Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review

Abstract

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 years of follow-up. Secondary oncological outcomes are prostate cancer specific mortality (PCSM), overall mortality (OM), biochemical recurrence and need for salvage treatment with ≥5 years of follow-up. Non-oncological 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 non-randomized) 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 (ISUP grade 4-5 [GS 8-10] or PSA >20 ng/mL or ≥cT2c) and/or locally advanced PCa (any PSA, cT3-4 or cN+, any ISUP grade/ GS score) 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 to 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 (post-operative) RT and/or ADT respectively. High levels of evidence exist for EBRT treatment with several RCTs 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 GU toxicity and sexual dysfunction, and EBRT in bowel problems. Conclusion. 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, also EBRT + BT can be offered, despite more grade 3 toxicity. Interesting, for selected patients, e.g. 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 be mos...

Oncologic outcome of radical prostatectomy versus radiotherapy as primary treatment for high and very high risk localized prostate cancer

“…Three‐ and 5‐years MFS were higher but, not statistically significant, after EBRT compared to RP. Our findings agree with a systematic review of primary treatment for high‐risk CaP, where data for MFS from four nonrandomized studies revealed no statistical difference between RP and EBRT + ADT 19 . Also, Kishan et al 17 reported similar 5‐year MFS after RP and EBRT 17,20 .…”

“…Longer follow‐up may reveal differences in CSS and OS by treatment. In a systematic review of primary treatments for high‐risk localized CaP, RP compared to EBRT + ADT produced a benefit in OS of 10%–28% and benefit in CSS of 4%–8% at 10 years 19 . Tewari et al 24 studied 453 patients with biopsy GS ≥8.…”

68Ga-PSMA-11 PET/CT-Guided Stereotactic Body Radiation Therapy Retreatment in Prostate Cancer Patients with PSA Failure after Salvage Radiotherapy

“…This study, however, included patients with oligo-metastatic disease in both the prostate bed and at other sites (skeleton, viscera), and a number of patients (17%) received concomitant antiandrogen therapy [11]. On the other hand, international guidelines suggest the use of ADT in metastatic patients, which, however, is not exempt from well-known side effects [12].…”

PREDICT Prostate, a useful tool in men with low- and intermediate-risk prostate cancer who are hesitant between conservative management and active treatment

“…Second, although reasonably high numbers of high-risk PCa patients (according to EAU risk grouping system) were included in the development and PCBaSe cohorts (22.4% and 15.1% ISUP grade group 4-5 PCa, respectively; 14.5% and 16% stage T3-4, respectively), it is unclear how well the model performs in actively treated high-risk and very-high-risk PCa patients. International guidelines recommend conducting multimodal therapy in high-risk PCa patients combining surgery, radiation therapy, and systemic therapy [5]. However, multimodal therapy was not considered radical therapy in these cohorts.…”