Efficacy of Androgen Deprivation Therapy (ADT) in Combination with Radiation Therapy, compared to ADT alone in Patients with High-Risk Prostate Cancer: a meta-analysis

Efficacy of Androgen Deprivation Therapy (ADT) in Combination with Radiation Therapy, compared to ADT alone in Patients with High-Risk Prostate Cancer: a meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of Androgen Deprivation Therapy (ADT) in Combination with Radiation Therapy, compared to ADT alone in Patients with High-Risk Prostate Cancer: a meta-analysis Emad Rajih, Mansour Alnazari, Abdulaziz Bakhsh, Walaa Borhan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6206964/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Androgen deprivation therapy (ADT) has long been a cornerstone of treatment for patients with locally advanced or metastatic hormone-sensitive prostate cancer. The efficacy of ADT plus radiotherapy (RT) compared to ADT alone remains unclear due to conflicting results in existing literature. The aim of the study is to systematically evaluate the effectiveness of ADT combined with RT versus ADT alone in patients with prostate cancer (clinically node positive, locally advancer disease, metastatic disease), focusing on overall survival (OS), prostate-specific mortality (PSM), progression-free survival (PFS), and the risk of complications. Methods A comprehensive search of PubMed, Embase, Web of Science and Scopus, between 1st January 2000 and 15th October 2024, was done to identify studies comparing ADT alone to ADT in combination with RT. Hazard ratios (HR) and relative risk (RR) with 95% confidence intervals (CI) were calculated for the outcomes. The certainty of the evidence was assessed using the standard GRADE approach. Results A total of 8 studies met the inclusion criteria (6 RCTs and 2 cohort studies). These studies included 18,456 patients. The combination of ADT and RT significantly improved OS (HR = 0.75, 95% CI: 0.63, 0.90), PFS (HR = 0.41, 95% CI: 0.20, 0.84), and reduced PSM (HR = 0.52, 95% CI: 0.34, 0.78) compared to ADT alone. Subgroup analysis showed greater OS (HR 0.66, 95% CI: 0.59, 0.75) and PSM (HR 0.43, 95% CI: 0.39, 0.49) in patients with locally advanced or node-positive disease. ADT + RT was also associated with increased risks of genitourinary (RR = 1.80, 95% CI: 1.15, 2.82), gastrointestinal (RR = 4.18, 95% CI: 1.46, 11.96), and sexual dysfunction (RR = 1.10, 95% CI: 1.02, 1.18) related complications. The overall certainty of evidence was judged to be “moderate” for survival outcomes and “Low” for risk of complications. Conclusion Combining ADT with radiation therapy RT significantly improves survival, compared to ADT alone, especially in patients with locally advanced or node-positive prostate cancer. However, this combination also increases the risk of complications. Further research is needed to refine treatment protocols and identify the optimal timing and patient subgroups for this approach. prostate cancer node positive locally advanced androgen deprivation radiotherapy survival progression complications meta-analysis systematic review Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Prostate cancer is one of the most prevalent cancers among men globally ( 1 ). In 2020, there were an estimated 1.41 million new cases and 375,000 deaths from prostate cancer worldwide ( 2 ). From 1990 to 2019, the incidence and mortality rates of prostate cancer increased by nearly 116.0% and 109.0%, respectively, a trend likely to continue as the global population ages ( 2 ). Over the past few decades, treatment strategies for prostate cancer have evolved significantly. For patients with locally advanced or metastatic hormone-sensitive prostate cancer, androgen deprivation therapy (ADT) has remained a cornerstone of treatment ( 3 , 4 ). By inhibiting androgen production, ADT helps slow disease progression and improves control ( 5 ). However, despite its effectiveness, ADT alone often fails to provide long-term remission, particularly in patients with more advanced stages of the disease ( 6 ). Recent advancements have investigated the combination of androgen deprivation therapy (ADT) with other treatment options, such as radiation therapy (RT), to improve survival outcomes ( 7 – 9 ). Radiation therapy targets localized tumour areas, aiming to reduce cancer progression and enhance overall survival. Randomized controlled trials have compared ADT alone to ADT combined with RT, yielding mixed results. While some studies report a notable survival benefit with the combined treatment ( 10 , 11 ), others either do not show any survival benefit or raise concerns about potential side effects ( 12 , 13 ). Previous efforts have attempted to synthesize the findings of studies comparing androgen deprivation therapy (ADT) alone to ADT combined with radiation therapy (RT), but the evidence has not been conclusive ( 8 , 14 , 15 ). Wang et al. conducted a meta-analysis including two randomized controlled trials comparing a combination of ADT and RT with ADT monotherapy, finding no significant difference in overall survival or progression-free survival, except for improved survival in cases of low-volume disease ( 14 ). Similarly, Lei et al.'s review of three RCTs reported that adding RT to long-term ADT improved overall survival in locally advanced prostate cancer ( 15 ). However, these reviews did not perform appropriate subgroup analyses to determine whether the effects on survival and disease progression differ across patient and disease characteristics. Since the publication of these reviews, more studies have been conducted on this topic and this necessitates the existing evidence to be updated. The current meta-analysis aims to comprehensively evaluate and compare the effectiveness of ADT combined with RT versus ADT alone, focusing on primary outcomes including overall survival, prostate-specific mortality, and progression-free survival. MATERIAL AND METHODS Compliance to relevant guidelines Our meta-analysis was conducted in accordance with the PRISMA guidelines ( 16 ). Additionally, prospectively registered the study protocol in PROSPERO ( https://www.crd.york.ac.uk/prospero/ ) (CRD42024602727). Identification of studies A systematic and thorough search strategy was developed to identify relevant studies from electronic databases, including PubMed, Embase, Web of Science and Scopus. The specific search strategy employed for each of the above databases has been presented in supplementary table 1 . The search was limited to studies published between 1st January 2000 and 15th October 2024. Manual searches of reference lists and relevant review articles was also done to ensure the inclusion of any additional studies that may have been overlooked during the electronic search process. Inclusion and exclusion criteria Studies involving adult patients (aged 18–75 years) with prostate cancer, confirmed through pathological evaluation, were eligible for inclusion. Eligible studies required an intervention group receiving a combination of androgen deprivation therapy (ADT) and radiation therapy, compared to a control group receiving ADT alone. Studies were excluded if participants had undergone other baseline treatments, such as radical prostatectomy. The primary outcomes of interest included overall survival (OS), progression-free survival (PFS) and prostate/cancer-specific mortality (PSM). The secondary outcome of interest was the risk of complications. Only studies with a randomized controlled trial (RCT), cohort, or case-control design were considered, and studies needed to report effect sizes with 95% confidence intervals for at least one outcome to ensure data relevance. Inclusion was restricted to English-language studies published in peer-reviewed journals. In cases where multiple studies originated from the same dataset, the study presenting data with the longest follow-up period was selected for inclusion. Studies involving patients younger than 18 or older than 75 years were excluded. Additionally, studies were not eligible if the comparison groups were irrelevant to the review objective, such as comparisons of ADT with radiation therapy (RT) to RT alone, studies assessing ADT as a concurrent versus neoadjuvant therapy to RT, or comparisons based on varying durations of ADT or different durations and doses of RT. Case reports, case series, review articles, editorials, letters to the editor, and commentaries were also excluded. Studies that did not report usable effect sizes for analysis were not considered. Process of study selection After applying the search strategy across designated databases, the first step was to remove duplicate studies. Two independent experts (A.S.R, W.M.B) then conducted a thorough review of the remaining studies. In the initial screening phase, each study’s title and abstract were carefully examined to assess their relevance to the research question. Studies that appeared potentially relevant were selected for further evaluation. In the next stage, a detailed assessment of the full text was performed to determine each study’s eligibility for inclusion in the meta-analysis. Any disagreements regarding study inclusion were resolved through in-depth discussions among the authors. During the initial screening phase, an inter-rater reliability assessment was also conducted among the reviewers (A.S.R, W.M.B) to evaluate consistency in study selection. If the initial agreement was found to be below the acceptable level (inter-rater reliability of less than 75%), a detailed discussion was organized with the screening team, led by the principal investigator (E.S.R), to ensure clarity and alignment on inclusion and exclusion criteria. Data extraction and quality assessment Data extraction from the final set of included studies was conducted independently by two authors using a standardized data extraction form. Extracted data included study identifiers (first author’s name and year of publication), study design, country of study, participant and tumour characteristics, management details for the intervention and control groups, sample size, follow-up duration, and relevant findings. Any discrepancies between the two authors were resolved through discussion to reach consensus. For risk of bias assessment, we used the Newcastle-Ottawa Scale (NOS) for cohort studies and the Cochrane Risk of Bias (RoB 2.0) tool for randomized controlled trials (RCTs) ( 17 , 18 ). Quality assessment was performed independently by the two independent experts (M.N., W.B.). The certainty of the evidence was assessed using the standard GRADE approach ( gradepro.org) and GRADE Pro Software ( 19 ). Statistical analysis Pooled effect sizes were reported as hazard ratios (HR) or relative risks (RR), each with corresponding 95% confidence intervals (CI). A random-effects model was used for all analyses to account for variations in baseline characteristics across studies ( 20 ). The pooled analysis primarily included RCTs, with two cohort studies that used propensity score matching for baseline comparability. A sensitivity analysis was conducted excluding these cohort studies. Publication bias was assessed using Egger's test and by visually inspecting funnel plots ( 21 ). Statistical significance was defined as a p-value of less than 0.05. Subgroup analysis for the primary outcomes was conducted based on type of prostate cancer (locally advanced prostate cancer, LAPC or node positivity, cN + and metastatic), baseline Gleason score (≤ 7 and ≥ 8), baseline prostate specific antigen (PSA) level (≥ 20 ng/ml or < 20 ng/ml) and sample size (< 500 and ≥ 500). RESULTS We conducted a systematic search and identified 1925 studies. After removing 498 duplicates, we screened the titles and abstracts of the remaining 1427 unique studies. This led to exclusion of 1382 studies based on their potential relevance to the review. We then reviewed the full texts of the remaining 45 studies and excluded 37 more that did not meet our inclusion criteria, as shown in Fig. 1 . This process resulted in a final selection of 8 studies for analysis ( 10 – 13 , 22 – 25 ). The study characteristics are provided in Table 1 . There were six randomized controlled trials (RCT) ( 10 – 13 , 22 , 23 ). In the remaining two cohort-based studies, propensity score matching was done which ensured that the baseline characteristics between the study groups was similar ( 24 , 25 ). Three studies were multicentric, two were done in the United States of America (USA) and one study each was conducted in Republic of Korea, France and Netherlands (Table 1 ). The two cohort studies obtained a score of 7 (out of the maximum attainable score of 9) on the NOS assessment (Supplementary table 2). The remaining 5 RCTs were also judged to have low risk of bias (Supplementary Fig. 1). Table 1 Summary characteristics of the studies included in the review Author (publication year) Study design and place of study Age Tumour characteristics Intervention(I) and comparator (C) Sample size Duration of follow up Lee TH et al (2024) ( 22 ) RCT; Republic of Korea Median age similar in both groups (70 years) T3/T4 (100%); cN+; median PSA (36 ng/ml); node positive but no distant metastasis Gleason score of 8–10 (85%) C: ADT administered using a combination of a gonadotropin-releasing hormone (GnRH) agonist and anti-androgen. ADT given for at least 2 years I: ADT along with radiotherapy (RT) (70 Gy in 28 fractions). RT started after 2–3 months of ADT 60 I: 29 C: 31 Median 3.3 years Sargos et al (2020) ( 13 ) RCT; France Mean age similar in both group (~ 71 years) LAPC; T3N0M0 (95%); median PSA of 26.8 ng/ml; PSA (≥ 20 ng/ml) in ~ 64% Gleason score of 7 or less (83%) C: LHRH agonist (leuprorelin) for 3 years, along with oral flutamide (750 mg/day) for the first month. I: In addition to ADT, external beam radiation therapy (EBRT) (whole pelvis dose of 46 Gy with prostate having boost from 20 to 28 Gy), initiated within 90 days of the first leuprorelin injection 263 I: 133 C: 130 Median 7.3 years Boevé et al (2019) ( 23 ) RCT; Netherlands Mean age similar in both group (~ 67 years) T3 (82%) with osseous metastasis; median PSA of around 135 ng/ml; PSA (> 20 ng/ml) in all; Gleason score of 7 or more (> 90%) C: Bicalutamide (50 mg daily) for 4 weeks as flare reduction, followed by LHRH agonist starting 1–2 weeks after randomization, continued until death. I: In addition to ADT, EBRT started within 3 months of ADT initiation, with a prescribed dose of 70 Gy 432 I: 216 C: 216 Median 47 months Parker et al (2018) ( 12 ) RCT; Multicentric (Switzerland and UK) Median age similar in both group (~ 68 years) T3/T4 (82%); N+ (64%); median PSA (98 ng/ml); with predominantly high metastatic burden; Gleason score of 8–10 (82%) C: lifelong androgen deprivation therapy as either gonadotrophin-releasing hormone agonists or antagonists or orchidectomy. I: ADT along with external-beam radiotherapy in one of the two ways; either 36 Gy in six consecutive weekly fractions of 6 Gy, or 55 Gy in 20 daily fractions of 2.75 Gy over 4 weeks. Median time of 75 days for start of RT from the time of ADT initiation 2061 I: 1032 C: 1029 Median 37 months Mason et al (2015) ( 11 ) RCT; Multicentric (UK and Canada) Median age similar in both groups (69.7 years) LAPC; T3/T4 (87%); PSA (> 20 ng/ml) in 63% subjects Gleason score of < 8 (63%) All patients received lifelong ADT before randomisation (patients chose between bilateral orchiectomy (7%) or LHRH agonist (93%)) I: RT was started within 8 weeks of randomisation (65–69 Gy to the prostate and seminal vesicles, 45 Gy to pelvic nodes) 1205 I: 603 C: 602 Median 8.0 years Lin CC et al (2015) ( 24 ) Retrospective cohort; USA Propensity score matching done Median age of subjects 66 years in both groups T1/T2 (58%); clinically node positive, cN+; PSA (> 20 ng/ml) in 49% subjects; Gleason score of 8–10 (64%) C: Data on type and duration of ADT not provided I: ADT along with external beam radiotherapy with median doses of 50.4 Gy to the pelvis and 75.6 Gy total 636 I: 318 C: 318 Median follow up period varied from 2.7 to 5.2 years Bekelman et al (2015) ( 25 ) Retrospective cohort; USA Propensity score matching done Mean age of 71 years in both groups T2 (90%) WHO grade 2 or Gleason score 5–7 (65%) C: ADT was defined as orchiectomy or ≥ 1dose of a gonadotropin-releasing hormone agonist within the first 9 months of diagnosis I: ADT with RT 12,924 I: 8282 C:4642 Mean follow up 6 years Widmark et al (2009) ( 10 ) RCT; Multicentric (Norway, Sweden, Denmark) Mean age similar in both group (~ 66 years) LAPC; T3N0M0 (78%); median PSA of 16.0 ng/ml PSA < 20 ng/ml (60%) WHO grade 2 (65%) C: Total androgen blockade with LHRH-agonist for 3 months along with simultaneous oral flutamide (250 mg, three times daily); Continued flutamide after 3 months until progression or death I: Same total androgen blockade and flutamide treatment for the first 3 months; After 3 months, radiotherapy (≥ 70 Gy) initiated while continuing flutamide until progression or death. 875 I: 436 C: 439 Median 7.6 years RCT- randomized controlled trial; LAPC-locally advanced prostate cancer; PSA- prostate specific antigen; cN + indicates clinically node positive prostate cancer The average age of the subjects in both the groups (i.e., ADT + RT and ADT alone) was similar in all included studies and ranged between 66 to 71 years. There were four studies with participants having locally advanced prostate cancer (LAPC) ( 10 , 11 , 13 , 25 ) two studies with clinically node positive prostate cancer (cN+) ( 22 , 24 ) and remaining two studies had subjects with distant metastasis ( 12 , 23 ). The included studies contributed to a sample of 18,456 with 11,049 subjects receiving ADT with RT and 7407 receiving only ADT. All the studies had a long term follow up (ranging between 2.7 to 8.0 years). In all the studies, except in two, RT was initiated within 2–3 months of starting the ADT (Table 1 ). In the two remaining studies, Lin CC et al. (2015) and Bekelman et al. (2015), information regarding the timing of RT initiation relative to the start of ADT was not reported ( 24 , 25 ). The definition of OS and PSM was largely similar among the included studies, however, the definition of PFS varied. Three studies i.e., Mason et al. ( 11 ), Parker et al. ( 12 ) and Sargos et al ( 13 ) defined PFS based on any of these: biochemical progression (rising PSA levels) or locoregional progression (expansion to nearby tissues or a larger prostatic area) or metastatic progression. On the other hand, Widmark et al ( 10 ) and Boevé et al ( 23 ) relied solely on rising PSA levels. Overall survival (OS), prostate specific mortality (PSM) and progression free survival (PFS) Compared to those who receive only ADT, those receiving a combination of ADT and RT had improved OS (HR 0.75, 95% CI: 0.63, 0.90; N = 7, I 2 = 86.5%) and PFS (HR 0.41 95% CI: 0.20, 0.84; N = 5, I 2 = 98.2%) (Fig. 2 ). The addition of RT to ADT also significantly reduced the risk of PSM (HR 0.52, 95% CI: 0.34, 0.78; N = 5, I 2 = 93.2%), compared to ADT alone (Fig. 2 ). There was no evidence of publication bias, both on eggers test (p = 0.29 for OS; p = 0.70 for PSM; p = 0.15 for PFS) and on visual inspection of the funnel plots (Supplementary Figs. 2–4). The overall certainty of evidence for these outcomes was judged to be “moderate” according to the GRADE assessment criteria (Table 3 ). Upon sensitivity analysis after removing two cohort studies, the effect of combining ADT with RT, compared to ADT alone on OS (HR 0.84, 95% CI: 0.72, 0.99; N = 5, I 2 = 62.6%) and PSM (HR 0.54, 95% CI: 0.33, 0.89; N = 4, I 2 = 89.4%) remained statistically significant (Supplementary Fig. 5). The subgroup analysis shows that patients with locally advanced prostate cancer (LAPC) or clinically node-positive (cN+) disease experience improved overall survival (HR 0.66, 95% CI: 0.59, 0.75; N = 5, I 2 = 51.6%) and lower prostate-specific mortality (HR 0.43, 95% CI: 0.39, 0.49; N = 4, I 2 = 0.0%) with a combination of ADT and RT, but not those with metastatic disease, who had no significant survival benefit (Table 2 ). Those with lower Gleason scores (≤ 7) and baseline PSA levels (< 20 ng/ml) had better overall survival and progression-free survival outcomes with ADT and RT, suggesting these factors could serve as favourable prognostic indicators (Table 2 ). Larger studies (≥ 500 participants) consistently demonstrate survival benefits with a combination of ADT and RT (HR 0.69, 95% CI: 0.57, 0.84; N = 5, I 2 = 85.7%), while smaller studies do not show significant effects on survival. Overall, the findings highlight that patient with LAPC/cN+, lower Gleason scores and lower baseline PSA tend to have better outcomes in survival and disease progression when provided with ADT and RT (Table 2 ). Table 2 Findings of the subgroup analysis comparing ADT and RT, with ADT alone Overall survival (OS) Prostate specific mortality (PSM) Progression free survival (PFS) HR (95% CI); (n, I 2 ) Type LAPC or cN+ Metastatic 0.66 (0.59, 0.75) (5, 51.6%) 0.98 (0.82, 1.17) (2, 39.8%) 0.43 (0.39, 0.49) (4, 0.0%) 0.93 (0.80, 1.09) (1, ---) 0.24 (0.15, 0.37) (3, 86.7%) 0.94 (0.84, 1.04) (2, 0.0%) Gleason score at baseline ≤ 7 ≥ 8 0.68 (0.61, 0.77) (4, 44.4%) 0.81 (0.55, 1.19) (3, 88.7%) 0.43 (0.39, 0.49) (4, 0.0%) 0.93 (0.80, 1.09) (1, ---) 0.24 (0.15, 0.37) (3, 86.7%) 0.94 (0.84, 1.04) (2, 0.0%) PSA at baseline High (≥ 20 ng/ml) Low (< 20 ng/ml) 0.88 (0.75, 1.04) (4, 60.6%) 0.59 (0.43, 0.79) (2, 55.9%) 0.58 (0.32, 1.05) (3, 90.5%) 0.44 (0.30, 0.65) (1, ---) 0.52 (0.28, 0.97) (4, 97.0%) 0.16 (0.12, 0.21) (1, ---) Sample size < 500 ≥ 500 0.97 (0.72, 1.30) (2, 57.0%) 0.69 (0.57, 0.84) (5, 85.7%) 0.40 (0.20, 0.80) (1, ---) 0.54 (0.34, 0.85) (4, 94.8%) 0.49 (0.16, 1.52) (2, 95.7%) 0.36 (0.12, 0.97) (3, 99.0%) HR- hazard ratio; LAPC- locally advanced prostate cancer; cN + clinically node positive prostate cancer Risk of complications Compared to those who receive only ADT, those receiving a combination of ADT and RT had an increased risk of genitourinary (RR 1.80, 95% CI: 1.15, 2.82; N = 3, I 2 = 68.8%) and gastrointestinal complications (RR 4.18, 95% CI: 1.46, 11.96; N = 4, I 2 = 83.7%) along with sexual dysfunction (RR 1.10, 95% CI: 1.02, 1.18; N = 2, I 2 = 0.0%) (Fig. 3 ). There was no evidence of publication bias, both on eggers test (p = 0.43 for genitourinary complications; p = 0.08 for gastrointestinal complications) and on visual inspection of the funnel plots (Supplementary Figs. 6,7). The publication bias for sexual dysfunction could not be assessed due to very few studies reporting on this outcome. The common complications reported in the included studies were bladder obstruction, urethral stricture, urinary incontinence, increased urinary frequency, moderate to severe diarrhoea, rectal bleeding, proctitis, loss of libido and erectile dysfunction. The overall certainty of evidence for outcomes related to the risk of complications was judged to be “low” according to the GRADE assessment criteria (Table 3 ). Table 3 Quality of the pooled evidence using the GRADE assessment Number of studies with design Certainty of the evidence (GRADE) Effect size (95% CI); I 2 Overall survival N = 7 (5 RCT; 2 cohort) ⨁⨁⨁◯ Moderate a HR 0.75, (0.63 to 0.90); 86.5% Prostate specific mortality N = 5 (4 RCT; 1 cohort) ⨁⨁◯◯ Moderate a HR 0.52, (0.34 to 0.78); 93.2% Progression free survival N = 5 (All RCT) ⨁⨁⨁◯ Moderate a HR 0.41, (0.20 to 0.84); 98.2% Genito-urinary complications N = 3 (All RCT) ⨁⨁⨁◯ Low b RR 1.80, (1.15 to 2.82); 68.8% Gastro-intestinal complications N = 4 (All RCT) ⨁⨁⨁◯ Low c RR 4.18, (1.46 to 11.9); 83.7% Sexual dysfunction N = 2 (All RCT) ⨁⨁⨁◯ Low d RR 1.10, (1.02 to 1.18); 0.0% a Downgraded one-level for serious inconsistency (high heterogeneity) b Downgraded two-levels for serious inconsistency (high heterogeneity) and sample size less than optimal information size (OIS) (serious imprecision) c Downgraded two-levels for serious inconsistency (high heterogeneity) and uncertainty due to wide-confidence intervals (imprecision) d Downgraded two-levels for serious inconsistency (small number of studies); serious imprecision (suboptimal sample size) RR: relative risk; HR: hazard ratio; RCT: randomized controlled trial Discussion The low to moderate certainty of findings from our meta-analysis are suggestive of the effectiveness of androgen deprivation therapy (ADT) in combination with radiation therapy (RT) compared to ADT alone for patients with prostate cancer. This analysis, encompassing eight studies with around 18,000 participants, reveals significant improvements in overall survival (OS), prostate-specific mortality (PSM), and progression-free survival (PFS) with the combined treatment approach, particularly in patients with locally advanced prostate cancer (LAPC) and clinically node-positive (cN+) disease. However, the analysis also underscores the increased risk of complications associated with the combination therapy, necessitating careful consideration of treatment strategies in clinical practice. Considering that the certainty of evidence is low or moderate, more robust studies are needed to support the findings. Previous meta-analyses have examined the efficacy of ADT combined with RT versus ADT alone but were limited by a small number of studies and lacked comprehensive subgroup analyses to explore variations in treatment effects across different patient populations and disease characteristics. Additionally, since the publication of these reviews, several new trials have emerged, providing updated data that necessitate a re-evaluation of the existing evidence. Our meta-analysis incorporates these recent studies, allowing for a more robust and nuanced assessment of the impact of ADT plus RT on key clinical outcomes. By performing detailed subgroup analyses, we aimed to clarify the patient populations that derive the most benefit from combined therapy, thereby addressing existing gaps in the literature and informing personalized treatment strategies for prostate cancer. Wang et al. conducted an indirect comparison of the efficacy of various systemic and local treatment combinations for metastatic hormone-sensitive prostate cancer ( 14 ). Their meta-analysis included 10 randomized controlled trials, but only two compared ADT combined with RT to ADT monotherapy. The review found no significant difference in overall survival and progression-free survival between the two groups. However, overall survival was significantly improved in patients with low-volume disease, similar to our analysis where those with LAPC and cN + had the maximum benefit ( 14 ). Another review by Lei et al, documented the long-term survival outcomes associated with ADT alone versus ADT combined with RT for locally advanced ( 15 ). A total of three RCTs (n = 2344) contributed to this analysis and found that adding RT to long-term ADT improved overall survival, similar to our findings ( 15 ). The enhanced effectiveness of combined therapy might be attributed to some underlying mechanisms. First, RT targets the tumor directly, providing localized control that may complement the systemic action of ADT, which aims to reduce circulating testosterone levels and limit tumor growth ( 26 , 27 ). The combination of these modalities may result in a more comprehensive approach to tumour eradication, leading to improved patient outcomes. Moreover, in patients with LAPC or cN + disease, the tumour is more likely to be responsive to both treatments. The localized control achieved through RT may lead to a reduction in tumour burden, enhancing the efficacy of ADT by mitigating the potential for cancer cells to adapt and resist hormonal therapy. This synergy might explain the observed survival benefits, particularly in these subgroups. One key aspect is the effect of ADT on the tumour microenvironment. By lowering testosterone levels, ADT may induce changes in the tumour microenvironment that enhance the susceptibility of cancer cells to radiation damage ( 28 , 29 ). Studies have shown that androgen deprivation can lead to increased tumour cell apoptosis and a more favorable response to RT ( 30 , 31 ). Additionally, the alteration of the cell cycle dynamics induced by ADT may further sensitize prostate cancer cells to radiation. Despite the observed survival benefits, our analysis highlights a concerning increase in the risk of complications associated with the combination of ADT and RT. Specifically, patients receiving both therapies faced a higher incidence of genitourinary and gastrointestinal complications, along with sexual dysfunction. These complications may significantly impact patients’ quality of life and overall treatment satisfaction. The increased risk of complications necessitates a nuanced approach to therapy selection, where the potential survival benefits must be weighed against the likelihood of adverse effects. Clinicians should engage in shared decision-making with patients, discussing the risks and benefits of combined therapy and considering patients’ preferences when determining the optimal treatment strategy. This meta-analysis has several limitations that warrant consideration. First, while the pooled analysis mainly included RCTs, it also incorporated two cohort studies, which raises questions about combining different study designs. However, these cohort studies used propensity score matching to ensure similar baseline characteristics between study groups, justifying their inclusion in the pooled analysis. Further, on sensitivity analysis after removing two cohort studies, the effect of combining ADT with RT, compared to ADT alone on overall survival and prostate specific mortality continued to remain statistically significant. Second, considerable heterogeneity was observed across studies for several outcomes, likely due to differences in patient characteristics, study settings, and outcome definitions, particularly with regards to defining progression. Although a random-effects model was applied to address this variability, interpreting the pooled results still requires caution. Third, while a broader range of complications would have added value to the analysis, inconsistent reporting across studies limited our ability to harmonize and pool data on complications beyond genitourinary, gastrointestinal, and sexual issues. Additionally, we could not perform a subgroup analysis based on whether ADT and RT were initiated concurrently or with ADT used as a neoadjuvant therapy, as in all included studies, RT began 2–3 months after ADT initiation. Lastly, our findings are applicable to the age range of 18–75 years and may not be generalizable to patients over 75. Implications for clinical practice and future research directions The findings have important implications for clinical practice and future research directions. The findings indicate the need for healthcare providers to engage patients in shared decision-making processes, discussing the benefits of improved survival outcomes alongside the risks of increased complications. Monitoring patients for these complications is essential, with proactive management strategies implemented to address any adverse effects on quality of life. Personalizing treatment strategies based on individual patient characteristics, such as Gleason scores and baseline PSA levels, may optimize outcomes while minimizing risks. There is a need for longitudinal studies aimed at identifying biomarkers that may predict favourable responses to combined therapy. Such information could lead to more effective patient stratification and personalized treatment plans. Additionally, mechanistic studies exploring the biological interactions between ADT and RT will deepen our understanding of treatment synergies. Comparative effectiveness research should investigate the efficacy of ADT and RT against emerging modalities, while patient-centered outcomes research should focus on quality of life, mental health, and treatment satisfaction. Conclusion Our analysis demonstrates that combining androgen deprivation therapy (ADT) with radiation therapy (RT) significantly improves overall survival, progression-free survival, and reduces prostate-specific mortality compared to ADT alone in patients with prostate cancer, particularly those with locally advanced or clinically node-positive disease. However, this combination also leads to a higher incidence of genitourinary, gastrointestinal, and sexual complications. While these findings suggest a strong therapeutic benefit for selected patients, they come with a trade-off in terms of increased adverse effects. Given the limitations of study heterogeneity and low to moderate certainty of evidence, further research is essential to refine treatment protocols, explore optimal timing of ADT and RT, and better define patient subgroups who might benefit most from this combined approach. Abbreviations ADT – Androgen Deprivation Therapy CI – Confidence Interval cN+ – Clinically Node-Positive Prostate Cancer GRADE – Grading of Recommendations Assessment, Development, and Evaluation HR – Hazard Ratio LAPC – Locally Advanced Prostate Cancer NOS – Newcastle-Ottawa Scale OS – Overall Survival PFS – Progression-Free Survival PRISMA – Preferred Reporting Items for Systematic Reviews and Meta-Analyses PSA – Prostate-Specific Antigen PSM – Prostate-Specific Mortality RCT – Randomized Controlled Trial RR – Relative Risk RT – Radiation Therapy Declarations Availability of data and materials All data generated, used, and analysed in this study are either included in this published article or are available from the corresponding author upon reasonable request. Ethics approval and consent to participate Not applicable Consent for publication No individual human participation in the current study. The current metanalysis recorded in the international database of prospectively registered systematic reviews (PROSPERO): CRD42024602727 Competing interests The authors declare no competing interests Funding No fund to declare Authors' contributions Data curation: E.R.,W.B., M.N., A.B. Formal analysis: E.R. Investigation: E.R.,W.B., M.N. Methodology: E.R.,W.B., M.N. validation: E.R.,W.B., M.N., A.B.Visualization: E.R.,W.B., M.N., A.B.. Writing – original draft: E.R.,W.B. Writing – review & editing: E.R.,W.B., M.N., A.B. Acknowledgements Not applicable Conflict of interest The authors declare no conflicts of interest. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338. Zhang W, Cao G, Wu F, Wang Y, Liu Z, Hu H, Xu K. 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BMJ (1997); 315:629–634. doi: 10.1136/bmj.315.7109.629 Lee TH, Pyo H, Yoo GS, Kim JH, Jeon SS, Seo SI, Jeong BC, Jeon HG, Sung HH, Kang M, Song W, Chung JH, Park W. Androgen deprivation alone versus combined with pelvic radiation for adverse events and quality of life in clinically node-positive prostate cancer. Sci Rep. 2024 Apr 8;14(1):8207. doi: 10.1038/s41598-024-54976-z. PMID: 38589463; PMCID: PMC11001889. Boevé LMS, Hulshof MCCM, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, Delaere KPJ, Moorselaar RJAV, Verhagen PCMS, van Andel G. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019 Mar;75(3):410-418. doi: 10.1016/j.eururo.2018.09.008. Epub 2018 Sep 25. PMID: 30266309. Lin CC, Gray PJ, Jemal A, Efstathiou JA. Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer. J Natl Cancer Inst. 2015 May 9;107(7):djv119. doi: 10.1093/jnci/djv119. PMID: 25957435. Bekelman JE, Mitra N, Handorf EA, Uzzo RG, Hahn SA, Polsky D, Armstrong K. Effectiveness of androgen-deprivation therapy and radiotherapy for older men with locally advanced prostate cancer. J Clin Oncol. 2015 Mar 1;33(7):716-22. doi: 10.1200/JCO.2014.57.2743. Epub 2015 Jan 5. PMID: 25559808; PMCID: PMC4334776. Gay HA, Michalski JM. Radiation Therapy for Prostate Cancer. Mo Med. 2018 Mar-Apr;115(2):146-150. PMID: 30228707; PMCID: PMC6139853. Katzenwadel A, Wolf P. Androgen deprivation of prostate cancer: Leading to a therapeutic dead end. Cancer Lett. 2015 Oct 10;367(1):12-7. doi: 10.1016/j.canlet.2015.06.021. Epub 2015 Jul 13. PMID: 26185001. Wu CT, Chen WC, Chen MF. The Response of Prostate Cancer to Androgen Deprivation and Irradiation Due to Immune Modulation. Cancers (Basel). 2018 Dec 26;11(1):20. doi: 10.3390/cancers11010020. PMID: 30587810; PMCID: PMC6356767. Kalina JL, Neilson DS, Comber AP, Rauw JM, Alexander AS, Vergidis J, Lum JJ. Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy. Cancers (Basel). 2017 Jan 27;9(2):13. doi: 10.3390/cancers9020013. PMID: 28134800; PMCID: PMC5332936. Lorenzo PI, Saatcioglu F. Inhibition of apoptosis in prostate cancer cells by androgens is mediated through downregulation of c-Jun N-terminal kinase activation. Neoplasia. 2008 May;10(5):418-28. doi: 10.1593/neo.07985. PMID: 18472959; PMCID: PMC2373916. Pelliccia A, Capradossi F, Corsi F, Tarquini GD, Bruni E, Reichle A, Torino F, Ghibelli L. Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase Inhibition. Int J Mol Sci. 2023 Jan 20;24(3):2040. doi: 10.3390/ijms24032040. PMID: 36768364; PMCID: PMC9917232. Ben-Salem S, Venkadakrishnan VB, Heemers HV. Novel insights in cell cycle dysregulation during prostate cancer progression. Endocr Relat Cancer. 2021 May 11;28(6):R141-R155. doi: 10.1530/ERC-20-0517. PMID: 33830069; PMCID: PMC8496945. Schiewer MJ, Augello MA, Knudsen KE. The AR dependent cell cycle: mechanisms and cancer relevance. Mol Cell Endocrinol. 2012 Apr 16;352(1-2):34-45. doi: 10.1016/j.mce.2011.06.033. Epub 2011 Jul 12. PMID: 21782001; PMCID: PMC3641823. Additional Declarations No competing interests reported. Supplementary Files SUPPLEMENTARYDOCUMENTbmc.doc Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6206964","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436955578,"identity":"cddb8600-cad7-4547-9fda-294259a34941","order_by":0,"name":"Emad 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University","correspondingAuthor":false,"prefix":"","firstName":"Mansour","middleName":"","lastName":"Alnazari","suffix":""},{"id":436955583,"identity":"c9c1fcd5-cbf8-42f8-a69f-891adc500d43","order_by":2,"name":"Abdulaziz Bakhsh","email":"","orcid":"","institution":"Taibah University","correspondingAuthor":false,"prefix":"","firstName":"Abdulaziz","middleName":"","lastName":"Bakhsh","suffix":""},{"id":436955584,"identity":"316c8ca8-0732-4348-ab91-4b903a7dc9a7","order_by":3,"name":"Walaa Borhan","email":"","orcid":"","institution":"Taibah University","correspondingAuthor":false,"prefix":"","firstName":"Walaa","middleName":"","lastName":"Borhan","suffix":""}],"badges":[],"createdAt":"2025-03-11 21:23:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6206964/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6206964/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80050201,"identity":"044ca1c7-510a-4e0d-a906-0dec0c230c6e","added_by":"auto","created_at":"2025-04-07 10:18:59","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79323,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSelection process of studies included in the review\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6206964/v1/11ca0fa4b6043af194af4f54.jpg"},{"id":80051913,"identity":"2c6301cd-cea3-43ae-b41a-d851398c3f72","added_by":"auto","created_at":"2025-04-07 10:34:59","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100750,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival (OS), progression free survival (PFS) and prostate specific mortality (PSM) in those receiving a combination of ADT and RT, compared to those with ADT alone\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6206964/v1/9060d2bc9fb970c85842e74f.jpg"},{"id":80050202,"identity":"d77288b1-fefd-496b-865d-b3995308f977","added_by":"auto","created_at":"2025-04-07 10:18:59","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":93167,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRisk of complications in those receiving a combination of ADT and RT, compared to those with ADT alone\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6206964/v1/5cb5d0a39d2be0318f46450c.jpg"},{"id":82267282,"identity":"f9d6ef05-f9ab-4524-ac25-00569be7d9c8","added_by":"auto","created_at":"2025-05-08 13:32:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1604661,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6206964/v1/3e19f755-b684-449d-824e-8c4267fdde92.pdf"},{"id":80050207,"identity":"6f0fd270-b658-43d7-98c9-81bda48759f6","added_by":"auto","created_at":"2025-04-07 10:18:59","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":972288,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYDOCUMENTbmc.doc","url":"https://assets-eu.researchsquare.com/files/rs-6206964/v1/d3b175d6bbe38a40bd83c07b.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of Androgen Deprivation Therapy (ADT) in Combination with Radiation Therapy, compared to ADT alone in Patients with High-Risk Prostate Cancer: a meta-analysis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eProstate cancer is one of the most prevalent cancers among men globally (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In 2020, there were an estimated 1.41\u0026nbsp;million new cases and 375,000 deaths from prostate cancer worldwide (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). From 1990 to 2019, the incidence and mortality rates of prostate cancer increased by nearly 116.0% and 109.0%, respectively, a trend likely to continue as the global population ages (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Over the past few decades, treatment strategies for prostate cancer have evolved significantly. For patients with locally advanced or metastatic hormone-sensitive prostate cancer, androgen deprivation therapy (ADT) has remained a cornerstone of treatment (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). By inhibiting androgen production, ADT helps slow disease progression and improves control (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, despite its effectiveness, ADT alone often fails to provide long-term remission, particularly in patients with more advanced stages of the disease (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRecent advancements have investigated the combination of androgen deprivation therapy (ADT) with other treatment options, such as radiation therapy (RT), to improve survival outcomes (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Radiation therapy targets localized tumour areas, aiming to reduce cancer progression and enhance overall survival. Randomized controlled trials have compared ADT alone to ADT combined with RT, yielding mixed results. While some studies report a notable survival benefit with the combined treatment (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), others either do not show any survival benefit or raise concerns about potential side effects (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious efforts have attempted to synthesize the findings of studies comparing androgen deprivation therapy (ADT) alone to ADT combined with radiation therapy (RT), but the evidence has not been conclusive (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Wang et al. conducted a meta-analysis including two randomized controlled trials comparing a combination of ADT and RT with ADT monotherapy, finding no significant difference in overall survival or progression-free survival, except for improved survival in cases of low-volume disease (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Similarly, Lei et al.'s review of three RCTs reported that adding RT to long-term ADT improved overall survival in locally advanced prostate cancer (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, these reviews did not perform appropriate subgroup analyses to determine whether the effects on survival and disease progression differ across patient and disease characteristics. Since the publication of these reviews, more studies have been conducted on this topic and this necessitates the existing evidence to be updated. The current meta-analysis aims to comprehensively evaluate and compare the effectiveness of ADT combined with RT versus ADT alone, focusing on primary outcomes including overall survival, prostate-specific mortality, and progression-free survival.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCompliance to relevant guidelines\u003c/h2\u003e \u003cp\u003eOur meta-analysis was conducted in accordance with the PRISMA guidelines (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Additionally, prospectively registered the study protocol in PROSPERO (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/prospero/\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/prospero/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (CRD42024602727).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIdentification of studies\u003c/h3\u003e\n\u003cp\u003eA systematic and thorough search strategy was developed to identify relevant studies from electronic databases, including PubMed, Embase, Web of Science and Scopus. The specific search strategy employed for each of the above databases has been presented in supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The search was limited to studies published between 1st January 2000 and 15th October 2024. Manual searches of reference lists and relevant review articles was also done to ensure the inclusion of any additional studies that may have been overlooked during the electronic search process.\u003c/p\u003e\n\u003ch3\u003eInclusion and exclusion criteria\u003c/h3\u003e\n\u003cp\u003eStudies involving adult patients (aged 18\u0026ndash;75 years) with prostate cancer, confirmed through pathological evaluation, were eligible for inclusion. Eligible studies required an intervention group receiving a combination of androgen deprivation therapy (ADT) and radiation therapy, compared to a control group receiving ADT alone. Studies were excluded if participants had undergone other baseline treatments, such as radical prostatectomy. The primary outcomes of interest included overall survival (OS), progression-free survival (PFS) and prostate/cancer-specific mortality (PSM). The secondary outcome of interest was the risk of complications. Only studies with a randomized controlled trial (RCT), cohort, or case-control design were considered, and studies needed to report effect sizes with 95% confidence intervals for at least one outcome to ensure data relevance. Inclusion was restricted to English-language studies published in peer-reviewed journals. In cases where multiple studies originated from the same dataset, the study presenting data with the longest follow-up period was selected for inclusion.\u003c/p\u003e \u003cp\u003eStudies involving patients younger than 18 or older than 75 years were excluded. Additionally, studies were not eligible if the comparison groups were irrelevant to the review objective, such as comparisons of ADT with radiation therapy (RT) to RT alone, studies assessing ADT as a concurrent versus neoadjuvant therapy to RT, or comparisons based on varying durations of ADT or different durations and doses of RT. Case reports, case series, review articles, editorials, letters to the editor, and commentaries were also excluded. Studies that did not report usable effect sizes for analysis were not considered.\u003c/p\u003e\n\u003ch3\u003eProcess of study selection\u003c/h3\u003e\n\u003cp\u003eAfter applying the search strategy across designated databases, the first step was to remove duplicate studies. Two independent experts (A.S.R, W.M.B) then conducted a thorough review of the remaining studies. In the initial screening phase, each study\u0026rsquo;s title and abstract were carefully examined to assess their relevance to the research question. Studies that appeared potentially relevant were selected for further evaluation. In the next stage, a detailed assessment of the full text was performed to determine each study\u0026rsquo;s eligibility for inclusion in the meta-analysis. Any disagreements regarding study inclusion were resolved through in-depth discussions among the authors. During the initial screening phase, an inter-rater reliability assessment was also conducted among the reviewers (A.S.R, W.M.B) to evaluate consistency in study selection. If the initial agreement was found to be below the acceptable level (inter-rater reliability of less than 75%), a detailed discussion was organized with the screening team, led by the principal investigator (E.S.R), to ensure clarity and alignment on inclusion and exclusion criteria.\u003c/p\u003e\n\u003ch3\u003eData extraction and quality assessment\u003c/h3\u003e\n\u003cp\u003eData extraction from the final set of included studies was conducted independently by two authors using a standardized data extraction form. Extracted data included study identifiers (first author\u0026rsquo;s name and year of publication), study design, country of study, participant and tumour characteristics, management details for the intervention and control groups, sample size, follow-up duration, and relevant findings. Any discrepancies between the two authors were resolved through discussion to reach consensus. For risk of bias assessment, we used the Newcastle-Ottawa Scale (NOS) for cohort studies and the Cochrane Risk of Bias (RoB 2.0) tool for randomized controlled trials (RCTs) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Quality assessment was performed independently by the two independent experts (M.N., W.B.). The certainty of the evidence was assessed using the standard GRADE approach ( gradepro.org) and GRADE Pro Software (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePooled effect sizes were reported as hazard ratios (HR) or relative risks (RR), each with corresponding 95% confidence intervals (CI). A random-effects model was used for all analyses to account for variations in baseline characteristics across studies (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The pooled analysis primarily included RCTs, with two cohort studies that used propensity score matching for baseline comparability. A sensitivity analysis was conducted excluding these cohort studies. Publication bias was assessed using Egger's test and by visually inspecting funnel plots (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Statistical significance was defined as a p-value of less than 0.05. Subgroup analysis for the primary outcomes was conducted based on type of prostate cancer (locally advanced prostate cancer, LAPC or node positivity, cN\u0026thinsp;+\u0026thinsp;and metastatic), baseline Gleason score (\u0026le;\u0026thinsp;7 and \u0026ge;\u0026thinsp;8), baseline prostate specific antigen (PSA) level (\u0026ge;\u0026thinsp;20 ng/ml or \u0026lt;\u0026thinsp;20 ng/ml) and sample size (\u0026lt;\u0026thinsp;500 and \u0026ge;\u0026thinsp;500).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eWe conducted a systematic search and identified 1925 studies. After removing 498 duplicates, we screened the titles and abstracts of the remaining 1427 unique studies. This led to exclusion of 1382 studies based on their potential relevance to the review. We then reviewed the full texts of the remaining 45 studies and excluded 37 more that did not meet our inclusion criteria, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. This process resulted in a final selection of 8 studies for analysis (\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe study characteristics are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were six randomized controlled trials (RCT) (\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In the remaining two cohort-based studies, propensity score matching was done which ensured that the baseline characteristics between the study groups was similar (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Three studies were multicentric, two were done in the United States of America (USA) and one study each was conducted in Republic of Korea, France and Netherlands (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The two cohort studies obtained a score of 7 (out of the maximum attainable score of 9) on the NOS assessment (Supplementary table 2). The remaining 5 RCTs were also judged to have low risk of bias (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary characteristics of the studies included in the review\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor (publication year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design and place of study\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTumour characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIntervention(I) and comparator (C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDuration of follow up\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLee TH et al (2024) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT; Republic of Korea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian age similar in both groups (70 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT3/T4 (100%); cN+; median PSA (36 ng/ml); node positive but no distant metastasis\u003c/p\u003e \u003cp\u003eGleason score of 8\u0026ndash;10 (85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC: ADT administered using a combination of a gonadotropin-releasing hormone (GnRH) agonist and anti-androgen.\u003c/p\u003e \u003cp\u003eADT given for at least 2 years\u003c/p\u003e \u003cp\u003eI: ADT along with radiotherapy (RT) (70 Gy in 28 fractions). RT started after 2\u0026ndash;3 months of ADT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003cp\u003eI: 29\u003c/p\u003e \u003cp\u003eC: 31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian 3.3 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSargos et al (2020) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT; France\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean age similar in both group (~\u0026thinsp;71 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLAPC; T3N0M0 (95%); median PSA of 26.8 ng/ml; PSA (\u0026ge;\u0026thinsp;20 ng/ml) in ~\u0026thinsp;64%\u003c/p\u003e \u003cp\u003eGleason score of 7 or less (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC: LHRH agonist (leuprorelin) for 3 years, along with oral flutamide (750 mg/day) for the first month.\u003c/p\u003e \u003cp\u003eI: In addition to ADT, external beam radiation therapy (EBRT) (whole pelvis dose of 46 Gy with prostate having boost from 20 to 28 Gy), initiated within 90 days of the first leuprorelin injection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e263\u003c/p\u003e \u003cp\u003eI: 133\u003c/p\u003e \u003cp\u003eC: 130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian 7.3 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoev\u0026eacute; et al (2019) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT; Netherlands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean age similar in both group (~\u0026thinsp;67 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT3 (82%) with osseous metastasis; median PSA of around 135 ng/ml; PSA (\u0026gt;\u0026thinsp;20 ng/ml) in all; Gleason score of 7 or more (\u0026gt;\u0026thinsp;90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC: Bicalutamide (50 mg daily) for 4 weeks as flare reduction, followed by LHRH agonist starting 1\u0026ndash;2 weeks after randomization, continued until death.\u003c/p\u003e \u003cp\u003eI: In addition to ADT, EBRT started within 3 months of ADT initiation, with a prescribed dose of 70 Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e432\u003c/p\u003e \u003cp\u003eI: 216\u003c/p\u003e \u003cp\u003eC: 216\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian 47 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParker et al (2018) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT; Multicentric (Switzerland and UK)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian age similar in both group (~\u0026thinsp;68 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT3/T4 (82%); N+ (64%); median PSA (98 ng/ml); with predominantly high metastatic burden; Gleason score of 8\u0026ndash;10 (82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC: lifelong androgen deprivation therapy as either gonadotrophin-releasing hormone agonists or antagonists or orchidectomy.\u003c/p\u003e \u003cp\u003eI: ADT along with external-beam radiotherapy in one of the two ways; either 36 Gy in six consecutive weekly fractions of 6 Gy, or 55 Gy in 20 daily fractions of 2.75 Gy over 4 weeks. Median time of 75 days for start of RT from the time of ADT initiation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2061\u003c/p\u003e \u003cp\u003eI: 1032\u003c/p\u003e \u003cp\u003eC: 1029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian 37 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMason et al (2015) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT; Multicentric (UK and Canada)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian age similar in both groups (69.7 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLAPC; T3/T4 (87%); PSA (\u0026gt;\u0026thinsp;20 ng/ml) in 63% subjects\u003c/p\u003e \u003cp\u003eGleason score of \u0026lt;\u0026thinsp;8 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAll patients received lifelong ADT before randomisation (patients chose between bilateral orchiectomy (7%) or LHRH agonist (93%))\u003c/p\u003e \u003cp\u003eI: RT was started within 8 weeks of randomisation (65\u0026ndash;69 Gy to the prostate and seminal vesicles, 45 Gy to\u003c/p\u003e \u003cp\u003epelvic nodes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1205\u003c/p\u003e \u003cp\u003eI: 603\u003c/p\u003e \u003cp\u003eC: 602\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian 8.0 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLin CC et al (2015) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort; USA\u003c/p\u003e \u003cp\u003ePropensity score matching done\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian age of subjects 66 years in both groups\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT1/T2 (58%); clinically node positive, cN+; PSA (\u0026gt;\u0026thinsp;20 ng/ml) in 49% subjects; Gleason score of 8\u0026ndash;10 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC: Data on type and duration of ADT not provided\u003c/p\u003e \u003cp\u003eI: ADT along with external beam radiotherapy with median doses of 50.4\u003c/p\u003e \u003cp\u003eGy to the pelvis and 75.6 Gy total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e636\u003c/p\u003e \u003cp\u003eI: 318\u003c/p\u003e \u003cp\u003eC: 318\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian follow up period varied from 2.7 to 5.2 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBekelman et al (2015) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetrospective cohort; USA\u003c/p\u003e \u003cp\u003ePropensity score matching done\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean age of 71 years in both groups\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT2 (90%)\u003c/p\u003e \u003cp\u003eWHO grade 2 or Gleason score 5\u0026ndash;7 (65%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC: ADT was defined as orchiectomy or \u0026ge;\u0026thinsp;1dose of a gonadotropin-releasing hormone agonist within the first 9 months of diagnosis\u003c/p\u003e \u003cp\u003eI: ADT with RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12,924\u003c/p\u003e \u003cp\u003eI: 8282\u003c/p\u003e \u003cp\u003eC:4642\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMean follow up 6 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWidmark et al (2009) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCT; Multicentric (Norway, Sweden, Denmark)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean age similar in both group (~\u0026thinsp;66 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLAPC; T3N0M0 (78%); median PSA of 16.0 ng/ml\u003c/p\u003e \u003cp\u003ePSA\u0026thinsp;\u0026lt;\u0026thinsp;20 ng/ml (60%)\u003c/p\u003e \u003cp\u003eWHO grade 2 (65%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC: Total androgen blockade with LHRH-agonist for 3 months along with simultaneous oral flutamide (250 mg, three times daily); Continued flutamide after 3 months until progression or death\u003c/p\u003e \u003cp\u003eI: Same total androgen blockade and flutamide treatment for the first 3 months; After 3 months, radiotherapy (\u0026ge;\u0026thinsp;70 Gy) initiated while continuing flutamide until progression or death.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e875\u003c/p\u003e \u003cp\u003eI: 436\u003c/p\u003e \u003cp\u003eC: 439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian 7.6 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eRCT- randomized controlled trial; LAPC-locally advanced prostate cancer; PSA- prostate specific antigen; cN\u0026thinsp;+\u0026thinsp;indicates clinically node positive prostate cancer\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe average age of the subjects in both the groups (i.e., ADT\u0026thinsp;+\u0026thinsp;RT and ADT alone) was similar in all included studies and ranged between 66 to 71 years. There were four studies with participants having locally advanced prostate cancer (LAPC) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) two studies with clinically node positive prostate cancer (cN+) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) and remaining two studies had subjects with distant metastasis (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The included studies contributed to a sample of 18,456 with 11,049 subjects receiving ADT with RT and 7407 receiving only ADT. All the studies had a long term follow up (ranging between 2.7 to 8.0 years). In all the studies, except in two, RT was initiated within 2\u0026ndash;3 months of starting the ADT (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In the two remaining studies, Lin CC et al. (2015) and Bekelman et al. (2015), information regarding the timing of RT initiation relative to the start of ADT was not reported (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The definition of OS and PSM was largely similar among the included studies, however, the definition of PFS varied. Three studies i.e., Mason et al. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), Parker et al. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and Sargos et al (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) defined PFS based on any of these: biochemical progression (rising PSA levels) or locoregional progression (expansion to nearby tissues or a larger prostatic area) or metastatic progression. On the other hand, Widmark et al (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and Boev\u0026eacute; et al (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) relied solely on rising PSA levels.\u003c/p\u003e\n\u003ch3\u003eOverall survival (OS), prostate specific mortality (PSM) and progression free survival (PFS)\u003c/h3\u003e\n\u003cp\u003eCompared to those who receive only ADT, those receiving a combination of ADT and RT had improved OS (HR 0.75, 95% CI: 0.63, 0.90; N\u0026thinsp;=\u0026thinsp;7, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;86.5%) and PFS (HR 0.41 95% CI: 0.20, 0.84; N\u0026thinsp;=\u0026thinsp;5, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;98.2%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The addition of RT to ADT also significantly reduced the risk of PSM (HR 0.52, 95% CI: 0.34, 0.78; N\u0026thinsp;=\u0026thinsp;5, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;93.2%), compared to ADT alone (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was no evidence of publication bias, both on eggers test (p\u0026thinsp;=\u0026thinsp;0.29 for OS; p\u0026thinsp;=\u0026thinsp;0.70 for PSM; p\u0026thinsp;=\u0026thinsp;0.15 for PFS) and on visual inspection of the funnel plots (Supplementary Figs.\u0026nbsp;2\u0026ndash;4). The overall certainty of evidence for these outcomes was judged to be \u0026ldquo;moderate\u0026rdquo; according to the GRADE assessment criteria (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Upon sensitivity analysis after removing two cohort studies, the effect of combining ADT with RT, compared to ADT alone on OS (HR 0.84, 95% CI: 0.72, 0.99; N\u0026thinsp;=\u0026thinsp;5, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;62.6%) and PSM (HR 0.54, 95% CI: 0.33, 0.89; N\u0026thinsp;=\u0026thinsp;4, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;89.4%) remained statistically significant (Supplementary Fig.\u0026nbsp;5).\u003c/p\u003e \u003cp\u003eThe subgroup analysis shows that patients with locally advanced prostate cancer (LAPC) or clinically node-positive (cN+) disease experience improved overall survival (HR 0.66, 95% CI: 0.59, 0.75; N\u0026thinsp;=\u0026thinsp;5, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;51.6%) and lower prostate-specific mortality (HR 0.43, 95% CI: 0.39, 0.49; N\u0026thinsp;=\u0026thinsp;4, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0%) with a combination of ADT and RT, but not those with metastatic disease, who had no significant survival benefit (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Those with lower Gleason scores (\u0026le;\u0026thinsp;7) and baseline PSA levels (\u0026lt;\u0026thinsp;20 ng/ml) had better overall survival and progression-free survival outcomes with ADT and RT, suggesting these factors could serve as favourable prognostic indicators (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Larger studies (\u0026ge;\u0026thinsp;500 participants) consistently demonstrate survival benefits with a combination of ADT and RT (HR 0.69, 95% CI: 0.57, 0.84; N\u0026thinsp;=\u0026thinsp;5, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;85.7%), while smaller studies do not show significant effects on survival. Overall, the findings highlight that patient with LAPC/cN+, lower Gleason scores and lower baseline PSA tend to have better outcomes in survival and disease progression when provided with ADT and RT (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFindings of the subgroup analysis comparing ADT and RT, with ADT alone\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall survival (OS)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProstate specific mortality (PSM)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProgression free survival (PFS)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eHR (95% CI); (n, I\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType\u003c/p\u003e \u003cp\u003eLAPC or cN+\u003c/p\u003e \u003cp\u003eMetastatic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.66 (0.59, 0.75) (5, 51.6%)\u003c/p\u003e \u003cp\u003e0.98 (0.82, 1.17) (2, 39.8%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43 (0.39, 0.49) (4, 0.0%)\u003c/p\u003e \u003cp\u003e0.93 (0.80, 1.09) (1, ---)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24 (0.15, 0.37) (3, 86.7%)\u003c/p\u003e \u003cp\u003e0.94 (0.84, 1.04) (2, 0.0%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGleason score at baseline\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;7\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.68 (0.61, 0.77) (4, 44.4%)\u003c/p\u003e \u003cp\u003e0.81 (0.55, 1.19) (3, 88.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43 (0.39, 0.49) (4, 0.0%)\u003c/p\u003e \u003cp\u003e0.93 (0.80, 1.09) (1, ---)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24 (0.15, 0.37) (3, 86.7%)\u003c/p\u003e \u003cp\u003e0.94 (0.84, 1.04) (2, 0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePSA at baseline\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHigh (\u0026ge;\u0026thinsp;20 ng/ml)\u003c/p\u003e \u003cp\u003eLow (\u0026lt;\u0026thinsp;20 ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.88 (0.75, 1.04) (4, 60.6%)\u003c/p\u003e \u003cp\u003e0.59 (0.43, 0.79) (2, 55.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.58 (0.32, 1.05) (3, 90.5%)\u003c/p\u003e \u003cp\u003e0.44 (0.30, 0.65) (1, ---)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.52 (0.28, 0.97) (4, 97.0%)\u003c/p\u003e \u003cp\u003e0.16 (0.12, 0.21) (1, ---)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSample size\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;500\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97 (0.72, 1.30) (2, 57.0%)\u003c/p\u003e \u003cp\u003e0.69 (0.57, 0.84) (5, 85.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.40 (0.20, 0.80) (1, ---)\u003c/p\u003e \u003cp\u003e0.54 (0.34, 0.85) (4, 94.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.49 (0.16, 1.52) (2, 95.7%)\u003c/p\u003e \u003cp\u003e0.36 (0.12, 0.97) (3, 99.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eHR- hazard ratio; LAPC- locally advanced prostate cancer; cN\u0026thinsp;+\u0026thinsp;clinically node positive prostate cancer\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRisk of complications\u003c/h2\u003e \u003cp\u003eCompared to those who receive only ADT, those receiving a combination of ADT and RT had an increased risk of genitourinary (RR 1.80, 95% CI: 1.15, 2.82; N\u0026thinsp;=\u0026thinsp;3, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;68.8%) and gastrointestinal complications (RR 4.18, 95% CI: 1.46, 11.96; N\u0026thinsp;=\u0026thinsp;4, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;83.7%) along with sexual dysfunction (RR 1.10, 95% CI: 1.02, 1.18; N\u0026thinsp;=\u0026thinsp;2, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There was no evidence of publication bias, both on eggers test (p\u0026thinsp;=\u0026thinsp;0.43 for genitourinary complications; p\u0026thinsp;=\u0026thinsp;0.08 for gastrointestinal complications) and on visual inspection of the funnel plots (Supplementary Figs.\u0026nbsp;6,7). The publication bias for sexual dysfunction could not be assessed due to very few studies reporting on this outcome. The common complications reported in the included studies were bladder obstruction, urethral stricture, urinary incontinence, increased urinary frequency, moderate to severe diarrhoea, rectal bleeding, proctitis, loss of libido and erectile dysfunction. The overall certainty of evidence for outcomes related to the risk of complications was judged to be \u0026ldquo;low\u0026rdquo; according to the GRADE assessment criteria (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eQuality of the pooled evidence using the GRADE assessment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of studies with design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCertainty of the evidence\u003c/p\u003e \u003cp\u003e(GRADE)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEffect size \u003c/p\u003e \u003cp\u003e(95% CI); I\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003cp\u003e(5 RCT; 2 cohort)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR 0.75,\u003c/p\u003e \u003cp\u003e(0.63 to 0.90); 86.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProstate specific mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003cp\u003e(4 RCT; 1 cohort)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁◯◯\u003c/p\u003e \u003cp\u003eModerate \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR 0.52,\u003c/p\u003e \u003cp\u003e(0.34 to 0.78); 93.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression free survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003cp\u003e(All RCT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eModerate \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR 0.41,\u003c/p\u003e \u003cp\u003e(0.20 to 0.84); 98.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenito-urinary complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003cp\u003e(All RCT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eLow \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR 1.80,\u003c/p\u003e \u003cp\u003e(1.15 to 2.82); 68.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastro-intestinal complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e \u003cp\u003e(All RCT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eLow \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR 4.18,\u003c/p\u003e \u003cp\u003e(1.46 to 11.9); 83.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSexual dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003cp\u003e(All RCT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e⨁⨁⨁◯\u003c/p\u003e \u003cp\u003eLow \u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR 1.10,\u003c/p\u003e \u003cp\u003e(1.02 to 1.18); 0.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ea Downgraded one-level for serious inconsistency (high heterogeneity)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eb Downgraded two-levels for serious inconsistency (high heterogeneity) and sample size less than optimal information size (OIS) (serious imprecision)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ec Downgraded two-levels for serious inconsistency (high heterogeneity) and uncertainty due to wide-confidence intervals (imprecision)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ed Downgraded two-levels for serious inconsistency (small number of studies); serious imprecision (suboptimal sample size)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eRR: relative risk; HR: hazard ratio; RCT: randomized controlled trial\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe low to moderate certainty of findings from our meta-analysis are suggestive of the effectiveness of androgen deprivation therapy (ADT) in combination with radiation therapy (RT) compared to ADT alone for patients with prostate cancer. This analysis, encompassing eight studies with around 18,000 participants, reveals significant improvements in overall survival (OS), prostate-specific mortality (PSM), and progression-free survival (PFS) with the combined treatment approach, particularly in patients with locally advanced prostate cancer (LAPC) and clinically node-positive (cN+) disease. However, the analysis also underscores the increased risk of complications associated with the combination therapy, necessitating careful consideration of treatment strategies in clinical practice. Considering that the certainty of evidence is low or moderate, more robust studies are needed to support the findings.\u003c/p\u003e \u003cp\u003ePrevious meta-analyses have examined the efficacy of ADT combined with RT versus ADT alone but were limited by a small number of studies and lacked comprehensive subgroup analyses to explore variations in treatment effects across different patient populations and disease characteristics. Additionally, since the publication of these reviews, several new trials have emerged, providing updated data that necessitate a re-evaluation of the existing evidence. Our meta-analysis incorporates these recent studies, allowing for a more robust and nuanced assessment of the impact of ADT plus RT on key clinical outcomes. By performing detailed subgroup analyses, we aimed to clarify the patient populations that derive the most benefit from combined therapy, thereby addressing existing gaps in the literature and informing personalized treatment strategies for prostate cancer. Wang et al. conducted an indirect comparison of the efficacy of various systemic and local treatment combinations for metastatic hormone-sensitive prostate cancer (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Their meta-analysis included 10 randomized controlled trials, but only two compared ADT combined with RT to ADT monotherapy. The review found no significant difference in overall survival and progression-free survival between the two groups. However, overall survival was significantly improved in patients with low-volume disease, similar to our analysis where those with LAPC and cN\u0026thinsp;+\u0026thinsp;had the maximum benefit (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Another review by Lei et al, documented the long-term survival outcomes associated with ADT alone versus ADT combined with RT for locally advanced (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). A total of three RCTs (n\u0026thinsp;=\u0026thinsp;2344) contributed to this analysis and found that adding RT to long-term ADT improved overall survival, similar to our findings (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe enhanced effectiveness of combined therapy might be attributed to some underlying mechanisms. First, RT targets the tumor directly, providing localized control that may complement the systemic action of ADT, which aims to reduce circulating testosterone levels and limit tumor growth (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). The combination of these modalities may result in a more comprehensive approach to tumour eradication, leading to improved patient outcomes. Moreover, in patients with LAPC or cN\u0026thinsp;+\u0026thinsp;disease, the tumour is more likely to be responsive to both treatments. The localized control achieved through RT may lead to a reduction in tumour burden, enhancing the efficacy of ADT by mitigating the potential for cancer cells to adapt and resist hormonal therapy. This synergy might explain the observed survival benefits, particularly in these subgroups. One key aspect is the effect of ADT on the tumour microenvironment. By lowering testosterone levels, ADT may induce changes in the tumour microenvironment that enhance the susceptibility of cancer cells to radiation damage (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Studies have shown that androgen deprivation can lead to increased tumour cell apoptosis and a more favorable response to RT (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Additionally, the alteration of the cell cycle dynamics induced by ADT may further sensitize prostate cancer cells to radiation.\u003c/p\u003e \u003cp\u003eDespite the observed survival benefits, our analysis highlights a concerning increase in the risk of complications associated with the combination of ADT and RT. Specifically, patients receiving both therapies faced a higher incidence of genitourinary and gastrointestinal complications, along with sexual dysfunction. These complications may significantly impact patients\u0026rsquo; quality of life and overall treatment satisfaction. The increased risk of complications necessitates a nuanced approach to therapy selection, where the potential survival benefits must be weighed against the likelihood of adverse effects. Clinicians should engage in shared decision-making with patients, discussing the risks and benefits of combined therapy and considering patients\u0026rsquo; preferences when determining the optimal treatment strategy.\u003c/p\u003e \u003cp\u003eThis meta-analysis has several limitations that warrant consideration. First, while the pooled analysis mainly included RCTs, it also incorporated two cohort studies, which raises questions about combining different study designs. However, these cohort studies used propensity score matching to ensure similar baseline characteristics between study groups, justifying their inclusion in the pooled analysis. Further, on sensitivity analysis after removing two cohort studies, the effect of combining ADT with RT, compared to ADT alone on overall survival and prostate specific mortality continued to remain statistically significant. Second, considerable heterogeneity was observed across studies for several outcomes, likely due to differences in patient characteristics, study settings, and outcome definitions, particularly with regards to defining progression. Although a random-effects model was applied to address this variability, interpreting the pooled results still requires caution. Third, while a broader range of complications would have added value to the analysis, inconsistent reporting across studies limited our ability to harmonize and pool data on complications beyond genitourinary, gastrointestinal, and sexual issues. Additionally, we could not perform a subgroup analysis based on whether ADT and RT were initiated concurrently or with ADT used as a neoadjuvant therapy, as in all included studies, RT began 2\u0026ndash;3 months after ADT initiation. Lastly, our findings are applicable to the age range of 18\u0026ndash;75 years and may not be generalizable to patients over 75.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eImplications for clinical practice and future research directions\u003c/h2\u003e \u003cp\u003eThe findings have important implications for clinical practice and future research directions. The findings indicate the need for healthcare providers to engage patients in shared decision-making processes, discussing the benefits of improved survival outcomes alongside the risks of increased complications. Monitoring patients for these complications is essential, with proactive management strategies implemented to address any adverse effects on quality of life. Personalizing treatment strategies based on individual patient characteristics, such as Gleason scores and baseline PSA levels, may optimize outcomes while minimizing risks.\u003c/p\u003e \u003cp\u003eThere is a need for longitudinal studies aimed at identifying biomarkers that may predict favourable responses to combined therapy. Such information could lead to more effective patient stratification and personalized treatment plans. Additionally, mechanistic studies exploring the biological interactions between ADT and RT will deepen our understanding of treatment synergies. Comparative effectiveness research should investigate the efficacy of ADT and RT against emerging modalities, while patient-centered outcomes research should focus on quality of life, mental health, and treatment satisfaction.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003e Our analysis demonstrates that combining androgen deprivation therapy (ADT) with radiation therapy (RT) significantly improves overall survival, progression-free survival, and reduces prostate-specific mortality compared to ADT alone in patients with prostate cancer, particularly those with locally advanced or clinically node-positive disease. However, this combination also leads to a higher incidence of genitourinary, gastrointestinal, and sexual complications. While these findings suggest a strong therapeutic benefit for selected patients, they come with a trade-off in terms of increased adverse effects. Given the limitations of study heterogeneity and low to moderate certainty of evidence, further research is essential to refine treatment protocols, explore optimal timing of ADT and RT, and better define patient subgroups who might benefit most from this combined approach.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eADT \u0026ndash; Androgen Deprivation Therapy\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCI \u0026ndash; Confidence Interval\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ecN+ \u0026ndash; Clinically Node-Positive Prostate Cancer\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGRADE \u0026ndash; Grading of Recommendations Assessment, Development, and Evaluation\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHR \u0026ndash; Hazard Ratio\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLAPC \u0026ndash; Locally Advanced Prostate Cancer\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNOS \u0026ndash; Newcastle-Ottawa Scale\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eOS \u0026ndash; Overall Survival\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePFS \u0026ndash; Progression-Free Survival\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePRISMA \u0026ndash; Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePSA \u0026ndash; Prostate-Specific Antigen\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePSM \u0026ndash; Prostate-Specific Mortality\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRCT \u0026ndash; Randomized Controlled Trial\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRR \u0026ndash; Relative Risk\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRT \u0026ndash; Radiation Therapy\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated, used, and analysed in this study are either included in this published article or are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo individual human participation in the current study. The current metanalysis recorded in the international database of prospectively registered systematic reviews (PROSPERO): CRD42024602727\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo fund to declare\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData curation: E.R.,W.B., M.N., A.B. Formal analysis: E.R. Investigation: E.R.,W.B., M.N. Methodology: E.R.,W.B., M.N. validation: E.R.,W.B., M.N., A.B.Visualization: E.R.,W.B., M.N., A.B.. Writing – original draft: E.R.,W.B. Writing – review \u0026amp; editing: E.R.,W.B., M.N., A.B.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.\u003c/li\u003e\n\u003cli\u003eZhang W, Cao G, Wu F, Wang Y, Liu Z, Hu H, Xu K. Global Burden of Prostate Cancer and Association with Socioeconomic Status, 1990-2019: A Systematic Analysis from the Global Burden of Disease Study. 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PMID: 21782001; PMCID: PMC3641823.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"prostate cancer, node positive, locally advanced, androgen deprivation, radiotherapy, survival, progression, complications, meta-analysis, systematic review","lastPublishedDoi":"10.21203/rs.3.rs-6206964/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6206964/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAndrogen deprivation therapy (ADT) has long been a cornerstone of treatment for patients with locally advanced or metastatic hormone-sensitive prostate cancer. The efficacy of ADT plus radiotherapy (RT) compared to ADT alone remains unclear due to conflicting results in existing literature. The aim of the study is to systematically evaluate the effectiveness of ADT combined with RT versus ADT alone in patients with prostate cancer (clinically node positive, locally advancer disease, metastatic disease), focusing on overall survival (OS), prostate-specific mortality (PSM), progression-free survival (PFS), and the risk of complications.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA comprehensive search of PubMed, Embase, Web of Science and Scopus, between 1st January 2000 and 15th October 2024, was done to identify studies comparing ADT alone to ADT in combination with RT. Hazard ratios (HR) and relative risk (RR) with 95% confidence intervals (CI) were calculated for the outcomes. The certainty of the evidence was assessed using the standard GRADE approach.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 8 studies met the inclusion criteria (6 RCTs and 2 cohort studies). These studies included 18,456 patients. The combination of ADT and RT significantly improved OS (HR\u0026thinsp;=\u0026thinsp;0.75, 95% CI: 0.63, 0.90), PFS (HR\u0026thinsp;=\u0026thinsp;0.41, 95% CI: 0.20, 0.84), and reduced PSM (HR\u0026thinsp;=\u0026thinsp;0.52, 95% CI: 0.34, 0.78) compared to ADT alone. Subgroup analysis showed greater OS (HR 0.66, 95% CI: 0.59, 0.75) and PSM (HR 0.43, 95% CI: 0.39, 0.49) in patients with locally advanced or node-positive disease. ADT\u0026thinsp;+\u0026thinsp;RT was also associated with increased risks of genitourinary (RR\u0026thinsp;=\u0026thinsp;1.80, 95% CI: 1.15, 2.82), gastrointestinal (RR\u0026thinsp;=\u0026thinsp;4.18, 95% CI: 1.46, 11.96), and sexual dysfunction (RR\u0026thinsp;=\u0026thinsp;1.10, 95% CI: 1.02, 1.18) related complications. The overall certainty of evidence was judged to be \u0026ldquo;moderate\u0026rdquo; for survival outcomes and \u0026ldquo;Low\u0026rdquo; for risk of complications.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCombining ADT with radiation therapy RT significantly improves survival, compared to ADT alone, especially in patients with locally advanced or node-positive prostate cancer. However, this combination also increases the risk of complications. Further research is needed to refine treatment protocols and identify the optimal timing and patient subgroups for this approach.\u003c/p\u003e","manuscriptTitle":"Efficacy of Androgen Deprivation Therapy (ADT) in Combination with Radiation Therapy, compared to ADT alone in Patients with High-Risk Prostate Cancer: a meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-07 10:18:54","doi":"10.21203/rs.3.rs-6206964/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"000e536b-41c7-4670-ab3b-6b296fa2aaad","owner":[],"postedDate":"April 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-08T13:24:01+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-07 10:18:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6206964","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6206964","identity":"rs-6206964","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}