ARAB JOURNAL OF UROLOGY 2022, VOL. 20, NO. 2, 71–80 https://doi.org/10.1080/2090598X.2022.2026010 REVIEW ARTICLE Radiation therapy compared to radical prostatectomy as first-line definitive therapy for patients with high-risk localised prostate cancer: An updated systematic review and meta-analysis a,b a,c d a,e a,f Abdulmajeed Aydh , Reza Sari Motlagh , Mohammad Abufaraj , Keiichiro Mori , Satoshi Katayama , a,g a,h a,i a,j a,k Nico Grossmann , Pawel Rajawa , Hadi Mostafai , Ekaterina Laukhtina , Benjamin Pradere , a,l a,m n o a Fahad Quhal , Victor M. Schuettfort , Alberto Briganti , Pierre I. Karakiewicz , Haron Fajkovic a,j,p,q,r,s,t and Shahrokh F. Shariat a b Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, King Faisal Medical City, Abha, Saudi Arabia; Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; The National Center for Diabetes, Endocrinology and Genetics, The University of Jordan, Amman, Jordan; e f Department of Urology, The Jikei University School of Medicine, Tokyo, Japan; Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Department of Urology, University Hospital Zurich, Zurich, h i Switzerland; Department of Urology, Medical University of Silesia, Zabrze, Poland; Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; k l Department of Urology, University Hospital of Tours, Tours, France; Department of Urology, King Fahad Specialist Hospital, Dammam, m n Saudi Arabia; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; Cancer Prognostics and Health Outcomes Unit, University of Montreal Health p q Center, Montreal, Canada; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; s t Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan ABSTRACT ARTICLE HISTORY Received 16 August 2021 Objective: To present an update of the available literature on external beam radiation therapy Accepted 31 October 2021 (EBRT) with or without brachytherapy (BT) compared to radical prostatectomy (RP) for patients with high-risk localised prostate cancer (PCa). KEYWORDS Methods: We conducted a systematic review and meta-analysis of the literature assessing Brachytherapy; external the survival outcomes in patients with high-risk PCa who received EBRT with or without beam radiation therapy; BT compared to RP as the first-line therapy with curative intent. We queried PubMed and high-risk prostate cancer; Web of Science database in January 2021. Moreover, we used random or fixed-effects radical prostatectomy; radiation therapy; androgen- meta-analytical models in the presence or absence of heterogeneity per the I statistic, deprivation therapy respectively. We performed six meta-analyses for overall survival (OS) and cancer-specific survival (CSS). Results: A total of 27 studies were selected with 23 studies being eligible for both OS and CSS. EBRT alone had a significantly worse OS and CSS compared to RP (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.16–1.65; and HR 1.55, 95% CI 1.25–1.93). However, there was no difference in OS (HR 1.1, 95% CI 0.76–1.34) and CSS (HR 0.69, 95% CI 0.45–1.06) between EBRT plus BT compared to RP. Conclusion: While cancer control affected by EBRT alone seems inferior to RP in patients with high-risk PCa, BT additive to EBRT was not different from RP. These data support the need for BT in addition to EBRT as part of multimodal RT for high-risk PCa. Abbreviations: ADT: androgen-deprivation therapy; BT: brachytherapy; CSS: cancer-specific survival; HR: hazard ratio; MFS, metastatic-free survival; MOOSE: Meta-analyses of Observational Studies in Epidemiology; OR: odds ratio; OS: overall survival; PCa: prostate cancer; RR: relative risk; RP: radical prostatectomy; RCT: randomised controlled trials; (EB)RT: (external beam) radiation therapy Introduction these patients remains unresolved with standard High-risk non-metastatic disease (i.e. PSA level local therapeutic options including radical prosta- >20 ng/mL, Gleason score of 8, and/or a clinical tectomy (RP) and radiation therapy (RT) consisting stage of T2c–3a) accounts for ~30% of newly diag- of external beam RT (EBRT) with or without bra- nosed prostate cancer (PCa) [1,2], depending on its chytherapy (BT). Owing to the heterogeneous nat- definition [3,4]. The optimal primary treatment for ure of the published cohort studies and the lack of CONTACT Shahrokh F. Shariat firstname.lastname@example.org Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria Supplemental data for this article can be accessed here. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 72 A. AYDH ET AL. Figure 1. The selection process of the articles to assess survival outcomes among patients with high-risk prostate cancer who received RT compared to RP. prospective randomised controlled trials (RCTs), it which provides a RCTs checklist . Moreover, the remains unclear which single and/or multimodal Preferred Reporting Items for Systematic Reviews and therapeutic strategy is optimal for each patient Meta-Analysis (PRISMA) was used. with high-risk PCa. In the current and likely future, the absence of propensity designed RCTs comparing RP to RT for Eligibility criteria patients with high-risk PCa, meta-analyses may help The question of this study was, ‘Do patients with high- a framework for clinical decision-making and risk PCa who receive EBRT with or without BT have patient counselling. To this end, we performed a better survival outcome compared to those who a systematic review and meta-analysis to summarise receive RP?’. All current articles covering the study the results of available studies including the latest question were eligible for this systematic review. We literature on this subject. We focussed on the addi- selected studies that perform quantitative synthesis tive value of BT in addition to EBRT. according to the similarity in Population, Interest, Context (PICO) elements to decrease the selection bias and heterogeneity. The inclusion criteria for the Methods quantitative meta-analysis were original research arti- In this meta-analysis, we followed the Meta-analyses of cles that assessed survival outcomes and reported an Observational Studies in Epidemiology (MOOSE) state- estimated risk effect (hazard ratio [HR], odds ratio [OR], ment guidelines that propose a checklist of items relative risk [RR]) for both patient and control groups. ARAB JOURNAL OF UROLOGY 73 Exclusion criteria were BT usage alone as definitive Information sources therapy and lack of definition of high-risk PCa in the We searched PubMed and the Web of Science for stu- main or subgroup analysis. dies published before 1 January 2021. The search Consequently, the more comparable cohort stu- queries line and search strategies were ‘((Prostate OR dies according to the MOOSE guidelines were prostatic) AND (cancer OR carcinoma) OR (Prostatic included in the analyses. Furthermore, the hetero- Neoplasms[Mesh])) AND external beam radiotherapy geneity of the population was explored by detect- OR brachytherapy OR radiotherapy [Mesh]) AND (radical ing the source and country of databases. According prostatectomy [Mesh])’ in PubMed and ‘((Prostate OR to OS, we categorised studies’ outcomes, CSS, bio- prostatic) AND (cancer OR carcinoma)) AND (external chemical recurrence survival, and metastatic-free beam radiotherapy OR brachytherapy OR radiotherapy) survival (MFS). AND (radical prostatectomy)’ in the Web of Science. Table 1. Characteristics of the included studies of patients treated locally for high-risk prostate cancer. High-risk PCa Sample Intervention Control Study Year definition size, n group group Outcomes Radiation dose Yasui et al. Japan (1970–2014)  2020 T3 4810 EBRT RP+ sRT OS/CSS NR Zhou et al.  2020 T3 9258 EBRT RP OS/CSS NR EBRT+BT Muralidhar et al. NCDB and SEER (2004–2012)  2019 GS: 9–10 4367/ EBRT+BT RP+aRT OS NR NCBD/ 2278 SEER Knipper et al. SEER 2004–2015  2019 GS: 9–10 16,018 EBRT RP+aRT OS/CSS NR Yin et al. SEER (2004–2015)  2019 NCCN 62178 EBRT RP+aRT OS/CSS NR EBRT+BT Berg et al. NCDB (2004–2009)  2019 NCCN 13985 EBRT+BT RP OS NR Jayadevappa et al. SEER–Medicare (1996–2003) 2019 GS: ≥8 or 4878 EBRT RP OS/CSS NR  T≥ T2c EBRT + BT Reichard et al. MD Anderson (2004–2013); 2019 NCCN 304 EBRT RP OS/MFS 75.6 Gy comparison with matched SEER cohort  Ennis et al. NCDB (2004–2013)  2018 NCCN 40123 EBRT RP OS NR EBRT+BT Tilki et al. Chicago Prostate Cancer Center, USA, 2018 GS: 9–10 452 EBRT+BT RP+aRT CSS/OS 45 Gy IMRT + BT: 125 103 and Martini-Klinik Prostate Cancer Center, I (108 Gy), Pa Germany (1992–2013)  (90 Gy), Cs (100 Gy) Jang et al. SEER Medicare (1992–2009)  2018 ≥T3a or GS 7946 EBRT RP+aRT CSS/OS NR 8–10 Kishan et al. University of California, Los Angeles 2018 NCCN 1373 EBRT RP CSS/OS/ XRT: median 74.3 Gy (2000–2013)  EBRT+BT MFS XRT+BT: median 91.5 Gy Robinson et al. NPCR of Sweden (1998–2012)  2018 NCCN 41503 EBRT RP CSS Markovina et al. Washington University, St. Louis 2018 NCCN 124 EBRT RP OS/MFS Median 75.6 Gy (2002–2011)  Gu et al. SEER (2004–2008)  2018 NCCN 7656 EBRT RP CSS/OS NR Feldman et al. SEER–Medicare (1992–2009)  2017 T3 2935 EBRT RP OS/CSS NR Ciezki et al. Cleveland Clinic (1996–2012)  2016 NCCN 2042 EBRT RP CSS/BRFS 78 Gy Taguchi et al. University of Tokyo (2005–2012)  2015 D’Amico 336 EBRT RP OS/CSS/ Median 76 Gy BRFS Yamamoto et al. Japan (1994–2005)  2014 T3 231 EBRT RP OS/CSS 70 Gy (60–72) Sooriakumaran et al. PCBaSe Sweden (1996–2010) 2014 Modified 7649 EBRT RP CSS NR  NCCN Merino et al. Pontificia Universidad Catolica de 2013 D’Amico 294 EBRT RP CSS/BRFS 76 Gy Chile (1999–2010)  Hoffman et al. PCOS (1994–2010)  2013 PSA 437 EBRT RP OS/CSS NR >10 ng/ mL or GS 8–10 Sun et al. SEER (1992–2005)  2013 T2c 5945 EBRT RP OS/CSS NR Westover et al. 21st century oncology, Chicago 2012 D’Amico 657 EBRT+BT RP CSS 45 Gy RT+ 90–108 Gy BT Prostate Center, Duke University (1988–2008)  Kibel et al. Barnes-Jewish Hospital and Cleveland 2012 D’Amico 1201 EBRT RP OS/CSS Median 74 Gy (Barnes Clinic (1995–2005)  Jewish) and 78 Gy (Cleveland Clinic) Abdollah et al. SEER (1992–2005)  2012 T2c or GS 6057 EBRT RP OS/CSS NR 8–10 Boorjian et al. MayoClinic, Fox Chase (1988–2004) 2011 NCCN 1582 EBRT RP OS/CSS 72 Gy (50–79)  aRT: adjuvant RT; BRFS: biochemical recurrence-free survival; GS: Gleason score; IMRT: intensity modulated RT; NCDB: National Cancer Database; NCCN: National Comprehensive Cancer Network; NR: not reported; PCBaSe: Prostate Cancer data Base Sweden; PCOS: Prostate Cancer Outcomes Study; SEER: Surveillance, Epidemiology and End Results; sRT: salvage radiotherapy. 74 A. AYDH ET AL. Table 2. The Newcastle-Ottawa scale for all studies in the quality of the included studies . Subsequently, the HRs quantitative synthesis. and 95% CIs with OS, CSS outcomes were retrieved, all Study Selection Comparability Outcome Total discrepancies regarding data extraction were resolved by Yasui et al.  **** ** ** 8 Delphi consensus with co-authors. Zhou et al.  **** ** ** 8 Muralidhar et al.  **** ** ** 8 Knipper et al.  **** ** *** 9 Yin et al.  **** ** ** 8 Statistical analysis Berg et al.  **** ** ** 8 Jayadevappa et al.  **** ** ** 8 Forest plots were used to assess the multivariable HRs. Reichard et al.  **** ** ** 8 Ennis et al.  **** ** * 7 We summarised them to depict the relationship of our Tilki et al.  *** ** * 6 outcomes with the type of treatment (i.e. RP, EBRT alone Jang et al.  **** ** ** 8 Kishan et al.  **** ** * 7 and EBRT plus BT). When HRs and P value only were Robinson et al.  **** ** * 7 reported, we calculated the corresponding 95% CIs. We Markovina et al.  **** ** * 7 Gu et al.  **** ** ** 8 utilised multivariable adjusted or propensity score Feldman et al.  **** ** ** 8 matched analyses in the quantitative meta-analyses. Ciezki et al.  **** ** ** 8 Taguchi et al.  **** ** * 7 Studies included in performing the meta-analyses were Yamamoto et al.  **** ** ** 8 adjusted for the effects of age, clinical T stage, Gleason Sooriakumaran et al.  **** ** *** 9 grade, and PSA. The primary meta-analysis was per- Merino et al.  **** ** * 7 Hoffman et al.  **** ** *** 9 formed for all studies that reported OS as an outcome. Sun et al.  **** ** * 7 A secondary meta-analysis was conducted using studies Westover et al.  *** ** * 6 Kibel et al.  **** ** ** 8 that reported CSS as an outcome. The next four meta- Abdollah et al.  **** ** ** 8 analyses were conducted among studies that reported Boorjian et al.  *** ** ** 7 the risk of OS and CSS according to the type of RT (i.e. *According to Newcastle-Ottawa scale, stars were awarded for each qual- ity item such that highest quality studies were awarded up to 9 stars. EBRT alone or EBRT plus BT). Heterogeneity across the studies was appraised using P values, Q and I statistics . In the presence of statistically significant heteroge- neity (˃50%), random effect meta-analysis was used. The search results were restricted to English language When there was no significant heterogeneity observed, articles. Two reviewers screened titles and abstracts inde- the fixed-effect model was used. Funnel plots was used pendently; any disagreement about the articles’ eligibility to detect the risk of publication bias. Statistical analyses was resolved by Delphi consensus with the co-authors. were considered significant if the P value was <0.05. All A data extraction sheet was developed based on the analyses were carried out using Stata version 14 (Stata Cochrane Consumers and the Communication Review Corp., College Station, TX, USA). Group’s (http://cccrg.cochrane.org/author-resources). We extracted the following data: first-author, type of article, year of publication, dates of the data collection Results or enrolment, cohort type, sample size, number of indi- viduals on treatment, outcome, how the outcome was After initial screening, 526 articles were available for measured, type of effect statistic, effect statistic error assessment. The selection process for the systematic measures, and effect statistic P value. There were no review is shown in Figure 1. With further assessment, limitations in the articles’ data, so we did not need to according to inclusion and exclusion criteria, 27 studies contact any authors for additional details. Modified were finally available for the systematic review and Newcastle-Ottawa Scale criteria were used to assess the meta-analysis (Table 1) [8–34]. Table 3. Reported data regarding multimodal therapy among studies that used EBRT plus BT compared to RP. Adjuvant ADT, % Adjuvant or salvage RT, % Study EBRT plus BT RP RP Zhou et al.  NR NR NR Muralidhar et al.  NR NR NR Yin et al.  NR NR NR Berg et al.  69 15 15 Jayadevappa et al.  NR NR NR Ennis et al.  11.1 NR NR Tilki et al.  1.0 8.8 15.7 Kishan et al.  92.4 11.3 8.7 Westover et al.  1.0 6 6 NR: not reported. ARAB JOURNAL OF UROLOGY 75 Figure 2. (a) Forest plots with summary HRs (all included study) for OS of the RT group vs RP (reference group) for high-risk prostate cancer. (b) Forest plots with summary HRs (all included study) for CSS of the RT group vs RP (reference group) for high-risk prostate cancer. Almost all of the studies in this review were P < 0.001), so a random-effect model was used. cohort studies. Of the 27 included studies, regardless The funnel plot was asymmetrical (Figure1S-A in of the type of RT (i.e. EBRT alone or EBRT plus BT), 23 supplemental data). In the second meta-analysis, studies assessed OS and CSS. The quality assessment 23 studies were again included. We found that of the included studies according to the Newcastle- patients with high-risk PCa who received RT Ottawa scale is summarised in Table 2 [8–34]. In (regardless of the type of RT) had significantly general, there were only two fair quality studies, worse CSS than those treated with RP with a HR while all 25 others had at least good quality of 1.37 (95% CI 1.15–1.65; Figure 2(b)). The 23 (Table 2). studies included in the meta-analysis showed a high heterogeneity (I = 84.6%, P < 0.001), so a random-effect model was used. The funnel plot OS and CSS for patients with high-risk PCa who was asymmetrical (Figure1S-B in supplemental received RT compared to RP data). In the first meta-analysis of OS, 23 were included. We found that patients with high-risk PCa who OS and CSS for patients with high-risk PCa who received RT (regardless of the type of RT) had received only EBRT compared to RP significantly worse OS than those treated with RP with a HR of 1.27 (95% CI 1.11–1.45; Figure 2(a)). In the first subgroup meta-analysis, 15 studies were The 23 studies included in the meta-analysis included. We found that patients with high-risk PCa demonstrated a high heterogeneity (I = 84.5%, who received EBRT alone (i.e. without 76 A. AYDH ET AL. Figure 3. (a) Forest plots with summary HRs (only EBRT) for OS of the RT group vs RP (reference group) for high-risk prostate cancer. (b) Forest plots with summary HRs (only EBRT) for CSS of the RT group vs RP (reference group) for high-risk prostate cancer. a concomitant BT) had significantly worse OS than OS and CSS for patients with high-risk PCa who those treated with RP with a HR of 1.38 (95% CI received EBRT plus BT compared to RP 1.16–1.65; Figure 3(a)). The 15 studies included in In the third subgroup meta-analysis, eight studies were the meta-analysis demonstrated a high heterogene- included. The HR of 1.1 (95% CI 0.76–1.34) suggested ity (I = 81.2%, P < 0.001), so a random-effect model that there was no difference in OS between patients was used. The funnel plot was slightly asymmetrical with high-risk PCa who received EBRT plus BT com- (Figure1S-C in supplemental data). In the second pared to those who underwent RP (Figure 4(a)). The subgroup meta-analysis, 18 studies were included. eight studies included in the meta-analysis demon- We found that patients with high-risk PCa who strated a high heterogeneity (I = 92.8%, P < 0.001), received EBRT alone had significantly worse CSS so a random-effect model was used. The funnel plot than those treated with RP with a HR of 1.55 (95% was asymmetrical (Figure1S-E in supplemental data). In CI 1.25–1.93; Figure 3(b)). The 18 studies included in the fourth subgroup meta-analysis, seven studies were the meta-analysis showed a high heterogeneity included. The HR of 0.69 (95% CI 0.45–1.06) suggested (I = 85.6%, P < 0.001), so a random-effect model no difference in CSS between patients with high-risk was used. The funnel plot was slightly asymmetrical PCa who received EBRT plus BT and those who (Figure1S-D in supplemental data). ARAB JOURNAL OF UROLOGY 77 Figure 4. (a) Forest plots with summary HRs (EBRT plus BT) for OS of the RT group vs RP (reference group) for high-risk prostate cancer. (b) Forest plots with summary HRs (EBRT plus BT) for CSS of the RT group vs RP (reference group) for high-risk prostate cancer. underwent RP; however, statistical significance was not BT combination had OS and CSS that were not inferior reached (Figure 4(b)). The seven studies included in the to RP. However, EBRT alone (i.e. without concomitant meta-analysis showed moderate heterogeneity BT) was inferior to RP with regards to OS and CSS. (I = 84.9%, P = 0.096), so a random-effect model was While there is no direct, well designed comparison used. The funnel plot was slightly asymmetrical of RP vs RT as the first step in a multimodal thera- (Figure1S-F in supplemental data). Table 3 [9,10,12– peutic concept in concordance with our meta- 14,16,17,19,29] shows the reported data regarding RT analyses, cumulative data support the concept of and RP components among studies included in this combining maximal RT consisting of EBRT plus BT systematic review. with androgen-deprivation therapy (ADT) as the first- line multimodal strategy for therapy of high-risk PCa [10,12,16,17,19,29]. Indeed, major guidelines recom- mend ADT combined with EBRT plus BT, based on the Discussion OS benefits shown in several RCTs that compared it to The present systematic review and meta-analyses EBRT plus ADT . There is to date no comparison assessed the comparative survival effectiveness of RT between the different multimodal therapies (i.e. EBRT and RP as a definitive therapy with curative intent of plus BT and ADT) vs RP with RT vs RP with ADT, etc. PCa patients with high-risk features. Although we Some single institution and small cohorts included in found that RT irrespective of RT type (i.e. EBRT alone this systematic review tried to conduct a fair compar- or plus BT) resulted in significantly worse OS and CSS ison between those strategies (i.e. RP plus adjuvant/ compared to RP, patients who underwent a EBRT plus salvage RT and ADT) [17,19,36,37]; however, the 78 A. AYDH ET AL. inherent selection bias limits any fair comparisons RT as a primary definitive strategy could be better (Table 2), this is especially true for in multi- when combined with EBRT and BT to achieve max- institutional and population-based datasets and regis- imal radiation dose combined with ADT. The role, tries, while they are at least likely to suffer from timing, indication of postoperative RT after RP, and systematic bias based on their geographic and speci- the type and duration of ADT for each patient need alty representativeness. assessment and evidence. Until then, we would Today, RT as adjuvant or salvage strategy is sup- postulate based on the findings of our present ported as a part of a multimodal therapy after RP by study an equipoise of EBRT with BT for local control major guidelines for patients with high-risk PCa as a part of multimodal flexible and dynamic treat- based on data recruiting from several RCTs [38– ment strategy tailored to each tumour in each 40]. However, more studies that compared EBRT patient. plus BT to RP have not reported postoperative RT usage, therefore making fair comparisons impossi- Disclosure statement ble [9,10,12,14,16]. Limitations for optionally com- bining BT with EBRT include dose distribution and No potential conflict of interest was reported by the prostate size, reflecting a selection bias that may author(s). reflect the local tumour burden. In contrast to most cohort studies that assessed EBRT (i.e. without ORCID a concomitant BT) vs RP for high-risk disease, we found a significantly worse OS and CSS [9,11,18,22]. Abdulmajeed Aydh http://orcid.org/0000-0001-6078- Finally, until well-designed RCTs assess survival out- Mohammad Abufaraj http://orcid.org/0000-0002-6603- comes between MaxRT and MaxRP, a multidisciplinary approach should be considered Nico Grossmann http://orcid.org/0000-0001-8698-6461 in treating patients with high-risk PCa beyond the Ekaterina Laukhtina http://orcid.org/0000-0002-8953- results of survival outcomes of cohort studies. The main limitation of the present systematic review Benjamin Pradere http://orcid.org/0000-0002-7768-8558 and meta-analysis was the lack of well-designed con- Fahad Quhal http://orcid.org/0000-0002-8163-6953 trolled trials. However, because of this lack, we believe that this systematic review and meta-analysis might Author contributions help frame and equipoise decisions to guide patients’ counselling as part of the shared decision process . 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Arab Journal of Urology
– Taylor & Francis
Published: Apr 3, 2022
Keywords: Brachytherapy; external beam radiation therapy; high-risk prostate cancer; radical prostatectomy; radiation therapy; androgen-deprivation therapy