were performed to investigate the prognostic value of clinicopathological factors, including BM and LM in HV-mCSPC.\u003c/p\u003e \u003cp\u003ePatient characteristics were compared using the chi-squared test (or Fisher\u0026rsquo;s exact test, if appropriate) for categorical variables and the Mann\u0026ndash;Whitney U test for continuous variables. All statistical analyses were performed using Stata 14 for Windows (Stata, Chicago, IL, USA). All P values were two-sided, and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.1. Patient characteristics\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 451 included patients, 379 met the inclusion criteria. Table 1 shows the characteristics of 115 patients with LV-EOD1 and 264 with HV-EOD1-4, including LM. Among those with HV disease, 197 (74.6%) had BM alone, and 67 (25.4%) had BM plus LM. Among those with LM, 19 (46.3%), 12 (17.1%), 19 (25.3%), and 17 (21.8%) had an EOD 1, 2, 3, and 4, respectively.\u003c/p\u003e\n\u003cp\u003eIn comparison with LV-EOD1, HV disease had significantly higher initial PSA levels, significantly greater proportions of GS \u0026ge; 9, clinical T \u0026ge; 3b, clinical N1 and clinical M1a, and a significantly lower proportion of prostate-directed RTx (PDRT) for mCSPC (17.8% vs. 40.9%, P \u0026lt; 0.001). PDRT for HV-EOD1-4 was seen in 31.7% (n = 13), 20.0% (n = 14), 16.0% (n = 12) and 10.3% (n = 8) patients, respectively. Proportions of patients with ARPI or DTX for mCSPC in HV and LV diseases were similar (HV disease, n= 57, 21.6% vs. LV disease, n = 19, 16.5%, P = 0.33); each proportion of the intensified ADT in HV-EOD1-4 accounted for 17.1% (n = 7), 24.3% (n = 17), 26.7% (n = 20) and 16.7% (n = 13), respectively, and 5.3% (n = 3) of the patients with the intensified ADT for mCSPC received DTX for HV disease.\u003c/p\u003e\n\u003cp\u003eIn the PSM analysis, there were no major differences in patient demographics between the PSM cohort except for a significantly lower proportion of patients with RT and PDRT in HV-EOD \u0026ge; 2 (Table 2 and Supplementary Table S1). First subsequent systemic treatments for CRPC in the PSM cohort are shown in Supplementary Table S2. The proportions of patients with ARPI or DTX for CRPC were similar among HV-EOD \u0026le; 2, including LM and LV-EOD1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.2 Survival outcomes in the overall cohort\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up of patients with LV-EOD1 and HV-EOD1-4 was 53 and 30 months, respectively. In the overall cohort, Kaplan\u0026ndash;Meier analyses showed a significant difference in OS and CFS during these follow-up periods (Fig. 1 and Supplementary Fig. S2). The median OS and CFS for LV-EOD1 were 105 and 52.3 months, while those for HV-EOD1-4, including LM were 120 and 28.1, 89.6 and 25.9, 40.9 and 16.1, and 38.9 and 9.2 months, respectively (P \u0026lt; 0.001). No significant differences were seen in the OS and CFS between HV-EOD1 and LV-EOD1 (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.37-2.05, P = 0.81, and HR: 1.44, 95% CI: 0.77-2.71, P = 0.25, respectively). Moreover, no significant differences were seen in the OS between HV-EOD2 and LV-EOD1 (HR: 1.48, 95% CI: 0.87-2.54, P = 0.15), whereas HV-EOD2 had better CFS compared with LV-EOD1 (HR: 1.85, 95% CI: 1.19-2.88, P = 0.006). In patients with HV-EOD2, the number of BM \u0026le; 10 was associated with better survival outcomes compared to BM \u0026ge; 11 with a median OS of 96.2 vs. 59.1 months (HR: 0.65, 95% CI: 0.35-2.12, P = 0.43) and CFS of 30.6 vs. 16.1 months (HR: 0.33, 95% CI: 0.13-081, P = 0.025) (Supplementary Fig. S3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.3 Survival outcomes in the PSM cohort\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn terms of BM alone, median follow-up of EOD1-4 for HV and LV were 46.2 and 55.3, 38.1 and 40.6, 29.7 and 49.4, and 27.2 and 49.8 months, respectively. Kaplan\u0026ndash;Meier analyses showed that HV-EOD 1 had no significant impact on OS and CFS compared with LV-EOD1 (HR: 0.79, 95% CI: 0.27-2.28, P = 0.35, and HR: 0.81, 95% CI: 0.39-2.41, P = 0.83, respectively). Similar trends were seen with HV-EOD2 (HR: 0.94, 95% CI: 0.50-1.44, P = 0.52, and HR: 1.07, 95% CI: 0.65-1.77, P = 0.58, respectively) (Fig. 2 and Supplementary Fig. S4). In contrast, significantly worse OS was associated with HV-EOD3 (HR: 2.26, 95% CI: 1.20-4.25, P \u0026lt; 0.001) and HV-EOD4 (HR: 2.32, 95% CI: 1.40-3.83, P \u0026lt; 0.001) compared with LV-EOD1 (Supplementary Fig. S5).\u003c/p\u003e\n\u003cp\u003eIn patients with BM and LM, the median follow-up for HV and LV were 32.9 and 31.1 months in patients with EOD1 and 38.8 and 39.9 months in those with EOD2. LM accounted for 45% (n = 18) in HV-EOD1 and 16.7% (n = 11) in HV-EOD2. Kaplan\u0026ndash;Meier analyses showed no significant impact of HV-EOD1, including LM, on OS and CFS compared with LV-EOD1 (HR: 0.54, 95% CI: 0.23-1.25, P = 0.20, and HR: 0.77, 95% CI: 0.41-1.43, P = 0.44, respectively). Similar results were seen for HV-EOD2, including LM (HR: 1.02, 95% CI: 0.58-1.80, P = 0.94, and HR: 1.13, 95% CI: 0.71-1.77, P = 0.64, respectively) (Fig. 3 and Supplementary Fig. S6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.4 LM-\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003especific survival outcomes\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 67 patients with BM plus LM, 8 (11.9%) had the radiographic progression of LM, whereas 42 (62.7%) developed progression to CRPC for any reason with HR of 0.12 (95% CI: 0.09-0.28, P \u0026lt; 0.001) (Supplementary Table S3). The proportions of site-specific radiographic progression to CRPC significantly differed between BM (n = 20, 29.9%) and LM (n = 4, 6.0%) (P \u0026lt; 0.001), and the number of LM did not correlate with the progression to CRPC (solitary, n = 1, 1.5%; 2-10, n = 1, 1.5% and \u0026ge; 11, n = 2, 3.0%; P = 0.62).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.5 Multivariate Cox regression analyses for survival outcomes in HV disease\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariate analysis for OS demonstrated that EOD \u0026ge; 3 (HR: 2.03, 95% CI: 1.32-3.11, P = 0.001), GS \u0026ge; 9 (HR: 1.69, 95% CI: 1.12-2.53, P = 0.001) and ARPI or DTX plus ADT (HR: 0.39, 95% CI: 0.22-0.72, P = 0.002) were independent prognostic factors (Table 3). The analysis for CFS revealed EOD \u0026ge; 3 (HR: 2.64, 95% CI: 1.87-3.71, P \u0026lt; 0.001), GS \u0026ge; 9 (HR: 1.48, 95% CI: 1.05-2.10, P = 0.026) and T \u0026ge; 3b (HR: 1.57, 95% CI: 1.08-2.27, P = 0.018) and ARPI or DTX plus ADT (HR: 0.21, 95% CI: 0.12-0.36, P \u0026lt; 0.001,) as independent prognostic factors (Supplementary Table S4). LM did not have a significant impact on OS (HR: 1.20, 95% CI: 0.82-1.75, P = 0.35) and CFS (HR: 1.22, 95% CI: 0.76-1.95, P = 0.41).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eSince the advent of TP for mCSPC, optimal treatment intensity for HV disease has been a clinical dilemma. This study focused on patients who had BM with and without LM and found some metastatic patterns in HV disease that had a survival impact comparable to that in LV-EOD1. First, in cases with BM alone, PSM analysis revealed no significant difference in OS and CFS between LV-EOD1 and HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2. In HV-EOD2, BM\u0026thinsp;\u0026le;\u0026thinsp;10 was associated with better outcomes compared to BM\u0026thinsp;\u0026ge;\u0026thinsp;11 in the unadjusted cohort. Second, PSM analysis also showed that in spite of being a VM, LM, along with BM, had no significant impact on OS and CFS compared with LV-EOD1. The multivariate analysis confirmed this potential mild aggressive behavior of LM. Patients with HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2, including LM, accounted for 36.3% (111/306) of the entire present cohort of HV-mCSPC.\u003c/p\u003e \u003cp\u003eBM without VM comprises the most frequent metastatic pattern, accounting for approximately 85% of mCSPC, as seen in the Surveillance, Epidemiology, and End Results (SEER) and TITAN databases [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Hence, we assumed that subclassification of this dominant pattern of BM alone would reveal a range of oncological characters. The present PSM analysis notably indicates that HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2 should be prognostically distinguished from HV-EOD\u0026thinsp;\u0026ge;\u0026thinsp;3. In comparison with LV-EOD1, HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2 had no significant impact on OS and CFS, whereas HV-EOD\u0026thinsp;\u0026ge;\u0026thinsp;3 had significantly worse OS (HV-EOD3, HR: 2.26, 95% CI: 1.20\u0026ndash;4.25 and HV-EOD4, HR: 2.32, 95% CI: 1.40\u0026ndash;3.83). This mild aggressive potential of HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2 will likely enhance its validity given the similar proportion of the first subsequent treatment of ARPI and DTX for CRPC among the cohorts. Moreover, the comparable survival outcomes for HV-EOD1 and LV-EOD1 appear logical according to robust evidence of favorable prognosis for oligometastatic PCa, which covers only the number of metastases irrespective of the metastatic site [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In contrast, the HV-EOD2 prognosis may need to be considered with caution because of the wide range of BM (6\u0026ndash;20) in EOD2. The limited data on EOD-based analysis reported significantly worse OS for non-subclassified EOD2 than that for EOD1 in mCSPC initially treated with ADT (P\u0026thinsp;=\u0026thinsp;0.013) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In other words, as the present study found that BM\u0026thinsp;\u0026le;\u0026thinsp;10 was associated with a better prognosis, especially with CFS, EOD2 potentially represents the bifacial biology of oligometastatic or widespread PCa. Therefore, TP will likely pose a risk of over-treatment for HV-EOD2 consisting of BM\u0026thinsp;\u0026le;\u0026thinsp;10 in particular.\u003c/p\u003e \u003cp\u003eLM is most commonly seen with BM, accounting for 35% of mCSPC based on the nationwide study [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Another intriguing finding of the present study is that LM can be interpreted separately from the aggressive behavior of VM. For example, PSM analysis showed that OS and CFS in HV-EOD1, including LM, did not significantly differ from those in LV-EOD1 in spite of as much as 45% of LM in HV-EOD1. Moreover, LM infrequently progressed to CRPC compared with BM (6.0% vs. 29.9%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Although literature has dominantly referred to the prognostic impact of solitary LM as a case report, some clinical research previously reported consistent results with the present study [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]; one of the largest studies based on the SEER database including 16,643 synchronous mCSPC patients demonstrated comparable five-year survival of BM plus LM (22.1%) vs. BM alone (24.2%). A rationale for such a mild prognostic impact of LM potentially relies on two mechanisms. First, LM may have a typical genomic landscape of nonmetastatic PCa, as shown in a retrospective study for metachronous mCSPC, wherein PTEN, SPOP, and chromosome 8p alterations were frequently observed, whereas TP53 and DNA damage repair gene mutations were absent [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Second, LM, irrespective of primary tumor origin, may have a high immunogenic status based on a clustering analysis that showed high infiltration of myeloid dendritic cells and cytotoxic lymphocytes into the cancer cell and the LM stroma, compared to other metastatic sites, such as liver, brain, and bone [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The myeloid dendritic cells and cytotoxic lymphocytes are essential partners for the initial antitumor step. Hence, based on our clinical findings and the available data, during treatment decision-making for HV-mCSPC, the mere presence of LM does not qualify for TP.\u003c/p\u003e \u003cp\u003eAndrogen receptor (AR)-independence is a key indicator of the inclusion of DTX in the treatment of mCSPC because DTX is classified as taxane-based cytotoxic chemotherapy. Transcriptional analysis showed that DTX or RT provided additional OS benefits compared to ADT alone for the synchronous pattern (HR: 0.47, 95% CI: 0.30\u0026ndash;0.72), which had significantly lower hallmark androgen response compared with the metachronous pattern (3.15 vs. 3.32; P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). In contrast, the metachronous pattern did not correlate with the additional effect of DTX or RT, and yet, ARPI plus ADT favored more than ADT alone in the metachronous-LV disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Exploring clinical features with some extent of AR independence may help identify patients who would benefit from a DTX-included regimen, and such candidates, besides the synchronous pattern, may correspond to advanced clinicopathological features. For example, GS\u0026thinsp;\u0026ge;\u0026thinsp;9 harbored approximately twice as much low-AR activity as GS\u0026thinsp;\u0026le;\u0026thinsp;7 (22% vs. 10%) even in treatment-na\u0026iuml;ve primary PCa, and seminal vesicle invasion in prostatectomy specimen correlated with ETS family, which could activate AR independent of the ligand (odds ratio: 2.27 vs. negative ETS member, P\u0026thinsp;=\u0026thinsp;0.004) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. From the perspectives of clinical data, significant additional OS benefit of DTX to ADT alone was found for GS\u0026thinsp;\u0026ge;\u0026thinsp;8 (HR: 0.68, 95% CI: 0.53\u0026ndash;0.87) in a subgroup analysis of the CHAARTED trial with mature follow-up, and that more favorable HR was demonstrated for a metastatic pattern of HV and T4 in a systematic review and meta-analysis based on STOPCAP program (HR: 0.38, 95% CI: 0.26\u0026ndash;0.53) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Hence, AR independence explains independent worse prognostic values of GS\u0026thinsp;\u0026ge;\u0026thinsp;9, EOD\u0026thinsp;\u0026ge;\u0026thinsp;3, and T\u0026thinsp;\u0026ge;\u0026thinsp;3b, as shown in the present multivariate analysis, which included only a limited proportion of patients with DTX (5.3%). DTX should thus be considered for HV-mCSPC with aggressive characteristics, and the recent evidence currently favored TP among the DTX-inclusive regimen [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In other words, our findings show that EOD\u0026thinsp;\u0026le;\u0026thinsp;2, especially without high GS and advanced T-stage, qualifies for DT with ARPI irrespective of the presence of LM.\u003c/p\u003e \u003cp\u003eOur study had some limitations. First, the present retrospective design might have introduced bias into the process of patient selection. Second, the proportions of RT and PSA\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml were not closely matched via PSM analysis between HV-EOD\u0026thinsp;\u0026ge;\u0026thinsp;2 and LV-EOD1. In part, this was because of the preexistence of significantly greater proportions of the two variables for HV-EOD1-4 than LV-EOD1 in the unadjusted cohort. This tendency may reflect the promising results of PDRT for LV-mCSPC as shown in the STAMPEDE trial and the positive correlation between tumor volume and PSA levels, thereby endorsing our findings of potential mild prognostic impact of HV-EOD2 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Third, the definition of CRPC in this study differs from that proposed in EAU guidelines, leading to relatively short periods of CFS when PSA failure alone occurred. Thus, in this study, we set the primary endpoint as OS, which has the same definition per any guideline.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eOur findings show that EOD\u0026thinsp;\u0026le;\u0026thinsp;2, irrespective of the presence of LM, even though classified as HV disease, has a survival impact comparable to LV-EOD1, accounting for approximately 35% of the entire HV disease cohort. Hence, among factors considered during decision-making, such as physical and social factors, clinicians should focus not only on tumor volume but also on the details of the tumor characteristics. Specifically, EOD\u0026thinsp;\u0026le;\u0026thinsp;2, especially without high GS and advanced T-stage, irrespective of the presence of LM, will be well qualified for DT, sparing DTX for the more formidable CRPC. Randomized trials are needed to validate our findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests:\u003c/h2\u003e\n\u003cp\u003eAll authors have no competing interests to disclose.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eConceptualization, D.K.; Data curation, D.K.; Formal analysis, D.K.; Investigation, T.H., K.T., S.H., S.S., T.S., M.I.; Methodology, D.K., H.T.; Writing-original draft, D.K., H.T.; Writing-review \u0026amp; editing, D.K., H.T.; Supervision, K.M. All authors reviewed the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data sets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKyriakopoulos, C. E. et al. 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Clinical significance of pulmonary metastases in stage D2 prostate cancer patients. \u003cem\u003eProstate Cancer Prostatic Dis.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 159\u0026ndash;163 (2002).\u003c/li\u003e\n\u003cli\u003eFonseca, N. M. et al. Genomic features of lung-recurrent hormone-sensitive prostate cancer. \u003cem\u003eJCO Precis Oncol\u003c/em\u003e. \u003cstrong\u003e6\u003c/strong\u003e, e2100543 (2022).\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a-Mulero, S. et al. Lung metastases share common immune features regardless of primary tumor origin. \u003cem\u003eJ. Immunother. Cancer\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, e000491 (2020).\u003c/li\u003e\n\u003cli\u003eSutera, P. A. et al. Transcriptomic and clinical heterogeneity of metastatic disease timing within metastatic castration-sensitive prostate cancer. \u003cem\u003eAnn. Oncol.\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 605\u0026ndash;614 (2023).\u003c/li\u003e\n\u003cli\u003eSweeney, C. J. et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. \u003cem\u003eLancet Oncol.\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, 323\u0026ndash;334 (2023).\u003c/li\u003e\n\u003cli\u003eSpratt, D. E. et al. Transcriptomic heterogeneity of androgen receptor activity defines a de novo low AR-active subclass in treatment na\u0026iuml;ve primary prostate cancer. \u003cem\u003eClin. Cancer Res.\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, 6721\u0026ndash;6730 (2019).\u003c/li\u003e\n\u003cli\u003eTomlins, S. A. et al. Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes. \u003cem\u003eEur. Urol.\u003c/em\u003e \u003cstrong\u003e68\u003c/strong\u003e, 555\u0026ndash;567 (2015).\u003c/li\u003e\n\u003cli\u003eVale, C. L. et al. Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials. \u003cem\u003eLancet Oncol.\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e, 783\u0026ndash;797 (2023).\u003c/li\u003e\n\u003cli\u003eSmith, M. R. et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. \u003cem\u003eN. Engl. J. Med\u003c/em\u003e. \u003cstrong\u003e386\u003c/strong\u003e, 1132\u0026ndash;1142 (2022).\u003c/li\u003e\n\u003cli\u003eParker, C. C. et al\u003cem\u003e.\u003c/em\u003e Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e392\u003c/strong\u003e, 2353\u0026ndash;2366 (2018).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Characteristics of patients at baseline\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"702\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLV-E\u003c/strong\u003e\u003cstrong\u003eOD1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en = 264\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en = 115\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eAge, median, yr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e73 (46-91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e72 (45-92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eCharlson Comorbidity Index \u0026ge; 1, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e88 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e35 (30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003ePSA, median, range (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e443 (2-13042)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e96 (5-6503)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eGleason score \u0026ge; 9, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e156 (59.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e50 (43.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eClinical T \u0026ge; 3b, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e186 (70.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e68 (59.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eClinical N1, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e159 (60.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e56 (48.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eMetastatic status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Lymph node metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e74 (26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e14 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Lung metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e67 (25.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Bone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e264 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e115 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; EOD1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e41 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e115 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; EOD2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e70 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; EOD3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e75 (28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; EOD4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e78 (29.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eTreatment for CSPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;ADT or CAB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e207 (78.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e96 (83.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 127px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;ARPI or DTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e57 (21.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e19 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eRadiation therapy for CSPC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e51 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e51 (44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eProstate-directed radiation therapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e47 (17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e47 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eCastration-resistant prostate cancer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e179 (67.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e51 (44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 289px;\"\u003e\n \u003cp\u003eDeath, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 150px;\"\u003e\n \u003cp\u003e129 (48.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e39 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 127px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 702px;\"\u003e\n \u003cp\u003eAbbreviation: HV, high-volume; LV, low-volume; EOD, extent of disease; PSA, prostate-specific antigen; CSPC, castration-sensitive prostate cancer; ADT, androgen-deprivation\u0026nbsp;therapy; CAB, combined androgen blockade; ARPI, androgen receptor pathway inhibitor; DTX, docetaxel.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Patient background after propensity score matching between HV-EOD1-4 and LV-EOD1\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"1063\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables,\u0026nbsp;\u003c/strong\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHV-EOD1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 22)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLV-EO\u003c/strong\u003e\u003cstrong\u003eD1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 22)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHV-EOD2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 57)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLV-EO\u003c/strong\u003e\u003cstrong\u003eD1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 57)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHV-EO\u003c/strong\u003e\u003cstrong\u003eD3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 53)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLV-EOD1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 53)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHV-EO\u003c/strong\u003e\u003cstrong\u003eD4\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 56)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLV-EOD1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 56)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eAge \u0026ge; 75, yr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e19 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e19 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e28 (52.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e29 (54.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e25 (44.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e27 (48.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eCharlson Comorbidity Index \u0026ge; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e18 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e19 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e18 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e17 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e17 (30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e19 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003ePSA \u0026ge; 100 ng/ml at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e16 (72.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e41 (71.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e34 (59.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e46 (86.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e35 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e49 (87.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e36 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eGleason score \u0026ge; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e15 (68.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e30 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e30 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e37 (69.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e35 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e41 (73.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e38 (67.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eClinical T \u0026ge; 3b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e38 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e38 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e40 (75.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e37 (69.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e38 (67.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e39 (69.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eClinical N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e12 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e29 (50.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e30 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e29 (54.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e29 (54.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e30 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e31(45.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eMetastatic status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Lymph node metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11(19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Bone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e22 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e22 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e57 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e57 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e53 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e53 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e56 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e56 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eTreatment for CSPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;ADT or CAB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e20 (90.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e21 (95.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e43 (75.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e43 (75.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e38 (71.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e40 (75.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e46 (82.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e45 (80.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;ARPI or DTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e15 (28.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e13 (24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eRadiation therapy for CSPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e25 (43.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e35 (66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e33 (58.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eProstate-directed radiation therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e24 (42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e33 (62.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e33 (58.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eCRPC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e34 (59.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e30 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e26 (49.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e22 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e47 (83.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e31 (55.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 217px;\"\u003e\n \u003cp\u003eDeath, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e21 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e17 (29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e39 (73.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e15 (28.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e39 (69.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e26 (46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\" valign=\"top\" style=\"width: 1063px;\"\u003e\n \u003cp\u003eAbbreviation: HV, high-volume; LV, low-volume; EOD, extent of disease; PSA, prostate-specific antigen; CSPC, castration-sensitive prostate cancer; ADT, androgen-deprivation\u0026nbsp;therapy; CAB, combined androgen blockade; ARPI, androgen receptor pathway inhibitor; DTX, docetaxel; CRPC, castration-resistant prostate cancer.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3. A multivariate COX analysis of overall survival in patients with HV disease\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95%CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eEOD \u0026ge; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eEOD \u0026le; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e2.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.32-3.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eAge \u0026ge; 75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAge \u0026le; 74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.74-1.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003ePSA at baseline \u0026ge; 100 g/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003ePSA \u0026lt; 100 ng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.39-1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eGleason score \u0026ge; 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eGleason score \u0026le; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.12-2.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eClinical T \u0026ge; 3b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eClinical T \u0026le; 3a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.77-1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eClinical N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eClinical N0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.60-1.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eClinical M1a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAbsence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.92-2.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eLung metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eAbsence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.76-1.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eARPI or DTX for CSPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eADT or CAB for CSPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.22-0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eRadiation therapy for CSPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.58-1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 633px;\"\u003e\n \u003cp\u003eAbbreviation: HV, high-volume; HR, hazard ratio; CI, confidence interval; EOD, extent of disease; PSA, prostate-specific antigen; CSPC, castration-sensitive prostate cancer; ARPI, androgen receptor pathway inhibitor; DTX, docetaxel; ADT, androgen-deprivation therapy; CAB, combined androgen blockade.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"prostate cancer, treatment, prognosis, high-volume disease, metastatic pattern, extent of disease","lastPublishedDoi":"10.21203/rs.3.rs-6006181/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6006181/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe aimed to investigate the prognostic impact of the extent of bone metastasis (BM) and lung metastasis (LM) in patients with high-volume (HV) castration-sensitive prostate cancer (CSPC). We retrospectively reviewed 379 patients with synchronous metastatic CSPC, focusing on BM patterns, with and without LM. According to the CHAARTED criteria, 115 and 264 patients were respectively classified as having low-volume (LV) disease with BM of extent of disease 1 (LV-EOD1) and HV disease with BM of EOD 1 to 4 (HV-EOD1-4; 197 with BM alone and 67 with BM plus LM). We compared overall survival (OS) between the LV-EOD1 and HV-EOD1-4 groups after propensity score matching (PSM). We used multivariate Cox regression analysis to assess the risk factors for OS in HV-EOD1-4 patients. There was no significant difference in the OS between LV-EOD1 group and HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2 group (in patients with BM alone or after adding patients with BM plus LM) after PSM. A multivariate analysis for OS in HV-EOD1-4, including LM, demonstrated that EOD\u0026thinsp;\u0026ge;\u0026thinsp;3 and Gleason score\u0026thinsp;\u0026ge;\u0026thinsp;9 were independent risk factors, and LM had no significant role. Therefore, HV-EOD\u0026thinsp;\u0026le;\u0026thinsp;2, regardless of LM, has a prognostic impact comparable to that of LV-EOD1.\u003c/p\u003e","manuscriptTitle":"Metastatic pattern with mild prognostic impact in high-volume castration-sensitive prostate cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-14 10:54:13","doi":"10.21203/rs.3.rs-6006181/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5e70b891-6776-4982-a79f-6163c7cd4c36","owner":[],"postedDate":"February 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44260046,"name":"Health sciences/Oncology"},{"id":44260047,"name":"Health sciences/Urology"}],"tags":[],"updatedAt":"2025-02-14T10:54:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-14 10:54:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6006181","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6006181","identity":"rs-6006181","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}