PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0309941 PONE-D-24-15232 Research Article Medicine and health sciencesOncologyCancers and neoplasmsNeurological tumorsBrain metastasis Medicine and health sciencesNeurologyNeurological tumorsBrain metastasis Medicine and health sciencesOncologyCancers and neoplasmsGenitourinary tract tumorsProstate cancer Medicine and health sciencesUrologyProstate diseasesProstate cancer Medicine and health sciencesOncologyMetastasis Medicine and health sciencesOncologyBasic cancer researchMetastasis Biology and life sciencesAnatomyLymphatic systemLymph nodes Medicine and health sciencesAnatomyLymphatic systemLymph nodes Medicine and health sciencesDiagnostic medicineCancer detection and diagnosis Medicine and health sciencesOncologyCancer detection and diagnosis People and placesPopulation groupingsEthnicitiesAfrican American people Research and analysis methodsResearch designClinical research designSurvival analysis Research and analysis methodsMathematical and statistical techniquesStatistical methodsSurvival analysis Physical sciencesMathematicsStatisticsStatistical methodsSurvival analysis Medicine and health sciencesDiagnostic medicinePrognosis Impact of different visceral metastatic sites on survival in metastatic prostate cancer patients Outcomes of visceral metastasis in prostate cancer https://orcid.org/0000-0003-1225-9100 Lai Gu-Shun Conceptualization Data curation Formal analysis Investigation Methodology Writing – original draft Writing – review & editing 1 2 Chen Chuan-Shu Writing – review & editing 1 2 3 Cheng Jason Chia-Hsien Conceptualization Writing – review & editing 4 Li Jian-Ri Methodology Writing – review & editing 1 2 3 4 5 Yang Cheng-Kuang Writing – review & editing 1 2 6 Lin Chia-Yen Writing – review & editing 1 2 7 Hung Sheng-Chun Writing – review & editing 1 2 3 Chiu Kun-Yuan Writing – review & editing 1 2 8 https://orcid.org/0000-0003-3032-0198 Wang Shian-Shiang Conceptualization Formal analysis Methodology Writing – original draft Writing – review & editing 1 2 8 * Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan Department of Urology, Taichung Veterans General Hospital, Taichung, Taiwan Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan Department of Medicine and Nursing, Hungkuang University, Taichung, Taiwan Jenteh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan Bauckneht Matteo Editor IRCCS Ospedale Policlinico San Martino, Genova, Italy, ITALY

The authors have declared that no competing interests exist.

 * E-mail: urologyssw@gmail.com 6 9 2024 2024 19 9 e0309941 2 5 2024 21 8 2024 2024 Lai et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction

Visceral metastasis is an important predictor for poor outcomes in prostate cancer, however, the prognostic significance surrounding the specific sites of visceral metastasis remains unclear. The aim of this study was to evaluate the impact of different visceral metastatic sites on survival in patients with prostate cancer.

 Methods

We identified patients with metastatic prostate cancer between January 1, 2010 and December 31, 2023 using the TriNetX database. Patients were divided into 4 cohorts according to their specific metastatic sites: lung metastases, brain metastases, liver metastases, and bone metastases. Survival analysis was calculated using the Kaplan-Meier method and Cox regression models.

 Results

In total, 59,875 patients diagnosed with metastatic prostate cancer were identified, with 39,495 (65.2%) having bone metastases, 7,573 (12.5%) lung metastases, 5,240 (8.7%) brain metastases, and 7,567 (12.5%) liver metastases. The median overall survival was 44.4 months for patients with bone metastases, 31.9 months for lung metastases, 9.6 months for brain metastases, and 10 months for liver metastases. Lung metastases were associated with an improved survival when compared with liver and brain metastases. For patients with two visceral metastatic sites or concomitant bone metastases, liver metastases were related to worse outcomes. Asian patients experienced better OS than Caucasian and African American patients in visceral metastatic prostate cancer.

 Conclusion

Patients with lung metastases experienced better survival outcomes in prostate cancer with only one visceral metastatic site. Liver metastases were associated with worse outcomes when there were two visceral metastatic sites combined or concomitant bone metastases. Asian patients displayed improved survival rates when compared with both Caucasian and African American patients in visceral metastatic prostate cancer.

 The author(s) received no specific funding for this work. Data Availability All relevant data are within the manuscript and its Supporting Information files. Introduction

Prostate cancer is the fourth most frequently diagnosed cancer in men and the eighth leading cause of cancer death worldwide. More than 1.4 million prostate cancer cases were diagnosed, with 397,430 patients dying of the disease in 2022 [1]. Although there are good survival outcomes for those with localized disease, the risk of death still remains high for metastatic prostate cancer (mPC) patients. Several studies have demonstrated the adverse impact of visceral metastases on overall survival (OS) for patients with metastatic prostate cancer (mPC) [2–13]. However, information regarding the significance of specific visceral metastases on patient prognosis remains scarce. A meta-analysis taken from randomized clinical trials conducted by Halabi et al. identified lung and liver metastases, when compared with bone and other non-visceral metastases, as being risk factors for poor prognosis in patient diagnosed with metastatic castration resistant prostate cancer (mCRPC) [9]. Tappero et al., in a population-based analysis, reported on there being better outcomes for patients with lung metastases when compared with other visceral metastases [13]. Despite the results of these studies, there remains limited data regarding the prognostic significance of specific metastatic sites for patient diagnosed with metastatic prostate cancer.

Herein, we performed a retrospective analysis using the TriNetX database in order to investigate the influence of specific sites of visceral metastases on overall survival in metastatic prostate cancer patients. We also evaluated the outcomes of visceral metastases with regard to different non-visceral metastases, as well as to race.

 Methods Data source, study population, and outcomes

We utilized the TriNetX network to conduct a retrospective analysis. Data were retrieved from the US Collaborative Network, which includes 57 healthcare organizations across the United States. Data collection and analysis for this research were performed on the TriNetX platform in February, 2024.

Through the network we identified patients aged ≥18 years who had been diagnosed with mPC during the period of January 1, 2010 and December 31, 2023. The diagnosis of mPC was performed according to the International Classification of Diseases, tenth edition, Clinical Modification (ICD-10-CM): ICD-10-CM C61, as well as ICD-10-CM: C77, C78, C78.7, C79.3, or C79.5 in order to confirm the distant metastases. The index date was set to be the date of diagnosis of distant metastasis. Patients enrolled were divided into 3 cohorts according to the sites of visceral metastases: brain, liver, and lung metastasis, while patients with bone metastasis without visceral metastases were included for comparison. Enrolled patients could either have or not have non-visceral metastasis. The primary end point was OS, which was calculated from the date of diagnosis of distant metastases (the index date) to the date of death or censored at the end of the study, whichever occurred first. We also performed survival analyses for patients with mPC among different races and concomitant non-visceral metastases.

 Statistical analyses

For analyzing patients baseline characteristics, mean with standard deviation (SD) was utilized for continuous variables, and number with percentage for categorical variables. Kaplan-Meier survival analysis along with the log-rank test and Cox proportional regression model were used for the evaluation of OS among the different cohorts. All statistical analyses were performed on the TriNetX network with a p value <0.05 being considered statistically significant.

 Ethics in research

This research was carried out after receiving approval from the Institutional Review Board (IRB) of Taichung Veterans General Hospital (IRB number: SE:22220A). Given the TriNetX platform provides only de-identified data, the ethics committee approved a waiver of informed consent.

 Results Demographics and characteristics

A total of 59,875 patients with metastatic prostate cancer were identified on the TriNetX database. Of them, 39,495 (65.2%) had bone metastases, 7,573 (12.5%) lung only visceral metastases, 5,240 (8.7%) brain only visceral metastases, and 7,567 (12.5%) liver only visceral metastases. Compared to the patients in the bone metastases cohort, patients in the visceral metastases cohort were at a significantly younger age, possessed a poor Eastern Cooperative Oncology Group (ECOG) performance status, and had more lymph node metastases, comorbidities, and a higher proportion of receiving novel hormone agents or chemotherapy. Patient demographics and characteristics are demonstrated in Table 1.

10.1371/journal.pone.0309941.t001 Baseline characteristics for patients with visceral and bone metastatic prostate cancer.
Bone n = 39,495 Lung n = 7573 Brain n = 5240 Liver n = 7567
Age at index, years, mean (SD) 73.7 (9.78) 72.6 (10.4)* 70.4 (9.95)* 71.8 (9.71)*
Race, n (%)
Caucasians 28,491 (71) 5452 (72)* 3825 (73)* 5523 (73)*
African Americans 5793 (15) 985 (13)* 681 (13)* 1059 (14)*
Asians 1028 (3) 227 (3) 157 (3) 151 (2)
Others/unknown 4183 (10) 909 (12) 577 (11) 834 (11)
BMI at index, mean (SD) 27.2 (5.53) 26.8 (5.64)* 26.2 (5.39)* 26.4 (5.44)*
ECOG at index, mean (SD) 0.924 (0.965) 1.2 (0.942)* 1.38 (1.01)* 1.23 (1.04)
PSA at index, ng/ml, mean (SD) 214 (1041) 184 (663)* 332 (1020)* 288 (866)*
Non-visceral metastatic sites, n (%)
Lymph Node 56 (3.5) 1673 (19)* 1263 (21)* 1354 (16)*
Bone 39,495 (100) 2338 (26) 2460 (40) 2138 (26)
Systemic therapies, n (%)
Abiraterone 2315 (6) 660 (9)* 758 (14)* 853 (11)*
Enzalutamide 1694 (7) 509 (6.7)* 568 (11)* 671 (9)*
Apalutamide 290 (0.7) 67 (0.8) 70 (1.3)* 75 (0.9)
Docetaxel 648 (1.6) 446 (6)* 628 (12)* 662 (9)*
Cabazitaxel 96 (0.2) 98 (1)* 198 (4)* 209 (3)*
Comorbidity, n (%)
Diabetes Mellitus 6923 (18) 2383 (27)* 1416 (23)* 2348 (28)*
Hypertension 16,748 (42) 2390 (61)* 3457 (57)* 4915 (59)*
Cerebrovascular disease 4044(10) 1400 (16)* 1153 (19)* 1268 (15)*
Ischemia heart disease 8086 (20) 2920 (33)* 1767 (29)* 2498 (30)*

BMI: Body Mass Index; ECOG, Eastern Cooperative Oncology Group; PSA, Prostate-Specific Antigen; SD, Standard Deviation.

* Statistical difference from the bone metastases group.

 Outcomes of overall population and different visceral metastatic sites

The median OS for mPC patients with visceral metastases was 15.7 months [95% confidence interval (CI) 15–16.2] and the survival probability at the 12th month was 24.7% (95% CI 54.1–55.5).

The median OS was 44.4 months (95% CI 43.1–45.5) for patients with bone metastases, 31.9 months (95% CI 29.8–34.4) for lung metastases, 9.6 months (95% CI 8.9–10.4) for brain metastases, and 10 months (95% CI 9.4–10.6) for liver metastases. In the bone metastases cohort, the survival probability at the 12th month was 72.2% (95% CI 76.7–77.7), 66.4% (95% CI 65.3–67.5) for the lung metastases cohort, 46.3% (95% CI 44.9–47.7) for the brain metastases cohort, and 46.2% (95% CI 45–47.4) for the liver metastases cohort (Fig 1 and S1 File). In Cox regression models, for patients with one site of visceral metastases, mPC patients with brain [Hazard ratio (HR) 1.692, 95% CI 1.623–1.765, p<0.0001] and liver metastases (HR 1.671, 95% CI 1.595–1.749, p<0.0001) experienced a poorer prognosis when compared to the lung metastases patients. There was no statistical difference seen in OS between the brain and liver metastases cohorts (Table 2).

10.1371/journal.pone.0309941.g001 Kaplan-Meier analysis of overall survival for prostate cancer patients with bone or one visceral metastatic site.

CI: confidence interval; OS: overall survival.

 10.1371/journal.pone.0309941.t002 Cox regression analysis of overall survival for patients with visceral metastases.
HR 95% CI p-value HR 95% CI p-value
Site of metastases (one site)
Bone (n = 39,495) Reference 0.775 0.748 0.802 <0.0001
Lung (n = 7,573) 1.29 1.245 1.355 <0.0001 Reference
Brain (n = 5,240) 2.246 2.166 2.333 <0.0001 1.671 1.595 1.749 <0.0001
Liver (n = 7,567) 2.3 2.229 2.379 <0.0001 1.692 1.623 1.765 <0.0001
Site of metastases (two sites)
Brain + Lung (n = 1,453) Reference 0.878 0.813 9494 0.001
Liver + Lung (n = 3,471) 1.138 1.054 1.23 0.001 Reference
Brain + Liver (n = 716) 1.707 1.529 1.906 <0.0001 1.488 1.349 1.64 <0.0001
Visceral metastases with concomitant bone metastases
Lung + Bone (n = 2,604) Reference 0.76 0.96 0.824 <0.0001
Brain + Bone (n = 1,620) 1.319 1.213 1.436 <0.0001 Reference
Liver + Bone (n = 2,418) 1.643 1.524 1.772 <0.0001 1.27 1.164 1.38 <0.0001
Visceral metastases with concomitant lymph node metastases
Lung + Lymph node (n = 1,307) Reference 0.613 0.512 0.735 <0.0001
Brain + Lymph node (n = 282) 1.63 1.361 1.952 <0.0001 Reference
Liver + Lymph node (n = 998) 1.706 1.513 1.922 <0.0001 1.06 0.886 1.269 0.5205
Visceral metastases with concomitant bone and lymph nodes metastases
Lung + Bone + Lymph node (n = 1,841) Reference 0.723 0.643 0.812 <0.0001
Brain + Bone + Lymph node (n = 243) 1.396 1.242 1.568 <0.0001 Reference
Liver + Bone + Lymph node (n = 1,453) 1.641 1.499 1.796 <0.0001 1.187 1.056 1.334 0.004
Race
Caucasians (n = 19,490) Reference 1.081 1.031 1.135 0.0015
African Americans (n = 3.737) 0.925 0.881 0.971 0.0015 Reference
Asians (n = 789) 0.627 0.56 0.702 <0.0001 0.681 0.604 0.768 <0.0001
Clinical T stage
cT2 Reference
cT3,4 1.133 1.003 1.28 0.0452
Lymph node metastases
No Reference
Yes 1.129 1.03 1.238 0.0099

HR: Hazard ration; 95% CI: 95% confidence interval.

 Impact of two visceral metastatic sites on outcomes

We subsequently evaluated the outcomes for mPC patients who had two visceral metastases. The median OS was 8 months (95%CI 6.8–9.2) for patients with brain + lung metastases, 6.6 months (95%CI 5.8–7.4) for liver + lung metastases, and 3.1 months (95% CI 2.4–3.8) for liver + brain metastases (Fig 2 and S2 File). In Cox regression models, patients diagnosed with brain + lung metastases experienced better outcomes when compared to the liver + lung metastases (HR 1.138, 95% CI 1.054–1.23, p<0.0001) and liver + brain metastases patients (HR 1.707, 95% CI 1.529–1.906, p<0.0001). Moreover, liver + brain metastases (HR 1.488, 95% CI 1.349–1.64, p<0.0001) were associated with a poor OS when compared to liver + lung metastases (Table 2).

10.1371/journal.pone.0309941.g002 Kaplan-Meier analysis of overall survival for prostate cancer patients with two visceral metastatic sites.

CI: confidence interval; OS: overall survival.

 Impact of concomitant non-visceral metastases on outcomes

In mPC patients with visceral metastases and concomitant bone metastases, median OS was 17 months (95% CI 14.5–19.1) for lung + bone metastases, 8.2 months (95% CI 7.2-.8) for brain + bone metastases, and 5.4 months (95% CI 4.8–6.2) for liver + bone metastases (Fig 3 and S3 File). Patients with liver + bone metastases experienced a worse OS when compared with brain + bone (HR 1.27, 95% CI 1.164–1.138, p<0.0001) and lung + bone metastases patients (HR 1.643, 95% CI 1.524–1.772, p<0.0001) (Table 2).

10.1371/journal.pone.0309941.g003 Kaplan-Meier analysis of overall survival for prostate cancer patients with bone and visceral metastases.

CI: confidence interval; OS: overall survival.

In mPC patients with visceral metastases and concomitant lymph node metastases, median OS was 42.2 months (95% CI 0.8–54.1) for lung + lymph node metastases, 13.5 months (95% CI 6.9–19.9) for brain + lymph node metastases, and 12.1 months (95% CI 9.9–13.7) for liver + lymph node metastases (Fig 4 and S4 File). Lung + lymph node metastases was shown to be a factor for better OS when compared with brain + lymph node (HR 1.63, 95% CI 1.361–1.952, p<0.0001) and liver + lymph nodes metastases (HR 1.706, 95% CI 1.513–1.922, p<0.0001). There was no significant difference seen in OS between brain + lymph node and liver + lymph node metastases (Table 2).

10.1371/journal.pone.0309941.g004 Kaplan-Meier analysis of overall survival for prostate cancer patients with lymph node and visceral metastases.

CI: confidence interval; LN: lymph node; OS: overall survival.

In mPC patients with visceral metastases and concomitant bone and lymph node metastases, median OS was 16 months (95% CI 13.6–18.1) for lung + bone + lymph node metastases, 8 months (95% CI 6.8–10.7) for brain + bone + lymph node metastases, and 5.6 months (95% CI 4.6–6.7) for liver + bone + lymph node metastases (Fig 5 and S5 File). Patients with liver + bone + lymph node metastases experienced a worse survival outcome when compared with both brain + bone + lymph node (HR 1.187, 95% CI 1.056–1.334, p = 0.004) and lung + bone + lymph node metastases (HR 1.641, 95% CI 1.499–1.796, p<0.0001) (Table 2).

10.1371/journal.pone.0309941.g005 Kaplan-Meier analysis of overall survival for prostate cancer patients with bone, lymph node, and visceral metastases.

CI: confidence interval; LN: lymph node; OS: overall survival.

 Impact of race on outcomes

We conducted survival analyses for mPC patients with visceral metastases among different races (Fig 6 and S6 File) and found that Caucasian patients had a poorer OS when compared with African American (HR 0.925, 95% CI 0.881–0.971, p<0.0001) and Asian patients (HR 0.627, 95% CI 0.56–0.702, p<0.0001). Asian patients were associated with an improved survival compared with African American patients (HR 0.681, 95% CI 0.604–0.768, p<0.0001) (Table 2).

10.1371/journal.pone.0309941.g006 Kaplan-Meier analysis of overall survival among different races for patients with visceral metastatic prostate cancer.

CI: confidence interval; OS: overall survival.

 Discussion

In his study, we performed a retrospective analysis to compare the impact of specific visceral metastases sites on survival in patients with metastatic prostate cancer in a real-world setting. In patients having one visceral metastatic site with or without lymph node metastases, lung metastases were associated with improved outcomes when compared with brain or liver metastases. When combined with bone metastases or two visceral metastatic sites, liver metastasis was a factor for the worst OS when compared with lung or brain metastases. For OS among different races, Caucasian patients experienced poorer survival, while Asian patients experienced better outcomes.

In this study, we found that mPC patients with liver metastases had a median OS of 10 months. Liver metastases were a factor for worse outcomes than lung and non-visceral metastases. These findings are consistent with the prior studies, which had reported a median OS of 9–14 months for mPC patients with liver metastases, with these patients presenting as a group having a poor prognosis [8–13].

Additionally, we found that patients with lung metastases exhibited a worse OS than those with non-visceral metastases (bone or lymph node). The results are similar to the previous studies and further confirm the poorer outcomes which result from the presence of visceral metastases than those seen in non-visceral metastases [8–12].

Limited data regarding outcomes of prostate cancer with brain metastases have been reported, which may be attributed to the lower incidence of brain metastases. In 2018, Shou et al., in a population-based study using the Surveillance, Epidemiology, and End Results (SEER) database, demonstrated that patients with brain metastases may exhibit better outcomes than those with liver metastases [11]. In 2023, Tappero et al., using the SEER database, reported a poor prognosis for liver and brain metastases when compared with lung metastases, with no difference being seen in survival between liver and brain metastases [13]. In this study, we found that liver and brain metastases were similar in OS for mPC patients with only one visceral metastases site. However, for mPC patients with two visceral metastatic sites or one visceral metastatic site with concomitant bone metastases, brain metastases may be associated with improved survival when compared with liver metastases. These findings may provide clinicians with better risk stratification and evaluation for these patients.

In this study, we found that Asian patients with visceral metastases experienced survival advantages more so than Caucasian and African American patients. This finding is consistent with the available prior literature, which shows Asian patients with metastatic prostate cancer having better OS [14–17]. The differences in genomics, lifestyle and/or treatment responsiveness may have contributed to these results. The survival outcomes seen between African American and Caucasian patients with mPC are controversial. Several studies have reported improved survival rates for African American patients when compared to Caucasian patients when receiving therapies [14, 18–22]. Our study also revealed that African American patients with visceral metastatic prostate cancer exhibited better OS than Caucasian patients. This may be explained by the increased immune response in African American patients during treatments when compared to the Caucasian patients [14].

There were limitations in our study. First, the retrospective design of the present study may have led to selection bias. Second, we could not assess the information regarding disease burden, such as the number or size of a specific visceral metastasis. Third, the detailed data, such as castration sensitive or resistant prostate cancer, BRCA gene mutation status, or family history of prostate cancer, were either not available or inadequate for analysis from the database. Fourth, our research lacked the information on methodology for diagnosis and follow-up, such as computed tomography, magnetic resonance imaging, bone scan or positron emission tomography, and different image tools may affect the diagnostic rate of metastases. Despite these limitations, our analysis included a large population diagnosed with visceral metastatic prostate cancer, and the results may offer clinicians useful information toward predicting a patient’s prognosis or for the better design of trials for these patients.

 Conclusion

For prostate cancer patients with visceral metastases, patients with lung metastases experience survival benefits when compared to those with either liver or brain metastases. When combining two visceral metastatic sites or concomitant bone metastases, liver metastases were associated with worse outcomes. Asian patients experienced better OS than both Caucasian and African American patients diagnosed with visceral metastatic prostate cancer.

 Supporting information Values for Kaplan-Meier survival analysis in prostate cancer patients with bone or one visceral metastatic site.

(XLSX)

 Values for Kaplan-Meier survival analysis in prostate cancer patients with two visceral metastatic sites.

(XLSX)

 Values for Kaplan-Meier survival analysis in prostate cancer patients with bone and visceral metastases.

(XLSX)

 Values for Kaplan-Meier survival analysis in prostate cancer patients with lymph node and visceral metastases.

(XLSX)

 Values for Kaplan-Meier survival analysis in prostate cancer patients with bone, lymph node, and visceral metastases.

(XLSX)

 Values for Kaplan-Meier survival analysis among different races in patients with visceral metastatic prostate cancer.

(XLSX)

The data used in this research was from the TriNetX network.

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JAMA Netw Open. 2022;5:e2142093. doi: 10.1001/jamanetworkopen.2021.42093 34985518 10.1371/journal.pone.0309941.r001 Decision Letter 0 Bauckneht Matteo Academic Editor 2024 Matteo Bauckneht This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

29 Jul 2024

PONE-D-24-15232Impact of different visceral metastatic sites on survival in metastatic prostate cancer patientsPLOS ONE

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Matteo Bauckneht

Academic Editor

PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors performed a very interesting analysis based on the work of Tappero et al. using the SEER databases. They successfully demonstrated that different metastatic sites serve as predictors of varying survival rates in patients with metastatic prostate cancer (PCa). The authors can boast a large population, solid methodology, and results that align with the previous work of Tappero, despite being based on a different population and database. The paper is well-written and easily readable. The tables and figures are well-crafted, presenting fundamental information without redundancy. I particularly appreciated the summary of median survival within the Kaplan-Meier analysis.

However, I have a few suggestions for improvement:

1. In the analysis of race/ethnicity, I recommend using the terms "African Americans" and "Caucasians" instead of "Black" and "White," respectively. Additionally, please note that "Black" was incorrectly reported as "Blake" in the summary.

2. I suggest adding the lack of information on the BRCA status of patients as a limitation.

3. Additionally, the absence of data on family history of PCa should be mentioned among the limitations.

4. The limitations should also include the absence of details regarding the modality of diagnosis and follow-up (i.e., CT scan, bone scintigraphy, PET-CT scan).

A major revision is required to address these points.

Reviewer #2: Authors' work is interesting. I read with pleasure the full manuscript, written in good English. It is noteworthy to implement the limitation section. Indeed, data regarding the primary diagnosis methodology, such as CT, PET should be added. With minor revision, the paper will be suitable for publication

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Reviewer #1: Yes: Nicola Longo

Reviewer #2: Yes: SIMONE MORRA

**********

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

 10.1371/journal.pone.0309941.r002 Author response to Decision Letter 0 Submission Version 1

7 Aug 2024

Dear Reviewers:

I am deeply grateful for the time and effort you dedicated to reviewing my article. Your feedback and thoughtful questions have been incredibly valuable in refining my work. I appreciate your constructive suggestions and am committed to addressing each point you raised as follows.

Reviewer #1:

1. In the analysis of race/ethnicity, I recommend using the terms "African Americans" and "Caucasians" instead of "Black" and "White," respectively. Additionally, please note that "Black" was incorrectly reported as "Blake" in the summary.

The “Blake” and “White” have changed to "African Americans" and "Caucasians", respectively, in the revised manuscript. Thank you for your recommendation.

2. I suggest adding the lack of information on the BRCA status of patients as a limitation.

The lack of data on BRCA mutation status of patients has been added in the limitation section. Thank you for your recommendation.

3. Additionally, the absence of data on family history of PCa should be mentioned among the limitations.

The absence of information on family history of prostate cancer has been added in the limitation section. Thank you for your recommendation.

4. The limitations should also include the absence of details regarding the modality of diagnosis and follow-up (i.e., CT scan, bone scintigraphy, PET-CT scan).

The lack of data regarding the methodology for diagnosis and follow-up has been added in the limitation section. Thank you for your recommendation.

Reviewer #2:

The lack of data regarding the methodology for diagnosis and follow-up has been added in the limitation section. Thank you for your recommendation.

Submitted filename: Response to Reviewers.docx

 10.1371/journal.pone.0309941.r003 Decision Letter 1 Bauckneht Matteo Academic Editor 2024 Matteo Bauckneht This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

22 Aug 2024

Impact of different visceral metastatic sites on survival in metastatic prostate cancer patients

PONE-D-24-15232R1

Dear Dr. Lai,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Matteo Bauckneht

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors exhaustively replied to all the concerns raised. Therefore, the manuscript is suitable in its current form

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: SIMONE MORRA

**********

 10.1371/journal.pone.0309941.r004 Acceptance letter Bauckneht Matteo Academic Editor 2024 Matteo Bauckneht This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

29 Aug 2024

PONE-D-24-15232R1

PLOS ONE

Dear Dr. Lai,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

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on behalf of

Dr. Matteo Bauckneht

Academic Editor

PLOS ONE