CONTEXT The optimal treatment for men with high-risk localized or locally advanced prostate cancer (PCa) remains unknown. OBJECTIVE To perform a systematic review of the existing literature on the effectiveness of the different primary treatment modalities for high-risk localized and locally advanced PCa. The primary oncological outcome is the development of distant metastases at ≥5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overall mortality, biochemical recurrence, and need for salvage treatment with ≥5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treatment-related side effects reported. EVIDENCE ACQUISITION Medline, Medline In-Process, Embase, and the Cochrane Central Register of Randomized Controlled Trials were searched. All comparative (randomized and nonrandomized) studies published between January 2000 and May 2019 with at least 50 participants in each arm were included. Studies reporting on high-risk localized PCa (International Society of Urologic Pathologists [ISUP] grade 4-5 [Gleason score {GS} 8-10] or prostate-specific antigen [PSA] >20 ng/ml or ≥ cT2c) and/or locally advanced PCa (any PSA, cT3-4 or cN+, any ISUP grade/GS) or where subanalyses were performed on either group were included. The following primary local treatments were mandated: radical prostatectomy (RP), external beam radiotherapy (EBRT) (≥64 Gy), brachytherapy (BT), or multimodality treatment combining any of the local treatments above (±any systemic treatment). Risk of bias (RoB) and confounding factors were assessed for each study. A narrative synthesis was performed. EVIDENCE SYNTHESIS Overall, 90 studies met the inclusion criteria. RoB and confounding factors revealed high RoB for selection, performance, and detection bias, and low RoB for correction of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective series suggested an advantage for RP, although with a low level of evidence. Both RT and RP should be seen as part of a multimodal treatment plan with possible addition of (postoperative) RT and/or androgen deprivation therapy (ADT), respectively. High levels of evidence exist for EBRT treatment, with several randomized clinical trials showing superior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposed for RT dose, but higher RT doses by means of dose escalation schemes result in an improved biochemical control. Twenty studies reported data on QoL, with RP resulting mainly in genitourinary toxicity and sexual dysfunction, and EBRT in bowel problems. CONCLUSIONS Based on the results of this systematic review, both RP as part of multimodal treatment and EBRT + long-term ADT can be recommended as primary treatment in high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offered despite more grade 3 toxicity. Interestingly, for selected patients, for example, those with higher comorbidity, a shorter duration of ADT might be an option. For locally advanced PCa, EBRT + BT shows promising result but still needs further validation. In this setting, it is important that patients are aware that the offered therapy will most likely be in the context a multimodality treatment plan. In particular, if radiation is used, the combination of local with systemic treatment provides the best outcome, provided the patient is fit enough to receive both. Until the results of the SPCG15 trial are known, the optimal local treatment remains a matter of debate. Patients should at all times be fully informed about all available options, and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment. PATIENT SUMMARY We reviewed the literature to see whether the evidence from clinical studies would tell us the best way of curing men with aggressive prostate cancer that had not spread to other parts of the body such as lymph glands or bones. Based on the results of this systematic review, there is good evidence that both surgery and radiation therapy are good treatment options, in terms of prolonging life and preserving quality of life, provided they are combined with other treatments. In the case of surgery this means including radiotherapy (RT), and in the case of RT this means either hormonal therapy or combined RT and brachytherapy.

中文翻译：

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高危局限性和局部晚期前列腺癌初级治疗的获益和风险：国际多学科系统评价。

上下文对于患有高危局限性或局部晚期前列腺癌（PCa）的男性，最佳治疗方法仍然未知。目的对高风险的局部和局部晚期PCa的不同主要治疗方式的有效性进行现有文献的系统评价。肿瘤的主要结局是随访≥5年发生远处转移。次要肿瘤学结局是特定于PCa的死亡率，总体死亡率，生化复发以及需要≥5年的随访进行挽救治疗。非肿瘤学结局为生活质量（QoL），功能结局以及与治疗相关的副作用。证据获取检索Medline，Medline进行中，embase和Cochrane随机对照试验的中央登记册。纳入了2000年1月至2019年5月之间发表的所有比较研究（随机和非随机），每组至少有50名参与者。关于高风险的局部PCa（国际泌尿外科病理学家学会[ISUP] 4-5级[Gleason评分{GS} 8-10]或前列腺特异性抗原[PSA]> 20 ng / ml或≥cT2c）的研究报告//或局部高级PCa（任何PSA，cT3-4或cN +，任何ISUP等级/ GS）或对任一组进行亚分析的情况都包括在内。必须进行以下主要的局部治疗：根治性前列腺切除术（RP），体外放射线治疗（EBRT）（≥64Gy），近距离放射治疗（BT）或结合上述任何局部治疗的多模式治疗（±任何全身治疗）。每项研究均评估了偏倚风险（RoB）和混杂因素。进行叙述性合成。证据综合总体而言，有90项研究符合纳入标准。RoB和混杂因素显示，选择，性能和检测偏倚的RoB较高，而校正初始PSA和活检GS的RoB较低。在将RP与EBRT进行比较时，回顾性研究表明RP具有优势，尽管证据水平较低。RT和RP都应被视为多模式治疗计划的一部分，并可能分别增加（术后）RT和/或雄激素剥夺治疗（ADT）。EBRT治疗已有大量证据，一些随机临床试验显示，将长期ADT或BT添加到EBRT可获得更好的疗效。不能为RT剂量建议明确的界限，但通过剂量递增方案提高RT剂量可改善生化控制。二十项研究报告了有关QoL的数据，RP导致泌尿生殖系统毒性和性功能障碍，而EBRT引起肠道问题。结论基于该系统评价的结果，可将RP作为多式联运治疗的一部分和EBRT +长期ADT推荐为高风险和局部晚期PCa的主要治疗方法。对于高风险的PCa，尽管具有更高的3级毒性，也可以提供EBRT + BT。有趣的是，对于某些患者，例如合并症较高的患者，ADT持续时间较短可能是一种选择。对于本地先进的PCa，EBRT + BT显示出可喜的结果，但仍需要进一步验证。在这种情况下，重要的是患者应意识到所提供的治疗很可能是在多模式治疗计划的背景下进行的。特别是如果使用辐射，局部治疗和全身治疗相结合可提供最佳结果，前提是患者足够适合接受两者。在知道SPCG15试验的结果之前，最佳的局部治疗尚有争议。应始终向患者充分告知所有可用的选择，以及采用多模式方法的可能性，包括局部和全身治疗的潜在副作用。病人总结我们回顾了文献，以查看临床研究的证据是否可以告诉我们治愈尚未扩散到身体其他部位（如淋巴腺或骨头）的侵略性前列腺癌男性的最佳方法。根据这项系统评价的结果，有充分的证据表明手术和放射治疗都是不错的治疗选择，在延长寿命和保持生活质量方面，前提是将它们与其他治疗方法结合使用。在外科手术中，这意味着包括放射疗法（RT）；在RT情况下，这意味着激素疗法或RT和近距离放射疗法的联合。