Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review

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Methods A systematic search was conducted on PubMed, Google Scholar, and ScienceDirect for original articles published until February 2024 that compared tumour characteristics, biochemical markers, and adverse effects associated with these treatments. The risk of bias from each study was assessed using the Newcastle Ottawa Scale and Risk of Bias-2 (ROB-2) tool. Results Eleven studies meeting the inclusion criteria were analysed. Both subcapsular orchiectomy and pharmacological ADT effectively reduced tumour size and prostate-specific antigen (PSA) levels. Subcapsular orchiectomy was linked to higher surgical complication rates. At the same time, due to its systemic pharmacological mechanisms, pharmacological ADT carries a greater risk of metabolic side effects, such as weight gain and insulin resistance. Conclusions Both subcapsular orchiectomy and pharmacological ADT are viable options for prostate cancer treatment. However, their differing safety and pharmacological profiles highlight the need for personalised treatment strategies based on individual patient factors and preferences. PROSPERO registration CRD42025634678 (17/01/2025). " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/14-254/v2", "name": "Examining Differences in Pathological Outcomes and Safety for Prostate..." } } ] } Home Browse Examining Differences in Pathological Outcomes and Safety for Prostate... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Frapancah E and Soerohardjo I. Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.12688/f1000research.161612.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Revised Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] Erick Frapancah https://orcid.org/0009-0009-7292-7693 1 , Indrawarman Soerohardjo 2 Erick Frapancah https://orcid.org/0009-0009-7292-7693 1 , Indrawarman Soerohardjo 2 PUBLISHED 10 Nov 2025 Author details Author details 1 Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 2 Staff of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Erick Frapancah Roles: Formal Analysis, Project Administration, Writing – Original Draft Preparation Indrawarman Soerohardjo Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Oncology gateway. Abstract Purpose The purpose of this systematic review is to investigate differences in pathological outcomes and safety between subcapsular orchiectomy and pharmacological androgen deprivation therapy (ADT) for prostate cancer management. Methods A systematic search was conducted on PubMed, Google Scholar, and ScienceDirect for original articles published until February 2024 that compared tumour characteristics, biochemical markers, and adverse effects associated with these treatments. The risk of bias from each study was assessed using the Newcastle Ottawa Scale and Risk of Bias-2 (ROB-2) tool. Results Eleven studies meeting the inclusion criteria were analysed. Both subcapsular orchiectomy and pharmacological ADT effectively reduced tumour size and prostate-specific antigen (PSA) levels. Subcapsular orchiectomy was linked to higher surgical complication rates. At the same time, due to its systemic pharmacological mechanisms, pharmacological ADT carries a greater risk of metabolic side effects, such as weight gain and insulin resistance. Conclusions Both subcapsular orchiectomy and pharmacological ADT are viable options for prostate cancer treatment. However, their differing safety and pharmacological profiles highlight the need for personalised treatment strategies based on individual patient factors and preferences. PROSPERO registration CRD42025634678 (17/01/2025). READ ALL READ LESS Keywords Keywords Prostate cancer, Subcapsular orchiectomy, Androgen deprivation therapy, Pathological outcomes, Comparative study, Systematic review Corresponding Author(s) Indrawarman Soerohardjo ( [email protected] ) Close Corresponding author: Indrawarman Soerohardjo Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Frapancah E and Soerohardjo I. 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 work is properly cited. How to cite: Frapancah E and Soerohardjo I. Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.12688/f1000research.161612.2 ) First published: 03 Mar 2025, 14 :254 ( https://doi.org/10.12688/f1000research.161612.1 ) Latest published: 10 Nov 2025, 14 :254 ( https://doi.org/10.12688/f1000research.161612.2 ) Revised Amendments from Version 1 1. Study Inclusion We acknowledge that the studies by Arogundade et al. and Islam et al. did not provide direct comparisons between surgical and medical ADT. Their inclusion was therefore inconsistent with our predefined inclusion criteria. We have now excluded these studies from the analysis and categorized them as “studies not meeting the inclusion criteria” in the PRISMA flowchart (Screening section). After reanalysis, we confirmed that their exclusion did not alter the overall results or conclusions of our systematic review. 2. Literature Search Clarification We also acknowledge the proofreading oversight that resulted in the placeholder phrase “The literature search started in [insert start date]”. This has been corrected, and we confirm that our literature search comprehensively included all eligible studies published up to February 2024. 3. High Heterogeneity We summarized the key findings from each included study in a structured manner, focusing on oncologic outcomes, survival, and adverse effects between surgical orchiectomy and medical ADT. We qualitatively explored potential sources of heterogeneity, including differences in study design, treatment duration, follow-up periods, and outcome definitions, to better understand variations across studies. Methodological quality was assessed using standardized criteria to support reliable interpretation. We discussed both consistent and divergent findings, providing a balanced narrative synthesis of the current evidence base. 4. Minor Revisions and Formatting Improvements We addressed all minor issues, including citation style inconsistencies and figure quality. The PRISMA flowchart has been replaced with a higher-resolution version, and statistical terminology has been refined for clarity. Deleted text is shown with strikethrough and yellow highlight, while revised or added text is marked in red. Reference numbering was updated following the exclusion of the two studies. 1. Study Inclusion We acknowledge that the studies by Arogundade et al. and Islam et al. did not provide direct comparisons between surgical and medical ADT. Their inclusion was therefore inconsistent with our predefined inclusion criteria. We have now excluded these studies from the analysis and categorized them as “studies not meeting the inclusion criteria” in the PRISMA flowchart (Screening section). After reanalysis, we confirmed that their exclusion did not alter the overall results or conclusions of our systematic review. 2. Literature Search Clarification We also acknowledge the proofreading oversight that resulted in the placeholder phrase “The literature search started in [insert start date]”. This has been corrected, and we confirm that our literature search comprehensively included all eligible studies published up to February 2024. 3. High Heterogeneity We summarized the key findings from each included study in a structured manner, focusing on oncologic outcomes, survival, and adverse effects between surgical orchiectomy and medical ADT. We qualitatively explored potential sources of heterogeneity, including differences in study design, treatment duration, follow-up periods, and outcome definitions, to better understand variations across studies. Methodological quality was assessed using standardized criteria to support reliable interpretation. We discussed both consistent and divergent findings, providing a balanced narrative synthesis of the current evidence base. 4. Minor Revisions and Formatting Improvements We addressed all minor issues, including citation style inconsistencies and figure quality. The PRISMA flowchart has been replaced with a higher-resolution version, and statistical terminology has been refined for clarity. Deleted text is shown with strikethrough and yellow highlight, while revised or added text is marked in red. Reference numbering was updated following the exclusion of the two studies. See the authors' detailed response to the review by Fakhri Taher See the authors' detailed response to the review by Chaidir Arif Mochtar See the authors' detailed response to the review by Syah Mirsya Warli READ REVIEWER RESPONSES Introduction Prostate cancer remains a prominent global health concern, affecting millions of men annually and contributing significantly to cancer-related morbidity and mortality. 1 Among the principal treatment modalities, androgen deprivation therapy (ADT) is a cornerstone in managing advanced prostate cancer by lowering testosterone levels to inhibit tumour growth and progression. Historically, two primary approaches have been employed to achieve androgen suppression: surgical androgen deprivation, typically via subcapsular orchiectomy, and pharmacological ADT utilising gonadotropin-releasing hormone (GnRH) agonists or antagonists. Although both methods aim to achieve castrate-level testosterone suppression, they differ markedly in invasiveness, reversibility, and patient acceptability. 2 Subcapsular orchiectomy, introduced by Riba et al. (1947), involves surgically removing the subcapsular tissue of the testes, effectively halting testosterone production while preserving the external testicular structure. In contrast, pharmacological ADT employs pharmaceutical agents to achieve androgen suppression without surgical intervention. Until the late 1980s, surgical castration was the predominant approach; however, the advent of extended-release GnRH analogues revolutionised the field, offering a non-invasive alternative with psychological and procedural benefits. 3 Despite their shared therapeutic goal, emerging evidence suggests that subcapsular orchiectomy and pharmacological ADT may yield distinct pathological outcomes and safety profiles, prompting the need for a systematic evaluation of these differences. 4 ADT-induced hypogonadism is associated with several adverse effects, including osteoporosis, an increased risk of fractures, cardiovascular complications, metabolic disturbances, and anaemia. However, there is limited direct comparison of the adverse effect profiles and clinical outcomes between surgical and medical ADT. Existing studies provide inconsistent findings regarding the superiority of one approach over the other in terms of disease control and management of side effects, underscoring the necessity for comprehensive investigation. 5 – 7 This systematic review aims to evaluate and compare pathological outcomes, including disease progression, survival rates, and adverse effects, in prostate cancer patients undergoing either subcapsular orchiectomy or pharmacological ADT. By synthesising evidence from clinical studies and trials, the review seeks to elucidate the impact of these treatment modalities on long-term outcomes and patient well-being. These findings will provide valuable insights to guide clinicians and patients in selecting treatment strategies that optimise therapeutic efficacy while prioritising quality-of-life considerations. 8 Methods This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. 9 The literature search was performed for evaluate and compare pathological outcomes, including disease progression, survival rates, and adverse effects, in prostate cancer patients undergoing either subcapsular orchiectomy or pharmacological ADT up to February 2024. The protocol of the present systematic review was registered with PROSPERO (CRD42025634678) (date of registration—17/01/2025). Study selection A complete literature search was performed across three electronic databases: PubMed, Science Direct, and Google Scholar. This systematic review included peer-reviewed literature published in the English language. The papers published until February 2024 that met the pre-determined inclusion and exclusion criteria were included in this review. Inclusion criteria: Examined pathological outcomes, including tumour characteristics, biochemical markers, or adverse effects, in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT). Directly or indirectly, outcomes between these two treatment methods were compared through randomised controlled trials, cohort studies, case-control studies, and observational studies. Involved adult male patients with a confirmed diagnosis of prostate cancer. Were published in peer-reviewed journals. Exclusion criteria: Reviews, commentaries, editorials, or conference abstracts without original data. They did not provide adequate information on pathological outcomes relevant to the comparison. They were conducted on non-human subjects. The full text was unavailable. Search strategy The search strategy involved using Medical Subject Headings (MeSH) terms and keywords like “prostate cancer,” “prostate neoplasm,” “androgen deprivation therapy,” and “subcapsular orchiectomy.” The search was limited to English-language articles with no regional restrictions. Additionally, manual searches were done in relevant journals and the reference lists of selected studies to find any articles not indexed in the electronic databases. Selection process The databases were searched by two authors (RIC and IDW) using the search strategy, followed by the removal of duplicates, if any. Title and abstract screening was performed by both authors independently, where each responded with a ‘Yes,’ ‘No,’ or ‘Maybe’ for each entry based on the inclusion and exclusion criteria. Any disagreements were resolved through discussion by mutual consensus. The articles included the following title and abstract screening and underwent independent full-text review by both authors. Disagreements were resolved through discussion with a second author (IDW). The articles that qualified at this stage were finalised for quality appraisal and data extraction for this systematic review. Quality assessment The methodological quality of the included studies was assessed using tools appropriate to their design, such as the Cochrane Risk of Bias Tool for randomised controlled trials and the Newcastle-Ottawa Scale for observational studies. Each study was evaluated for potential biases in selection, performance, detection, attrition, reporting, and other relevant domains. Data extraction Two independent reviewers evaluated the titles and abstracts of identified studies for relevance according to the inclusion and exclusion criteria. Full-text articles of studies deemed potentially relevant were obtained and assessed for eligibility. Disagreements between reviewers regarding study eligibility were resolved through discussion and consensus. Data extraction was conducted using a standardised form, capturing details such as study characteristics (author, publication year, and study design), participant demographics (sample size, age, and allocation), interventions (type of ADT or subcapsular orchiectomy), and outcomes of interest (pathological outcomes and adverse effects). Results The PRISMA flow diagram representing the results of the review process is depicted in Figure 1 . Figure 1. PRISMA flowchart of the included studies. 9 An initial search yielded 129 publications. After removing duplicate entries, 70 records were screened for eligibility. Of these, 46 records were excluded for being unrelated to the topic. Following a detailed evaluation, four records were ineligible articles because they did not meet the inclusion criteria, three were inaccessible in full text, and four did not have pathological outcomes. Ultimately, 11 records met the inclusion criteria and were incorporated into the review that consisted of 7 Randomized Controlled Trials (RCTs), 3 retrospective cohort, and 1 prospective cohort studies ( Figure 1 ). Summaries of the selected studies are provided in Table 1 . Table 1. Eligible studies and summary characteristics. Study, year Number of patients Study type Nation Subcapsular orchiectomy Medical androgen deprivation therapy Outcome Kaisary et al., 1991. 358 Randomized Clinical Trial UK 144 patients with a mean age of 72.5 ± 55.89 148 patients with a median age of 71.8 (49-86) - Both Zoladex and orchiectomy were effective in lowering testosterone levels in metastatic prostate cancer cases. - Both had similar response rates, treatment failure times, and survival outcomes. Østergren et al., 2019. 58 Randomized Clinical Trial Denmark 28 patients with a mean age of 72 ± 8.8 29 patients with a mean age of 75 ± 5.8 - There is no significant difference in fasting plasma glucose changes between group treated with a gonadotropin-releasing hormone agonist and orchiectomy group in men with advanced prostate cancer. Østergren, et al., 2017. 58 Randomized Clinical Trial Denmark 28 patients with a mean age of 72 ± 8.8 29 patients with a mean age of 75 ± 5.8 - Triptorelin achieves lower testosterone levels within the castrate range more effectively than orchiectomy in men with prostate cancer. Parmar et al., 1987. 15 Randomized Clinical Trial UK 7 patients (data for patient's age were not applicable) 8 patients (data for patient's age were not applicable) - No notable difference is observed in response or disease progression between the D-Trp-6-LHRH and orchiectomy groups. - Long-acting D-Trp-6-LHRH was a safe and effective alternative to orchiectomy for treating advanced prostate cancer. Ryan et al., 1998. 292 Randomized Clinical Trial UK 144 (data for patients' age were not applicable) 148 (data for patient's age were not applicable) - Repeated Zoladex treatments lowered testosterone to castrate levels, with similar results in response, duration, treatment failure time, and survival between both groups. Soloway et al., 1991. 162 Randomized Clinical Trial USA 83 patients with a median age of 70 (46-92) 81 patients with a median age of 68 (48—82) - Zoladex and orchiectomy were equally effective in treating Stage D2 prostate cancer - Both lowering testosterone to castrate levels within the first month. Vogelzang et al., 1995. 283 Randomized Clinical Trial USA 145 patients with a median age of 69 (46-92) 138 patients with a median age of 69 (44-95) - In patients with Stage D2 prostate cancer, goserelin and orchiectomy had similar outcomes - There is no significant effect of treatments or baseline testosterone levels on survival outcomes. Garje, et al., 2020. 33,585 Retrospective cohort Multiple geographic location 1,328 patients >65 years old and 657 65 years old and 10,753 <65 years old - Surgical castration is as effective as medical castration for metastatic prostate cancer, with no difference in overall survival (OS) outcomes. Selvi et al., 2019. 123 Retrospective cohort Turkey 63 patients with a mean age of 70.22 ± 5.65 60 patients with a mean age of 69.83 ± 5.28 - Subcapsular orchiectomy caused fewer psychosocial side effects compared to total orchiectomy and showed similar outcomes to LHRH analog treatment. Tan, et al., 2020. 523 Retrospective cohort Singapore 151 with a median age of 73 372 with a median age of 73 - Surgical Orchidectomy (SO) and Medical Castration offer similar results and side effects in treating metastatic prostate cancer (mPCa). - SO is more cost-effective for long-term androgen deprivation therapy (ADT). Vargas et al., 2016. 102 Prospective cohort Brazil 46 patients with a mean age of 72.4 ± 7.7 56 patients with a mean age of 67.3 ± 6.5 - LHRH analogs caused a bigger drop in hemoglobin levels, worse insulin resistance, more severe anemia, and greater bone loss compared to bilateral orchiectomy, especially in diabetic patients. Using the Cochrane Risk of Bias tool, four studies were identified as having a low risk of bias, three were classified as having an unclear risk, and one article was determined to have a high risk of selection bias. Based on the Newcastle Ottawa Scale, one study was of moderate quality, and four were of high quality in Tables 2 and 3 . Table 2. Newcastle Ottawa Scale Cohort. Study Selection Comparability Outcome Total (9/9) Representative of the exposed cohort Selection of external control Ascertainment of exposure Outcome of interest not present at the start of the study Comparability of Cohorts Assessment of outcomes Sufficient follow-up time Adequacy of follow-up Main Factor Additional Factor Garje, et al., 2020 * * * * * 0 * * * 8/9 Selvi et al., 2020 * 0 * * * 0 * * * 7/9 Tan, et al., 2020 * * * * * 0 * * * 8/9 Vargas et al., 2016 * * * * * 0 * * * 8/9 Table 3. ROB-2. Author Randomisation process Deviations from the intended interventions Missing outcome data Measurement of the outcome Selection of the reported result Overall Kaisary et al. 1991 Low Low Low High Moderate Moderate Østergren et al. 2019 Moderate Moderate Low Moderate Low Moderate Østergren, et al. 2017 Low Moderate Low Low Low Low Parmar et al. 1987 High Low Low High High High Ryan et al. 1988 Low Low Low High Low Low Soloway et al. 1991 Moderate Low Low Low High Low Vogelzang et al. 1995 Low Moderate Low High High Moderate Østergren et al. conducted a comparative study examining the impact of Luteinizing Hormone-Releasing Hormone (LHRH) agonists and subcapsular orchiectomy on testosterone reduction in men with prostate cancer. After adjusting for baseline levels of testosterone, DHEAS, and androstenedione, serum testosterone levels were 29% lower (95% CI 17.2, 41.7) following triptorelin therapy compared to subcapsular orchiectomy (p < .001). Within 48 weeks of follow-up, all patients achieved testosterone levels below 30 ng/dL. The proportion of patients with testosterone levels below 20 ng/dL was 79% for subcapsular orchiectomy and 97% for triptorelin at 12 weeks (p < .05), 92% and 90% at 24 weeks (p = .73), and 87% and 100% at 48 weeks (p < .05), respectively. While LH and FSH levels increased as expected after subcapsular orchiectomy, they were suppressed in the triptorelin group, with LH consistently remaining below the lower reference limit (LRL) except for three patients at the 24-week visit. One of these patients had testosterone levels above the castrate threshold (>50 ng/dL) at that visit, but levels returned to the castrate range by 48 weeks. No significant differences were observed between the two treatment groups regarding their effects on estradiol or adrenal androgens over time. Both groups experienced significant reductions in DHEAS, androstenedione, 17-hydroxyprogesterone, and estradiol levels (p < .001). 10 In 2019, Østergren et al. conducted a study to compare the metabolic effects of two androgen deprivation therapy (ADT) methods for advanced prostate cancer: gonadotropin-releasing hormone (GnRH) agonists and orchiectomy. Both treatments showed minimal differences in fasting plasma glucose levels, with a relative change of 0.2 mmol/L at 48 weeks (95% CI -0.1; 0.4), suggesting neither approach significantly affected blood sugar levels. However, the orchiectomy group experienced more pronounced increases in total fat mass, subcutaneous adipose tissue (SAT), and body fat percentage compared to the GnRH agonist group. By 48 weeks, these increases were +2.06 kg, +133 cm 3 , and +1.3%, respectively, all statistically significant (P < .05). Additionally, the orchiectomy group showed a more significant average weight gain of 3.30 kg compared to the GnRH agonist group (P = .02), primarily attributed to increases in fat mass, especially SAT. A moderate correlation was observed between the rise in fat mass and SAT and the increase in insulin resistance, as measured by HOMA-IR (r = 0.436, P < .001 and r = 0.366, P < .001, respectively). These findings suggest that orchiectomy may pose a higher risk of fat accumulation and insulin resistance compared to GnRH agonists. The study highlights that the choice of ADT can influence metabolic outcomes, with orchiectomy being more strongly associated with increased fat accumulation and a higher potential for insulin resistance. 11 Tan et al. conducted a study to assess and compare the outcomes, adverse effects (AEs), and costs of two primary androgen deprivation therapy (ADT) methods for metastatic prostate cancer (mPCa): surgical orchiectomy (SO) and medical castration (MC). The findings offer valuable insights into these treatments’ efficacy, safety, and economic aspects. The study revealed that SO and MC are similarly effective in managing metastatic prostate cancer, as demonstrated by comparable PSA response rates and androgen suppression levels. The PSA response rate (PSA <1 ng/ml) was 65.6% for SO and 67.2% for MC, showing no significant difference in their ability to reduce PSA levels, a key marker of prostate cancer activity. Time to castrate resistance, defined as the period until cancer becomes unresponsive to ADT, was also similar between the two groups (18 months for SO versus 16 months for MC). 12 Furthermore, overall survival rates were comparable, with median survival times of 42 months for SO patients and 38.5 months for MC patients, indicating equivalent effectiveness in prolonging life. Significant differences were observed in the adverse effect profiles of SO and MC. Both treatments showed similar outcomes regarding haemoglobin level changes, newly diagnosed diabetes mellitus, coronary artery disease events, and skeletal-related fractures, suggesting comparable safety profiles. One key finding was the cost advantage of SO over MC. After accounting for government subsidies and inflation, the median cost of SO was significantly lower than that of MC (5275 vs. 9185.80), highlighting SO’s greater cost-effectiveness. 13 Regarding survivability, Garje et al. reported 5-year overall survival (OS) rates of 24.3% for patients receiving medical castration and 18.3% for those undergoing surgical castration. Although an initial analysis showed a notable survival difference between the groups, this disparity was no longer statistically significant after multivariable adjustments for various factors. This suggests that the choice of castration method may not play a decisive role in determining overall survival. 13 A prospective study by Vargas et al. examines notable metabolic changes, including insulin resistance and the onset of diabetes mellitus, in prostate cancer patients undergoing androgen deprivation therapy (ADT). The study revealed that patients treated with LHRH analogues experienced worse insulin resistance outcomes than those undergoing bilateral orchiectomy. Specifically, the LHRH analogue group demonstrated higher fasting glucose levels, basal insulin levels, and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) scores, indicating an elevated risk of diabetes. Anaemia was also observed, with patients on LHRH analogues showing a more significant reduction in haemoglobin levels than those who underwent surgical castration, suggesting a more substantial impact of LHRH analogues on erythropoiesis (red blood cell production). Furthermore, bone health was negatively affected across all ADT recipients, with LHRH analog-treated patients exhibiting more pronounced bone demineralisation, particularly in the lumbar spine. The study reported a significantly more significant loss of bone mineral density (BMD) in the lumbar spine for the LHRH analogue group than those with bilateral orchiectomy. 5 A randomised clinical trial conducted by Soloway et al. revealed that the effectiveness of the two treatments was highly comparable. An objective response—complete response, partial response, or stable disease—was achieved in 81% of patients treated with Zoladex and 78% of those undergoing orchiectomy. This difference was not statistically significant, indicating similar efficacy between the treatments. Additionally, the time to treatment failure, primarily attributed to disease progression, showed no significant variation between the Zoladex and orchiectomy groups, further supporting their comparable effectiveness over time. 14 Selvi et al. compared the effects of total orchiectomy, subcapsular orchiectomy, and LHRH analogue therapy in patients with hormone-sensitive metastatic prostate cancer. The study concluded that all three treatments effectively achieved therapeutic castration levels, successfully reducing testosterone to the desired range. Patients undergoing subcapsular orchiectomy reported higher satisfaction levels than those undergoing total orchiectomy, suggesting that subcapsular orchiectomy, being less invasive, may be more favourable due to its organ-preserving nature and perceived less radical approach. Health-related quality of life (HRQoL) scores were also higher in the subcapsular orchiectomy group, likely due to the reduced psychological impact of this organ-preserving method. Furthermore, the frequency and severity of post-traumatic stress (PTS) and post-traumatic stress disorder (PTSD) were lower in patients who underwent subcapsular orchiectomy compared to those who had total orchiectomy. Patient satisfaction in the subcapsular orchiectomy group was comparable to those receiving LHRH analogue therapy. 15 Research conducted by Kaisary et al. compared the efficacy of the LHRH analogue Zoladex with orchiectomy in managing metastatic prostatic carcinoma. The study found that both Zoladex and orchiectomy were equally effective in reducing serum testosterone levels to the surgically castrate range, demonstrating their success in achieving the necessary hormonal suppression for treating the condition. The time between the two groups was comparable until treatment failure or patient withdrawal. Additionally, at a median follow-up of two years, no significant difference in overall survival was observed between patients receiving Zoladex and those undergoing orchiectomy. 16 A study by Agarwala et al. provides an in-depth comparison of the outcomes between surgical and medical castration for treating metastatic hormone-sensitive prostate cancer (mHSPC). The analysis revealed no significant difference in the time to progression (TTP) between patients undergoing bilateral orchiectomy and those receiving medical castration. The mean TTP was 13.9 months for the bilateral orchiectomy group and 13.8 months for the medical castration group, indicating that both methods are equally effective in delaying the progression of mHSPC to castration-resistant prostate cancer. The mean nadir PSA levels were lower in the surgical group (4.7 ng/ml) compared to the medical group (9.8 ng/ml). However, the time required to reach the nadir PSA level was nearly identical, averaging 8.7 months in the surgical group and 8.8 months in the medical group. This suggests that while both treatments successfully lower PSA levels, surgical castration may achieve a more significant reduction. Additionally, testosterone suppression was more pronounced in the surgical group during the follow-up period, though the difference was not statistically significant. 17 Vogelzang et al. conducted a study comparing the efficacy and safety of goserelin, a luteinizing hormone-releasing hormone (LHRH) agonist, with orchiectomy (surgical removal of the testes) in patients with Stage D2 prostate cancer. By the fourth week, serum testosterone levels had decreased to castrate levels in both groups and remained stable throughout the treatment. Reductions in acid and alkaline phosphatase levels were also observed, indicating a positive response to treatment. The objective response rates were comparable between the groups, 82% for goserelin and 77% for orchiectomy, with no statistically significant differences after adjusting for stratification factors. Median time to treatment failure was nearly the same for both treatments, and survival times showed no significant differences, demonstrating similar effectiveness. Both treatments were well tolerated, with the most common adverse events reported being pain, hot flashes, and lower urinary tract symptoms. The pattern of adverse events was consistent across both groups, with no significant differences noted. 18 A Randomized Controlled Trial conducted by Parmar et al. in 1985 sought to evaluate and compare the safety and efficacy of two treatments for advanced prostate carcinoma: a slow-release formulation of D-Trp-6 luteinizing hormone-releasing hormone (D-Trp-6-LHRH) microcapsules and orchiectomy. Both treatment approaches effectively suppressed testosterone levels and reduced prostatic acid phosphatase levels, demonstrating equivalent effectiveness in disease management. A treatment response, either improvement or stabilization, was observed in 87% of patients treated with D-Trp-6-LHRH microcapsules and 81% of those who underwent orchiectomy, highlighting comparable efficacy between the two methods. Testosterone suppression-related side effects were similar in both groups, suggesting that the safety profile of D-Trp-6-LHRH microcapsules aligns with that of orchiectomy. Follow-up evaluations revealed a slight trend toward reduced psychological distress in patients receiving hormonal treatment, although no statistically significant differences in psychological outcomes were detected between the groups. 19 In 1987, Parmar et al. conducted a study revealing that the psychological distress linked to orchiectomy, the surgical removal of one or both testicles, was only marginally more significant than that experienced by patients receiving alternative treatments. Both orchiectomy and D-Trp-6-LHRH therapy were shown to be effective in managing advanced prostate cancer. Orchiectomy provides the benefit of an immediate reduction in testosterone levels without requiring continuous medication. However, it is associated with the risks inherent to surgical procedures and anaesthesia, and some patients may not respond to this treatment. 20 Ryan et al. conducted a detailed study comparing the efficacy of the LH-RH analogue Zoladex and orchidectomy in managing metastatic prostate cancer. The findings demonstrated that administering Zoladex every 28 days was equally effective as orchidectomy in reducing serum testosterone levels to the castrate range. Both treatment approaches yielded comparable subjective and objective response rates. Furthermore, the two groups had no significant differences in the duration of response, time to treatment failure, or survival rates. Follow-up data collected ten months after trial recruitment concluded that Zoladex and orchidectomy are equally effective options for treating metastatic prostate cancer. 21 Discussion The ongoing debate between surgical and chemical methods for achieving castration-level testosterone in prostate cancer treatment highlights differing preferences. Many patients tend to favour pharmacological approaches over surgery due to their non-invasive nature, avoidance of permanent physical changes, and potentially reduced risk of immediate postoperative complications. 22 , 23 Reducing testosterone levels plays a vital role in managing prostate cancer by slowing disease progression and potentially enhancing patient survival. 24 , 25 A study suggests that LHRH agonist therapy is more effective in achieving testosterone reduction to the target castrate range. 16 , 20 LHRH agonists ensure sustained testosterone suppression over time. With an appropriate dosing schedule, patients can consistently maintain castrate testosterone levels through regular injections. In contrast, surgical outcomes may differ based on the method and thoroughness of the orchiectomy. 26 In contrast to subcapsular orchiectomy, a surgical intervention, LHRH agonists are delivered via injections. This non-invasive approach minimizes the risk of surgical complications, including postoperative scrotal swelling or hematoma, which some patients experience after orchiectomy. Additionally, pharmacological treatment provides the benefit of being reversible. 27 If side effects become unmanageable or a patient decides to discontinue treatment, ceasing LHRH agonist therapy allows testosterone levels to gradually return to their normal range. 28 Subcapsular orchiectomy achieves androgen deprivation by surgically removing the testes, which serve as the primary source of testosterone production. Testosterone plays a critical role in driving prostate cancer progression and PSA production. By eliminating testosterone production, this surgical approach effectively lowers PSA levels. Similarly, medical androgen deprivation therapy (ADT) achieves over 95% suppression of androgen levels, reducing testosterone to below 50 ng/dL. This substantial decrease in testosterone also results in a significant reduction in PSA levels. 4 , 17 The findings of this review demonstrate that both subcapsular orchiectomy and medical ADT effectively reduce prostate-specific antigen (PSA) levels. These results align with the systematic review by Zhang et al., which reported similar outcomes between these treatment modalities. However, it is essential to acknowledge that the high heterogeneity among studies included in this review influences the ability to draw definitive conclusions. Some studies prioritized oncological parameters, such as testosterone and PSA levels, while others examined progression, metabolic effects, psychological impacts, or survival outcomes associated with these treatments. 13 , 14 , 16 , 18 – 20 A recent study by Osunaiye et al. observed a significant correlation between the percentage changes in serum testosterone and PSA levels two months after orchidectomy (P < 0.001). However, no significant correlation was found at four and six months, suggesting the possibility of subclinical tumour progression despite achieving the castrated state. These findings highlight the importance of serum PSA as a key biomarker for monitoring prostate cancer progression and treatment effectiveness. The extent and duration of PSA decline following orchidectomy appear to vary, influenced by the surgical approach and underlying tumour dynamics. 11 PSA is a highly sensitive marker for predicting prostate cancer in symptomatic patients, with an estimated sensitivity of around 93%. However, its specificity is relatively low, at approximately 20%. When combined, the testosterone-to-PSA ratio enhances diagnostic accuracy, achieving a sensitivity of 79.17% and a specificity of 89.01%. 29 Progression, defined as two consecutive increases in total PSA following the achievement of a nadir PSA or the development of new or worsening lesions on bone scans or soft tissue lesions (based on RECIST criteria), showed no significant differences between subcapsular orchiectomy and medical ADT. 14 , 17 , 19 This phenomenon can be attributed to the shared objective and mechanism of action of both modalities, as androgen suppression drives the progression control of prostate cancer in both approaches. However, factors like race, income level, and the type of healthcare facility may influence the treatment choice and potentially impact progression outcomes. 17 ADT therapy has been linked to heightened insulin resistance, a central feature of metabolic syndrome. This increased resistance can result in elevated fasting glucose levels and a greater likelihood of developing diabetes mellitus. 10 , 30 Patients undergoing ADT have been observed to experience unfavourable alterations in lipid profiles, such as increased levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. 30 These changes elevate the risk of cardiovascular diseases. 1 , 10 Additionally, one study indicated that neither treatment significantly affected blood sugar levels. 31 This variability may result from compensatory mechanisms that remain unaffected by androgen levels. 32 ADT has been associated with adverse effects on psychological well-being. 15 , 20 Research indicates that patients undergoing orchiectomy may experience more significant psychological distress compared to those receiving medical castration with LHRH analogues. This is primarily attributed to the irreversible nature of the surgery and its immediate physical and emotional consequences. Orchiectomy often leads to decreased libido and impotence, which can significantly impact a patient’s self-esteem and intimate relationships. The resulting loss of sexual function may provoke feelings of inadequacy and depression. Additionally, physical changes such as the removal of the testes and alterations in body composition can contribute to body image concerns. 30 Many patients report feeling less masculine or incomplete, exacerbating their psychological distress. 15 Some individuals also experience phantom testis syndrome, characterized by sensations or pain in the area where the testes were removed, serving as a persistent reminder of the surgery and further contributing to psychological discomfort. 15 , 18 Most studies concluded no significant differences between the two modalities regarding survivability. 13 , 14 , 16 , 18 At present, no definitive explanation exists for this outcome. However, risk factor adjustments or sample selection variations could influence survivability results, as patients with differing risk stratifications may experience varying outcomes. Potential confounding biases and influencing factors should be carefully considered. 31 , 33 This systematic review has certain limitations. As mentioned earlier, the substantial heterogeneity among studies complicates the ability to draw definitive conclusions. Furthermore, advancements in medical technologies may have introduced variability, as differences in surgical techniques and medical ADT drugs utilised across studies conducted in different years could significantly influence outcomes, increasing the potential for bias. Consequently, carefully designed future studies are strongly recommended to produce more reliable and precise results. Future direction Further research is needed to evaluate the long-term comparison between subcapsular orchiectomy and medical androgen deprivation therapy (ADT) in managing prostate cancer. Future studies should focus on the psychological, metabolic, and oncological impacts of both methods, as well as their potential side effects. Additional research is also required to examine the effects of ADT on insulin resistance and cardiovascular risk, as well as the psychological impact of physical changes due to orchiectomy. More well-designed, controlled intervention studies will provide clearer insights for better patient management. Conclusion This systematic review underscores the similar effectiveness of subcapsular orchiectomy and medical ADT in producing favourable pathological outcomes for prostate cancer patients. However, selecting between these treatment options should account for therapeutic effectiveness, patient-specific considerations, and potential side effects. Future prospective studies with standardised protocols are needed to determine the most suitable androgen deprivation therapy approach for prostate cancer patients. Data availability Underlying data No data are associated with this article. Reporting guidelines Figshare: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review. http://doi.org/10.6084/m9.figshare.28300943 . 32 • This project contains the below mentioned reporting guidelines. Prisma diagram.jpg • Prisma 2020 Checklist.docx Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). References 1. Zhang W, Cao G, Wu F, et al. : Global Burden of Prostate Cancer and Association with Socioeconomic Status, 1990–2019: A Systematic Analysis from the Global Burden of Disease Study. J. Epidemiol. Glob. Health. 2023 May 6; 13 (3): 407–421. PubMed Abstract | Publisher Full Text | Free Full Text 2. Reyes C, Groshel C, Given R: Androgen Deprivation Therapy BT - Chemotherapy and Immunotherapy in Urologic Oncology: A Guide for the Advanced Practice Provider. 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Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 03 Mar 2025 ADD YOUR COMMENT Comment Author details Author details 1 Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 2 Staff of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Erick Frapancah Roles: Formal Analysis, Project Administration, Writing – Original Draft Preparation Indrawarman Soerohardjo Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 10 Nov 2025, 14:254 https://doi.org/10.12688/f1000research.161612.2 version 1 Published: 03 Mar 2025, 14:254 https://doi.org/10.12688/f1000research.161612.1 Copyright © 2025 Frapancah E and Soerohardjo I. 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 work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Frapancah E and Soerohardjo I. Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.12688/f1000research.161612.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 10 Nov 2025 Revised Views 0 Cite How to cite this report: Warli SM. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.189352.r431087 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v2#referee-response-431087 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Nov 2025 Syah Mirsya Warli , Universitas Sumatera Utara, Medan, Indonesia Approved VIEWS 0 https://doi.org/10.5256/f1000research.189352.r431087 I have reviewed the revised manuscript and have no further ... Continue reading READ ALL I have reviewed the revised manuscript and have no further comments from my side. Thank you for the opportunity to review. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Uro-Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Warli SM. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.189352.r431087 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v2#referee-response-431087 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 03 Mar 2025 Views 0 Cite How to cite this report: Taher F. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r412958 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-412958 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 07 Oct 2025 Fakhri Taher , University of Indonesia Center for Clinical Epidemiology and Evidence Based Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.177664.r412958 This study aims to summarise the outcomes and adverse effects of orchidectomy and hormonal therapy for prostate cancer. Although these treatment modalities have been established for quite some time, the topic remains relevant in the current clinical landscape. ... Continue reading READ ALL This study aims to summarise the outcomes and adverse effects of orchidectomy and hormonal therapy for prostate cancer. Although these treatment modalities have been established for quite some time, the topic remains relevant in the current clinical landscape. The authors have clearly stated the objectives of the study and have provided a general overview of the methodology. However, I would like to request clarification on several points in the Methods section: Please elaborate on the definition and criteria used for pathological outcomes . compared across studies. You mentioned that disagreements between authors were resolved by a third author . Since only two authors are listed, kindly clarify this process or correct the statement if necessary. In the methodology, you stated that literature was searched through electronic databases. However, in the results section, you mentioned an additional publication identified through other sources . Could you please clarify what those sources were (manual search, snowballing, or reference checking)? The authors have done a commendable job in describing the included studies. However, as multiple outcomes are reported across the studies, it would significantly improve clarity if this information were summarised in a table forma t. This would allow readers to more easily compare results and draw conclusions. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Not applicable Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Urology Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Taher F. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r412958 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-412958 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Nov 2025 Erick Frapancah , Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 10 Nov 2025 Author Response Dear reviewer, We sincerely thank you for your constructive and insightful comments on our manuscript. We have carefully revised the paper in accordance with your suggestions. Each point has ... Continue reading Dear reviewer, We sincerely thank you for your constructive and insightful comments on our manuscript. We have carefully revised the paper in accordance with your suggestions. Each point has been addressed in detail below, and the corresponding changes have been incorporated into the revised version of the manuscript: We acknowledge that our operational definition of “pathological outcomes” in the sentence “Examined pathological outcomes, including tumour characteristics, biochemical markers, or adverse effects, in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT)” within the Study selection section may not have clearly explained the definition used in this study. We have therefore revised the sentence to read: “Examined pathological outcomes including: (1) tumour characteristics (tumour stage [localized vs. metastatic], castration-resistant progression, and time to treatment failure); (2) biochemical markers (serum testosterone level and prostate-specific antigen (PSA) reduction or nadir level); and (3) adverse effects (metabolic changes such as insulin resistance, body mass index, lipid profile; haematologic effects such as anaemia or haemoglobin change; and surgical or psychological complications), in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT).” We appreciate the reviewer’s observation and agree that this statement required clarification. The text has now been corrected. The screening and data extraction were performed independently by two authors (RIC and IDW). Any disagreements were resolved through discussion and consensus between these two authors; no third author was involved in these processes. We also agree that clarification was required regarding the additional publication mentioned in the Results section. This publication was identified through manual reference checking (snowballing) from the bibliographies of previously selected articles. However, we did not identify any eligible studies that were not indexed within the electronic databases included in our search strategy. Finally, we have carefully reviewed the entire manuscript to ensure that the terminology, methodology, and descriptions are clear and consistent. We sincerely appreciate the reviewer’s valuable feedback, which has significantly improved the precision, transparency, and readability of our paper. We believe that the revised version now fully addresses all reviewer comments and strengthens the overall scientific quality of the manuscript. Respectfully, Erick Frapancah Indrawarman Soerohardjo (Corresponding Author) Division of Urology, Department of Surgery Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada-Dr. Sardjito Hospital, Yogyakarta, Indonesia Dear reviewer, We sincerely thank you for your constructive and insightful comments on our manuscript. We have carefully revised the paper in accordance with your suggestions. Each point has been addressed in detail below, and the corresponding changes have been incorporated into the revised version of the manuscript: We acknowledge that our operational definition of “pathological outcomes” in the sentence “Examined pathological outcomes, including tumour characteristics, biochemical markers, or adverse effects, in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT)” within the Study selection section may not have clearly explained the definition used in this study. We have therefore revised the sentence to read: “Examined pathological outcomes including: (1) tumour characteristics (tumour stage [localized vs. metastatic], castration-resistant progression, and time to treatment failure); (2) biochemical markers (serum testosterone level and prostate-specific antigen (PSA) reduction or nadir level); and (3) adverse effects (metabolic changes such as insulin resistance, body mass index, lipid profile; haematologic effects such as anaemia or haemoglobin change; and surgical or psychological complications), in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT).” We appreciate the reviewer’s observation and agree that this statement required clarification. The text has now been corrected. The screening and data extraction were performed independently by two authors (RIC and IDW). Any disagreements were resolved through discussion and consensus between these two authors; no third author was involved in these processes. We also agree that clarification was required regarding the additional publication mentioned in the Results section. This publication was identified through manual reference checking (snowballing) from the bibliographies of previously selected articles. However, we did not identify any eligible studies that were not indexed within the electronic databases included in our search strategy. Finally, we have carefully reviewed the entire manuscript to ensure that the terminology, methodology, and descriptions are clear and consistent. We sincerely appreciate the reviewer’s valuable feedback, which has significantly improved the precision, transparency, and readability of our paper. We believe that the revised version now fully addresses all reviewer comments and strengthens the overall scientific quality of the manuscript. Respectfully, Erick Frapancah Indrawarman Soerohardjo (Corresponding Author) Division of Urology, Department of Surgery Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada-Dr. Sardjito Hospital, Yogyakarta, Indonesia Competing Interests: The author declares no competing interests Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Nov 2025 Erick Frapancah , Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 10 Nov 2025 Author Response Dear reviewer, We sincerely thank you for your constructive and insightful comments on our manuscript. We have carefully revised the paper in accordance with your suggestions. Each point has ... Continue reading Dear reviewer, We sincerely thank you for your constructive and insightful comments on our manuscript. We have carefully revised the paper in accordance with your suggestions. Each point has been addressed in detail below, and the corresponding changes have been incorporated into the revised version of the manuscript: We acknowledge that our operational definition of “pathological outcomes” in the sentence “Examined pathological outcomes, including tumour characteristics, biochemical markers, or adverse effects, in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT)” within the Study selection section may not have clearly explained the definition used in this study. We have therefore revised the sentence to read: “Examined pathological outcomes including: (1) tumour characteristics (tumour stage [localized vs. metastatic], castration-resistant progression, and time to treatment failure); (2) biochemical markers (serum testosterone level and prostate-specific antigen (PSA) reduction or nadir level); and (3) adverse effects (metabolic changes such as insulin resistance, body mass index, lipid profile; haematologic effects such as anaemia or haemoglobin change; and surgical or psychological complications), in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT).” We appreciate the reviewer’s observation and agree that this statement required clarification. The text has now been corrected. The screening and data extraction were performed independently by two authors (RIC and IDW). Any disagreements were resolved through discussion and consensus between these two authors; no third author was involved in these processes. We also agree that clarification was required regarding the additional publication mentioned in the Results section. This publication was identified through manual reference checking (snowballing) from the bibliographies of previously selected articles. However, we did not identify any eligible studies that were not indexed within the electronic databases included in our search strategy. Finally, we have carefully reviewed the entire manuscript to ensure that the terminology, methodology, and descriptions are clear and consistent. We sincerely appreciate the reviewer’s valuable feedback, which has significantly improved the precision, transparency, and readability of our paper. We believe that the revised version now fully addresses all reviewer comments and strengthens the overall scientific quality of the manuscript. Respectfully, Erick Frapancah Indrawarman Soerohardjo (Corresponding Author) Division of Urology, Department of Surgery Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada-Dr. Sardjito Hospital, Yogyakarta, Indonesia Dear reviewer, We sincerely thank you for your constructive and insightful comments on our manuscript. We have carefully revised the paper in accordance with your suggestions. Each point has been addressed in detail below, and the corresponding changes have been incorporated into the revised version of the manuscript: We acknowledge that our operational definition of “pathological outcomes” in the sentence “Examined pathological outcomes, including tumour characteristics, biochemical markers, or adverse effects, in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT)” within the Study selection section may not have clearly explained the definition used in this study. We have therefore revised the sentence to read: “Examined pathological outcomes including: (1) tumour characteristics (tumour stage [localized vs. metastatic], castration-resistant progression, and time to treatment failure); (2) biochemical markers (serum testosterone level and prostate-specific antigen (PSA) reduction or nadir level); and (3) adverse effects (metabolic changes such as insulin resistance, body mass index, lipid profile; haematologic effects such as anaemia or haemoglobin change; and surgical or psychological complications), in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT).” We appreciate the reviewer’s observation and agree that this statement required clarification. The text has now been corrected. The screening and data extraction were performed independently by two authors (RIC and IDW). Any disagreements were resolved through discussion and consensus between these two authors; no third author was involved in these processes. We also agree that clarification was required regarding the additional publication mentioned in the Results section. This publication was identified through manual reference checking (snowballing) from the bibliographies of previously selected articles. However, we did not identify any eligible studies that were not indexed within the electronic databases included in our search strategy. Finally, we have carefully reviewed the entire manuscript to ensure that the terminology, methodology, and descriptions are clear and consistent. We sincerely appreciate the reviewer’s valuable feedback, which has significantly improved the precision, transparency, and readability of our paper. We believe that the revised version now fully addresses all reviewer comments and strengthens the overall scientific quality of the manuscript. Respectfully, Erick Frapancah Indrawarman Soerohardjo (Corresponding Author) Division of Urology, Department of Surgery Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada-Dr. Sardjito Hospital, Yogyakarta, Indonesia Competing Interests: The author declares no competing interests Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Warli SM. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r412960 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-412960 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 Sep 2025 Syah Mirsya Warli , Universitas Sumatera Utara, Medan, Indonesia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.177664.r412960 Firstly, I would like to commend this manuscript. It is written in accordance with a well-structured PRISMA approach and includes an appropriate PROSPERO registration. The authors have developed a robust search strategy involving multiple databases (PubMed, ScienceDirect, Google Scholar) and ... Continue reading READ ALL Firstly, I would like to commend this manuscript. It is written in accordance with a well-structured PRISMA approach and includes an appropriate PROSPERO registration. The authors have developed a robust search strategy involving multiple databases (PubMed, ScienceDirect, Google Scholar) and the use of appropriate MeSH terms. The application of the Newcastle-Ottawa Scale and ROB-2 tools to different study designs demonstrates the study's rigorous quality assessment. The inclusion and exclusion criteria are sound, with clear definitions for both patient population and outcomes. The manuscript effectively emphasizes its clinical relevance by addressing a genuine clinical dilemma with practical implications, covering a comprehensive range of outcomes, including biochemical, metabolic, psychological, and survival measures. However, I have several concerns that need to be addressed by the authors. First, regarding the methodology: it was correctly identified that the studies by Arogundade et al. and Islam et al. do not provide direct comparisons between surgical and medical ADT, yet they were included. This represents a fundamental violation of the stated inclusion criteria and compromises the validity of the conclusions. I suggest either excluding these studies or modifying the inclusion criteria and providing a clear justification for the inclusion of single-arm studies. If these studies are retained, I encourage the authors to perform sensitivity analyses that exclude them. My second concern relates to incomplete search documentation. The phrase “The literature search started in [insert start date]” is unprofessional and suggests inadequate manuscript preparation. This must be corrected with the actual search dates. Although this may sound trivial, in my opinion, it is a major flaw. Heterogeneity is also an issue. While you acknowledge heterogeneity, the clinical and methodological diversity is substantial—different surgical techniques (subcapsular vs. total orchiectomy), various medical ADT agents with different mechanisms, wide ranges of follow-up periods (months to years), as well as different outcome definitions and measurement timepoints. I suggest providing more detailed subgroup analyses and considering forest plots showing individual study effects even in the absence of meta-analysis. Lastly, I want to emphasize some minor issues, such as inconsistencies in citation style, the low image quality of the PRISMA flowchart, and the incorrect usage of a few statistical terms. In summary, while this manuscript addresses an important clinical question, employs the correct methodology, and features a comprehensive outcome assessment, there are major flaws that need to be corrected. I encourage the authors to undertake a major revision of the manuscript to meet the standards of a highly esteemed journal. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Uro-Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Warli SM. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r412960 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-412960 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Nov 2025 Erick Frapancah , Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 10 Nov 2025 Author Response Dear Reviewer, Thank you very much for your valuable and insightful comments on our manuscript. Your feedback has been instrumental in helping us improve the quality of our paper. We ... Continue reading Dear Reviewer, Thank you very much for your valuable and insightful comments on our manuscript. Your feedback has been instrumental in helping us improve the quality of our paper. We have addressed all the points raised as follows: 1. Study inclusion (Arogundade et al. and Islam et al.) We acknowledge that the studies by Arogundade et al. and Islam et al. did not provide direct comparisons between surgical and medical ADT. We recognize that their inclusion was inconsistent with our strict inclusion criteria. Therefore, we have excluded these studies from our analysis and include them as “studies not meeting the inclusion criteria” in the PRISMA flowchart (Screening section). After reanalysis, we confirmed that the exclusion of these studies did not affect the overall results or conclusions of our systematic review. 2. Literature search clarification We also acknowledge the oversight in proofreading that resulted in the placeholder phrase “The literature search started in [insert start date]”. This has been corrected, and we confirm that our literature search included all eligible studies published up to February 2024. 3. High Heterogeneity We summarized the key findings from each included study in a structured manner, focusing on trends in oncologic outcomes, survival, and adverse effects between surgical orchiectomy and medical ADT. We qualitatively explored potential sources of heterogeneity, including differences in study design, treatment duration, and follow-up period, to better understand variations in results across studies. The methodological quality of each study was assessed using standardized criteria to support a more reliable interpretation of the evidence. Finally, we discussed both the consistency and discrepancies among the studies to highlight areas where findings converged or differed, thereby providing a comprehensive narrative synthesis of the current evidence. 4. Minor revisions and formatting improvements We have addressed all minor issues, including inconsistencies in citation style and figure quality. The PRISMA flowchart has been updated with higher resolution, and statistical terminology has been refined for clarity. All deleted text is shown with a strikethrough and yellow highlight, while all revised or added text is highlighted in red. Following the exclusion of the two aforementioned studies, we also updated the reference numbering accordingly. We sincerely hope that these revisions improve the quality of our manuscript and that it now meets the publication standards of F1000Research. Thank you once again for your constructive comments and valuable time. Warm regards, Erick Frapancah (on behalf of all authors) Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Dear Reviewer, Thank you very much for your valuable and insightful comments on our manuscript. Your feedback has been instrumental in helping us improve the quality of our paper. We have addressed all the points raised as follows: 1. Study inclusion (Arogundade et al. and Islam et al.) We acknowledge that the studies by Arogundade et al. and Islam et al. did not provide direct comparisons between surgical and medical ADT. We recognize that their inclusion was inconsistent with our strict inclusion criteria. Therefore, we have excluded these studies from our analysis and include them as “studies not meeting the inclusion criteria” in the PRISMA flowchart (Screening section). After reanalysis, we confirmed that the exclusion of these studies did not affect the overall results or conclusions of our systematic review. 2. Literature search clarification We also acknowledge the oversight in proofreading that resulted in the placeholder phrase “The literature search started in [insert start date]”. This has been corrected, and we confirm that our literature search included all eligible studies published up to February 2024. 3. High Heterogeneity We summarized the key findings from each included study in a structured manner, focusing on trends in oncologic outcomes, survival, and adverse effects between surgical orchiectomy and medical ADT. We qualitatively explored potential sources of heterogeneity, including differences in study design, treatment duration, and follow-up period, to better understand variations in results across studies. The methodological quality of each study was assessed using standardized criteria to support a more reliable interpretation of the evidence. Finally, we discussed both the consistency and discrepancies among the studies to highlight areas where findings converged or differed, thereby providing a comprehensive narrative synthesis of the current evidence. 4. Minor revisions and formatting improvements We have addressed all minor issues, including inconsistencies in citation style and figure quality. The PRISMA flowchart has been updated with higher resolution, and statistical terminology has been refined for clarity. All deleted text is shown with a strikethrough and yellow highlight, while all revised or added text is highlighted in red. Following the exclusion of the two aforementioned studies, we also updated the reference numbering accordingly. We sincerely hope that these revisions improve the quality of our manuscript and that it now meets the publication standards of F1000Research. Thank you once again for your constructive comments and valuable time. Warm regards, Erick Frapancah (on behalf of all authors) Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Competing Interests: The author declares no competing interests Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Nov 2025 Erick Frapancah , Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 10 Nov 2025 Author Response Dear Reviewer, Thank you very much for your valuable and insightful comments on our manuscript. Your feedback has been instrumental in helping us improve the quality of our paper. We ... Continue reading Dear Reviewer, Thank you very much for your valuable and insightful comments on our manuscript. Your feedback has been instrumental in helping us improve the quality of our paper. We have addressed all the points raised as follows: 1. Study inclusion (Arogundade et al. and Islam et al.) We acknowledge that the studies by Arogundade et al. and Islam et al. did not provide direct comparisons between surgical and medical ADT. We recognize that their inclusion was inconsistent with our strict inclusion criteria. Therefore, we have excluded these studies from our analysis and include them as “studies not meeting the inclusion criteria” in the PRISMA flowchart (Screening section). After reanalysis, we confirmed that the exclusion of these studies did not affect the overall results or conclusions of our systematic review. 2. Literature search clarification We also acknowledge the oversight in proofreading that resulted in the placeholder phrase “The literature search started in [insert start date]”. This has been corrected, and we confirm that our literature search included all eligible studies published up to February 2024. 3. High Heterogeneity We summarized the key findings from each included study in a structured manner, focusing on trends in oncologic outcomes, survival, and adverse effects between surgical orchiectomy and medical ADT. We qualitatively explored potential sources of heterogeneity, including differences in study design, treatment duration, and follow-up period, to better understand variations in results across studies. The methodological quality of each study was assessed using standardized criteria to support a more reliable interpretation of the evidence. Finally, we discussed both the consistency and discrepancies among the studies to highlight areas where findings converged or differed, thereby providing a comprehensive narrative synthesis of the current evidence. 4. Minor revisions and formatting improvements We have addressed all minor issues, including inconsistencies in citation style and figure quality. The PRISMA flowchart has been updated with higher resolution, and statistical terminology has been refined for clarity. All deleted text is shown with a strikethrough and yellow highlight, while all revised or added text is highlighted in red. Following the exclusion of the two aforementioned studies, we also updated the reference numbering accordingly. We sincerely hope that these revisions improve the quality of our manuscript and that it now meets the publication standards of F1000Research. Thank you once again for your constructive comments and valuable time. Warm regards, Erick Frapancah (on behalf of all authors) Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Dear Reviewer, Thank you very much for your valuable and insightful comments on our manuscript. Your feedback has been instrumental in helping us improve the quality of our paper. We have addressed all the points raised as follows: 1. Study inclusion (Arogundade et al. and Islam et al.) We acknowledge that the studies by Arogundade et al. and Islam et al. did not provide direct comparisons between surgical and medical ADT. We recognize that their inclusion was inconsistent with our strict inclusion criteria. Therefore, we have excluded these studies from our analysis and include them as “studies not meeting the inclusion criteria” in the PRISMA flowchart (Screening section). After reanalysis, we confirmed that the exclusion of these studies did not affect the overall results or conclusions of our systematic review. 2. Literature search clarification We also acknowledge the oversight in proofreading that resulted in the placeholder phrase “The literature search started in [insert start date]”. This has been corrected, and we confirm that our literature search included all eligible studies published up to February 2024. 3. High Heterogeneity We summarized the key findings from each included study in a structured manner, focusing on trends in oncologic outcomes, survival, and adverse effects between surgical orchiectomy and medical ADT. We qualitatively explored potential sources of heterogeneity, including differences in study design, treatment duration, and follow-up period, to better understand variations in results across studies. The methodological quality of each study was assessed using standardized criteria to support a more reliable interpretation of the evidence. Finally, we discussed both the consistency and discrepancies among the studies to highlight areas where findings converged or differed, thereby providing a comprehensive narrative synthesis of the current evidence. 4. Minor revisions and formatting improvements We have addressed all minor issues, including inconsistencies in citation style and figure quality. The PRISMA flowchart has been updated with higher resolution, and statistical terminology has been refined for clarity. All deleted text is shown with a strikethrough and yellow highlight, while all revised or added text is highlighted in red. Following the exclusion of the two aforementioned studies, we also updated the reference numbering accordingly. We sincerely hope that these revisions improve the quality of our manuscript and that it now meets the publication standards of F1000Research. Thank you once again for your constructive comments and valuable time. Warm regards, Erick Frapancah (on behalf of all authors) Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Competing Interests: The author declares no competing interests Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Arif Mochtar C. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r397793 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-397793 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 03 Sep 2025 Chaidir Arif Mochtar , Universitas Indonesia, Depok, West Java, Indonesia; Urology, Ciptomangunkusumo Hospital - Universitas Indonesia, Central Jakarta, DKI Jakarta, Indonesia Approved VIEWS 0 https://doi.org/10.5256/f1000research.177664.r397793 The objectives of this study are clearly described, and the research methods are presented in sufficient detail. In the Methods section, the sentence "The literature search started in [insert start date]" appears incomplete. I recommend that the authors clarify whether ... Continue reading READ ALL The objectives of this study are clearly described, and the research methods are presented in sufficient detail. In the Methods section, the sentence "The literature search started in [insert start date]" appears incomplete. I recommend that the authors clarify whether the initial year of the search is missing or if this is simply a typographical error. In addition, while the inclusion criteria specify that eligible studies should compare surgical orchiectomy with ADT, two included studies (Arogundade et al. and Islam et al.) did not provide such a comparison but only reported outcomes of surgical orchiectomy. I suggest the authors address this inconsistency for greater clarity. It should be noted that the studies included in this review were retrospective cohorts rather than prospective ones. The statistical approach chosen by the authors is appropriate. Given the heterogeneity of the included studies, the decision not to perform a meta-analysis is justified and well explained. The narrative synthesis is clearly presented. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Not applicable Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: Urologic Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Arif Mochtar C. Reviewer Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r397793 ) The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-397793 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Nov 2025 Erick Frapancah , Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 10 Nov 2025 Author Response Dear Reviewer, Thank you very much for your thoughtful and constructive comments on our manuscript. We highly appreciate your detailed review, which has helped us improve the clarity and quality ... Continue reading Dear Reviewer, Thank you very much for your thoughtful and constructive comments on our manuscript. We highly appreciate your detailed review, which has helped us improve the clarity and quality of our work. Our responses to your points are as follows: 1.Comment 1: “In the Methods section, the sentence ‘The literature search started in [insert start date]’ appears incomplete. I recommend that the authors clarify whether the initial year of the search is missing or if this is simply a typographical error.” Response: We appreciate the reviewer’s observation. This was indeed a typographical oversight that occurred during proofreading. The correct statement now reads: “The literature search was performed for evaluate and compare pathological outcomes, including disease progression, survival rates, and adverse effects, in prostate cancer patients undergoing either subcapsular orchiectomy or pharmacological ADT up to February 2024.” We have revised the text accordingly in the Methods section. 2.Comment 2: “While the inclusion criteria specify that eligible studies should compare surgical orchiectomy with ADT, two included studies (Arogundade et al. and Islam et al.) did not provide such a comparison but only reported outcomes of surgical orchiectomy. I suggest the authors address this inconsistency for greater clarity.” Response: We thank the reviewer for highlighting this important point. Upon re-evaluation, we acknowledge that the studies by Arogundade et al. and Islam et al. did not meet our strict inclusion criteria, as they did not directly compare surgical orchiectomy with medical ADT. We have therefore excluded these two studies and categorized them as “studies not meeting the inclusion criteria” in the updated PRISMA flowchart (Screening section). We also rechecked the data and confirmed that their exclusion did not affect the results or conclusions of our review. 3.Comment 3: “It should be noted that the studies included in this review were retrospective cohorts rather than prospective ones.” Response: We thank the reviewer for this clarification. We have updated the manuscript and included 7 Randomized Controlled Trials, 3 Retrospective Cohort, and 1 Prospective cohort studies. This information is now clearly stated in the Results section. 4. Comment 4: “The statistical approach chosen by the authors is appropriate. Given the heterogeneity of the included studies, the decision not to perform a meta-analysis is justified and well explained. The narrative synthesis is clearly presented.” Response: We sincerely appreciate the reviewer’s positive feedback regarding our methodological approach and presentation. 5. Additional Revisions: Response: We have also corrected minor formatting inconsistencies, improved figure quality (including the PRISMA flowchart), and refined statistical terminology for clarity. All deleted text is shown with strikethrough and yellow highlight, while revisions and additions are highlighted in red. Reference numbering has been updated accordingly after the exclusion of the two studies. We hope these revisions address all comments satisfactorily and enhance the quality and clarity of our manuscript. Thank you again for your valuable time and insightful feedback. Dear Reviewer, Thank you very much for your thoughtful and constructive comments on our manuscript. We highly appreciate your detailed review, which has helped us improve the clarity and quality of our work. Our responses to your points are as follows: 1.Comment 1: “In the Methods section, the sentence ‘The literature search started in [insert start date]’ appears incomplete. I recommend that the authors clarify whether the initial year of the search is missing or if this is simply a typographical error.” Response: We appreciate the reviewer’s observation. This was indeed a typographical oversight that occurred during proofreading. The correct statement now reads: “The literature search was performed for evaluate and compare pathological outcomes, including disease progression, survival rates, and adverse effects, in prostate cancer patients undergoing either subcapsular orchiectomy or pharmacological ADT up to February 2024.” We have revised the text accordingly in the Methods section. 2.Comment 2: “While the inclusion criteria specify that eligible studies should compare surgical orchiectomy with ADT, two included studies (Arogundade et al. and Islam et al.) did not provide such a comparison but only reported outcomes of surgical orchiectomy. I suggest the authors address this inconsistency for greater clarity.” Response: We thank the reviewer for highlighting this important point. Upon re-evaluation, we acknowledge that the studies by Arogundade et al. and Islam et al. did not meet our strict inclusion criteria, as they did not directly compare surgical orchiectomy with medical ADT. We have therefore excluded these two studies and categorized them as “studies not meeting the inclusion criteria” in the updated PRISMA flowchart (Screening section). We also rechecked the data and confirmed that their exclusion did not affect the results or conclusions of our review. 3.Comment 3: “It should be noted that the studies included in this review were retrospective cohorts rather than prospective ones.” Response: We thank the reviewer for this clarification. We have updated the manuscript and included 7 Randomized Controlled Trials, 3 Retrospective Cohort, and 1 Prospective cohort studies. This information is now clearly stated in the Results section. 4. Comment 4: “The statistical approach chosen by the authors is appropriate. Given the heterogeneity of the included studies, the decision not to perform a meta-analysis is justified and well explained. The narrative synthesis is clearly presented.” Response: We sincerely appreciate the reviewer’s positive feedback regarding our methodological approach and presentation. 5. Additional Revisions: Response: We have also corrected minor formatting inconsistencies, improved figure quality (including the PRISMA flowchart), and refined statistical terminology for clarity. All deleted text is shown with strikethrough and yellow highlight, while revisions and additions are highlighted in red. Reference numbering has been updated accordingly after the exclusion of the two studies. We hope these revisions address all comments satisfactorily and enhance the quality and clarity of our manuscript. Thank you again for your valuable time and insightful feedback. Competing Interests: The author declares no competing interests. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Nov 2025 Erick Frapancah , Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia 10 Nov 2025 Author Response Dear Reviewer, Thank you very much for your thoughtful and constructive comments on our manuscript. We highly appreciate your detailed review, which has helped us improve the clarity and quality ... Continue reading Dear Reviewer, Thank you very much for your thoughtful and constructive comments on our manuscript. We highly appreciate your detailed review, which has helped us improve the clarity and quality of our work. Our responses to your points are as follows: 1.Comment 1: “In the Methods section, the sentence ‘The literature search started in [insert start date]’ appears incomplete. I recommend that the authors clarify whether the initial year of the search is missing or if this is simply a typographical error.” Response: We appreciate the reviewer’s observation. This was indeed a typographical oversight that occurred during proofreading. The correct statement now reads: “The literature search was performed for evaluate and compare pathological outcomes, including disease progression, survival rates, and adverse effects, in prostate cancer patients undergoing either subcapsular orchiectomy or pharmacological ADT up to February 2024.” We have revised the text accordingly in the Methods section. 2.Comment 2: “While the inclusion criteria specify that eligible studies should compare surgical orchiectomy with ADT, two included studies (Arogundade et al. and Islam et al.) did not provide such a comparison but only reported outcomes of surgical orchiectomy. I suggest the authors address this inconsistency for greater clarity.” Response: We thank the reviewer for highlighting this important point. Upon re-evaluation, we acknowledge that the studies by Arogundade et al. and Islam et al. did not meet our strict inclusion criteria, as they did not directly compare surgical orchiectomy with medical ADT. We have therefore excluded these two studies and categorized them as “studies not meeting the inclusion criteria” in the updated PRISMA flowchart (Screening section). We also rechecked the data and confirmed that their exclusion did not affect the results or conclusions of our review. 3.Comment 3: “It should be noted that the studies included in this review were retrospective cohorts rather than prospective ones.” Response: We thank the reviewer for this clarification. We have updated the manuscript and included 7 Randomized Controlled Trials, 3 Retrospective Cohort, and 1 Prospective cohort studies. This information is now clearly stated in the Results section. 4. Comment 4: “The statistical approach chosen by the authors is appropriate. Given the heterogeneity of the included studies, the decision not to perform a meta-analysis is justified and well explained. The narrative synthesis is clearly presented.” Response: We sincerely appreciate the reviewer’s positive feedback regarding our methodological approach and presentation. 5. Additional Revisions: Response: We have also corrected minor formatting inconsistencies, improved figure quality (including the PRISMA flowchart), and refined statistical terminology for clarity. All deleted text is shown with strikethrough and yellow highlight, while revisions and additions are highlighted in red. Reference numbering has been updated accordingly after the exclusion of the two studies. We hope these revisions address all comments satisfactorily and enhance the quality and clarity of our manuscript. Thank you again for your valuable time and insightful feedback. Dear Reviewer, Thank you very much for your thoughtful and constructive comments on our manuscript. We highly appreciate your detailed review, which has helped us improve the clarity and quality of our work. Our responses to your points are as follows: 1.Comment 1: “In the Methods section, the sentence ‘The literature search started in [insert start date]’ appears incomplete. I recommend that the authors clarify whether the initial year of the search is missing or if this is simply a typographical error.” Response: We appreciate the reviewer’s observation. This was indeed a typographical oversight that occurred during proofreading. The correct statement now reads: “The literature search was performed for evaluate and compare pathological outcomes, including disease progression, survival rates, and adverse effects, in prostate cancer patients undergoing either subcapsular orchiectomy or pharmacological ADT up to February 2024.” We have revised the text accordingly in the Methods section. 2.Comment 2: “While the inclusion criteria specify that eligible studies should compare surgical orchiectomy with ADT, two included studies (Arogundade et al. and Islam et al.) did not provide such a comparison but only reported outcomes of surgical orchiectomy. I suggest the authors address this inconsistency for greater clarity.” Response: We thank the reviewer for highlighting this important point. Upon re-evaluation, we acknowledge that the studies by Arogundade et al. and Islam et al. did not meet our strict inclusion criteria, as they did not directly compare surgical orchiectomy with medical ADT. We have therefore excluded these two studies and categorized them as “studies not meeting the inclusion criteria” in the updated PRISMA flowchart (Screening section). We also rechecked the data and confirmed that their exclusion did not affect the results or conclusions of our review. 3.Comment 3: “It should be noted that the studies included in this review were retrospective cohorts rather than prospective ones.” Response: We thank the reviewer for this clarification. We have updated the manuscript and included 7 Randomized Controlled Trials, 3 Retrospective Cohort, and 1 Prospective cohort studies. This information is now clearly stated in the Results section. 4. Comment 4: “The statistical approach chosen by the authors is appropriate. Given the heterogeneity of the included studies, the decision not to perform a meta-analysis is justified and well explained. The narrative synthesis is clearly presented.” Response: We sincerely appreciate the reviewer’s positive feedback regarding our methodological approach and presentation. 5. Additional Revisions: Response: We have also corrected minor formatting inconsistencies, improved figure quality (including the PRISMA flowchart), and refined statistical terminology for clarity. All deleted text is shown with strikethrough and yellow highlight, while revisions and additions are highlighted in red. Reference numbering has been updated accordingly after the exclusion of the two studies. We hope these revisions address all comments satisfactorily and enhance the quality and clarity of our manuscript. Thank you again for your valuable time and insightful feedback. Competing Interests: The author declares no competing interests. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 03 Mar 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 2 (revision) 10 Nov 25 read Version 1 03 Mar 25 read read read Chaidir Arif Mochtar , Universitas Indonesia, Depok, Indonesia; Ciptomangunkusumo Hospital - Universitas Indonesia, Central Jakarta, Indonesia Syah Mirsya Warli , Universitas Sumatera Utara, Medan, Indonesia Fakhri Taher , University of Indonesia Center for Clinical Epidemiology and Evidence Based Medicine, Jakarta, Indonesia Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Warli S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Nov 2025 | for Version 2 Syah Mirsya Warli , Universitas Sumatera Utara, Medan, Indonesia 0 Views copyright © 2025 Warli S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I have reviewed the revised manuscript and have no further comments from my side. Thank you for the opportunity to review. Competing Interests No competing interests were disclosed. Reviewer Expertise Uro-Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Warli SM. Peer Review Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.189352.r431087) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-254/v2#referee-response-431087 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Taher F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 07 Oct 2025 | for Version 1 Fakhri Taher , University of Indonesia Center for Clinical Epidemiology and Evidence Based Medicine, Jakarta, Special Capital Region of Jakarta, Indonesia 0 Views copyright © 2025 Taher F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This study aims to summarise the outcomes and adverse effects of orchidectomy and hormonal therapy for prostate cancer. Although these treatment modalities have been established for quite some time, the topic remains relevant in the current clinical landscape. The authors have clearly stated the objectives of the study and have provided a general overview of the methodology. However, I would like to request clarification on several points in the Methods section: Please elaborate on the definition and criteria used for pathological outcomes . compared across studies. You mentioned that disagreements between authors were resolved by a third author . Since only two authors are listed, kindly clarify this process or correct the statement if necessary. In the methodology, you stated that literature was searched through electronic databases. However, in the results section, you mentioned an additional publication identified through other sources . Could you please clarify what those sources were (manual search, snowballing, or reference checking)? The authors have done a commendable job in describing the included studies. However, as multiple outcomes are reported across the studies, it would significantly improve clarity if this information were summarised in a table forma t. This would allow readers to more easily compare results and draw conclusions. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Not applicable Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No Competing Interests No competing interests were disclosed. Reviewer Expertise Urology Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 10 Nov 2025 Erick Frapancah, Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Dear reviewer, We sincerely thank you for your constructive and insightful comments on our manuscript. We have carefully revised the paper in accordance with your suggestions. Each point has been addressed in detail below, and the corresponding changes have been incorporated into the revised version of the manuscript: We acknowledge that our operational definition of “pathological outcomes” in the sentence “Examined pathological outcomes, including tumour characteristics, biochemical markers, or adverse effects, in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT)” within the Study selection section may not have clearly explained the definition used in this study. We have therefore revised the sentence to read: “Examined pathological outcomes including: (1) tumour characteristics (tumour stage [localized vs. metastatic], castration-resistant progression, and time to treatment failure); (2) biochemical markers (serum testosterone level and prostate-specific antigen (PSA) reduction or nadir level); and (3) adverse effects (metabolic changes such as insulin resistance, body mass index, lipid profile; haematologic effects such as anaemia or haemoglobin change; and surgical or psychological complications), in prostate cancer patients treated with subcapsular orchiectomy or medical androgen deprivation therapy (ADT).” We appreciate the reviewer’s observation and agree that this statement required clarification. The text has now been corrected. The screening and data extraction were performed independently by two authors (RIC and IDW). Any disagreements were resolved through discussion and consensus between these two authors; no third author was involved in these processes. We also agree that clarification was required regarding the additional publication mentioned in the Results section. This publication was identified through manual reference checking (snowballing) from the bibliographies of previously selected articles. However, we did not identify any eligible studies that were not indexed within the electronic databases included in our search strategy. Finally, we have carefully reviewed the entire manuscript to ensure that the terminology, methodology, and descriptions are clear and consistent. We sincerely appreciate the reviewer’s valuable feedback, which has significantly improved the precision, transparency, and readability of our paper. We believe that the revised version now fully addresses all reviewer comments and strengthens the overall scientific quality of the manuscript. Respectfully, Erick Frapancah Indrawarman Soerohardjo (Corresponding Author) Division of Urology, Department of Surgery Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada-Dr. Sardjito Hospital, Yogyakarta, Indonesia View more View less Competing Interests The author declares no competing interests reply Respond Report a concern Taher F. Peer Review Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r412958) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-412958 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Warli S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 Sep 2025 | for Version 1 Syah Mirsya Warli , Universitas Sumatera Utara, Medan, Indonesia 0 Views copyright © 2025 Warli S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Firstly, I would like to commend this manuscript. It is written in accordance with a well-structured PRISMA approach and includes an appropriate PROSPERO registration. The authors have developed a robust search strategy involving multiple databases (PubMed, ScienceDirect, Google Scholar) and the use of appropriate MeSH terms. The application of the Newcastle-Ottawa Scale and ROB-2 tools to different study designs demonstrates the study's rigorous quality assessment. The inclusion and exclusion criteria are sound, with clear definitions for both patient population and outcomes. The manuscript effectively emphasizes its clinical relevance by addressing a genuine clinical dilemma with practical implications, covering a comprehensive range of outcomes, including biochemical, metabolic, psychological, and survival measures. However, I have several concerns that need to be addressed by the authors. First, regarding the methodology: it was correctly identified that the studies by Arogundade et al. and Islam et al. do not provide direct comparisons between surgical and medical ADT, yet they were included. This represents a fundamental violation of the stated inclusion criteria and compromises the validity of the conclusions. I suggest either excluding these studies or modifying the inclusion criteria and providing a clear justification for the inclusion of single-arm studies. If these studies are retained, I encourage the authors to perform sensitivity analyses that exclude them. My second concern relates to incomplete search documentation. The phrase “The literature search started in [insert start date]” is unprofessional and suggests inadequate manuscript preparation. This must be corrected with the actual search dates. Although this may sound trivial, in my opinion, it is a major flaw. Heterogeneity is also an issue. While you acknowledge heterogeneity, the clinical and methodological diversity is substantial—different surgical techniques (subcapsular vs. total orchiectomy), various medical ADT agents with different mechanisms, wide ranges of follow-up periods (months to years), as well as different outcome definitions and measurement timepoints. I suggest providing more detailed subgroup analyses and considering forest plots showing individual study effects even in the absence of meta-analysis. Lastly, I want to emphasize some minor issues, such as inconsistencies in citation style, the low image quality of the PRISMA flowchart, and the incorrect usage of a few statistical terms. In summary, while this manuscript addresses an important clinical question, employs the correct methodology, and features a comprehensive outcome assessment, there are major flaws that need to be corrected. I encourage the authors to undertake a major revision of the manuscript to meet the standards of a highly esteemed journal. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Uro-Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 10 Nov 2025 Erick Frapancah, Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Dear Reviewer, Thank you very much for your valuable and insightful comments on our manuscript. Your feedback has been instrumental in helping us improve the quality of our paper. We have addressed all the points raised as follows: 1. Study inclusion (Arogundade et al. and Islam et al.) We acknowledge that the studies by Arogundade et al. and Islam et al. did not provide direct comparisons between surgical and medical ADT. We recognize that their inclusion was inconsistent with our strict inclusion criteria. Therefore, we have excluded these studies from our analysis and include them as “studies not meeting the inclusion criteria” in the PRISMA flowchart (Screening section). After reanalysis, we confirmed that the exclusion of these studies did not affect the overall results or conclusions of our systematic review. 2. Literature search clarification We also acknowledge the oversight in proofreading that resulted in the placeholder phrase “The literature search started in [insert start date]”. This has been corrected, and we confirm that our literature search included all eligible studies published up to February 2024. 3. High Heterogeneity We summarized the key findings from each included study in a structured manner, focusing on trends in oncologic outcomes, survival, and adverse effects between surgical orchiectomy and medical ADT. We qualitatively explored potential sources of heterogeneity, including differences in study design, treatment duration, and follow-up period, to better understand variations in results across studies. The methodological quality of each study was assessed using standardized criteria to support a more reliable interpretation of the evidence. Finally, we discussed both the consistency and discrepancies among the studies to highlight areas where findings converged or differed, thereby providing a comprehensive narrative synthesis of the current evidence. 4. Minor revisions and formatting improvements We have addressed all minor issues, including inconsistencies in citation style and figure quality. The PRISMA flowchart has been updated with higher resolution, and statistical terminology has been refined for clarity. All deleted text is shown with a strikethrough and yellow highlight, while all revised or added text is highlighted in red. Following the exclusion of the two aforementioned studies, we also updated the reference numbering accordingly. We sincerely hope that these revisions improve the quality of our manuscript and that it now meets the publication standards of F1000Research. Thank you once again for your constructive comments and valuable time. Warm regards, Erick Frapancah (on behalf of all authors) Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia View more View less Competing Interests The author declares no competing interests reply Respond Report a concern Warli SM. Peer Review Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r412960) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-254/v1#referee-response-412960 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Arif Mochtar C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 03 Sep 2025 | for Version 1 Chaidir Arif Mochtar , Universitas Indonesia, Depok, West Java, Indonesia; Urology, Ciptomangunkusumo Hospital - Universitas Indonesia, Central Jakarta, DKI Jakarta, Indonesia 0 Views copyright © 2025 Arif Mochtar C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The objectives of this study are clearly described, and the research methods are presented in sufficient detail. In the Methods section, the sentence "The literature search started in [insert start date]" appears incomplete. I recommend that the authors clarify whether the initial year of the search is missing or if this is simply a typographical error. In addition, while the inclusion criteria specify that eligible studies should compare surgical orchiectomy with ADT, two included studies (Arogundade et al. and Islam et al.) did not provide such a comparison but only reported outcomes of surgical orchiectomy. I suggest the authors address this inconsistency for greater clarity. It should be noted that the studies included in this review were retrospective cohorts rather than prospective ones. The statistical approach chosen by the authors is appropriate. Given the heterogeneity of the included studies, the decision not to perform a meta-analysis is justified and well explained. The narrative synthesis is clearly presented. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Not applicable Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Urologic Oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 10 Nov 2025 Erick Frapancah, Resident of Urology Division, Department of Surgery, Sardjito Hospital, Faculty of Medicine, Nursing, and Public Health, Gadjah Mada University, Yogyakarta, 55284, Indonesia Dear Reviewer, Thank you very much for your thoughtful and constructive comments on our manuscript. We highly appreciate your detailed review, which has helped us improve the clarity and quality of our work. Our responses to your points are as follows: 1.Comment 1: “In the Methods section, the sentence ‘The literature search started in [insert start date]’ appears incomplete. I recommend that the authors clarify whether the initial year of the search is missing or if this is simply a typographical error.” Response: We appreciate the reviewer’s observation. This was indeed a typographical oversight that occurred during proofreading. The correct statement now reads: “The literature search was performed for evaluate and compare pathological outcomes, including disease progression, survival rates, and adverse effects, in prostate cancer patients undergoing either subcapsular orchiectomy or pharmacological ADT up to February 2024.” We have revised the text accordingly in the Methods section. 2.Comment 2: “While the inclusion criteria specify that eligible studies should compare surgical orchiectomy with ADT, two included studies (Arogundade et al. and Islam et al.) did not provide such a comparison but only reported outcomes of surgical orchiectomy. I suggest the authors address this inconsistency for greater clarity.” Response: We thank the reviewer for highlighting this important point. Upon re-evaluation, we acknowledge that the studies by Arogundade et al. and Islam et al. did not meet our strict inclusion criteria, as they did not directly compare surgical orchiectomy with medical ADT. We have therefore excluded these two studies and categorized them as “studies not meeting the inclusion criteria” in the updated PRISMA flowchart (Screening section). We also rechecked the data and confirmed that their exclusion did not affect the results or conclusions of our review. 3.Comment 3: “It should be noted that the studies included in this review were retrospective cohorts rather than prospective ones.” Response: We thank the reviewer for this clarification. We have updated the manuscript and included 7 Randomized Controlled Trials, 3 Retrospective Cohort, and 1 Prospective cohort studies. This information is now clearly stated in the Results section. 4. Comment 4: “The statistical approach chosen by the authors is appropriate. Given the heterogeneity of the included studies, the decision not to perform a meta-analysis is justified and well explained. The narrative synthesis is clearly presented.” Response: We sincerely appreciate the reviewer’s positive feedback regarding our methodological approach and presentation. 5. Additional Revisions: Response: We have also corrected minor formatting inconsistencies, improved figure quality (including the PRISMA flowchart), and refined statistical terminology for clarity. All deleted text is shown with strikethrough and yellow highlight, while revisions and additions are highlighted in red. Reference numbering has been updated accordingly after the exclusion of the two studies. We hope these revisions address all comments satisfactorily and enhance the quality and clarity of our manuscript. Thank you again for your valuable time and insightful feedback. View more View less Competing Interests The author declares no competing interests. reply Respond Report a concern Arif Mochtar C. Peer Review Report For: Examining Differences in Pathological Outcomes and Safety for Prostate Cancer Patients Undergoing Either Subcapsular Orchiectomy or Medical Androgen Deprivation Therapy: A Systematic Review [version 2; peer review: 2 approved, 1 approved with reservations] . F1000Research 2025, 14 :254 ( https://doi.org/10.5256/f1000research.177664.r397793) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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