Systematic Review of Systemic Therapies and Therapeutic Combinations with Local Treatments for High-risk Localized Prostate Cancer

Abstract

Context: Systemic therapies, combinedwith local treatment for high-risk prostate cancer, are recommended by the international guidelines for specific subgroups of patients; however, for many of the clinical scenarios, it remains a research field. Objective: To perform a systematic review, and describe current evidence and perspectives about the multimodal treatment of high-risk prostate cancer. Evidence acquisition: We performed a systematic review of PubMED, Embase, Cochrane Library, European Society of Medical Oncology/American Society of Clinical Oncology Annual proceedings, and clinicalTrial.gov between January 2010 and February 2018 following the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Evidence synthesis: Seventy-seven prospective trials were identified. According to multiple randomized trials, combining androgen deprivation therapy (ADT) with external-beam radiotherapy (EBRT) outperforms EBRT alone for both relapse-free and overall survival. Neoadjuvant ADT did not show significant improvement compared with prostatectomy alone. The role of adjuvant ADT after prostatectomy in patients with high-risk disease is still debated, with lack of data from phase 3 trials in pNO patients. Novel androgen pathway inhibitors have been tested only in early-phase trials in addition to primary treatment. GETUG 12, RTOG 0521, and nonmetastatic subgroup of the STAMPEDE trial showed improved relapse-free survival for docetaxel in patients treated with EBRT plus ADT, although mature metastasis-free survival data are still pending. Both the SPCG-12 and the VACSP#553 trial showed no improvement in relapse free survival for adjuvant docetaxel after prostatectomy. Conclusions: In contrast to the clearly demonstrated survival benefits of long-term adjuvant ADT when used with EBRT, its role after prostatectomy remains unclear especially in pNO patients. Adding docetaxel to EBRT-ADT improves relapse-free survival, with immature results on overall survival. Novel androgen receptor pathway inhibitors are currently being tested in the neoadjuvant and adjuvant setting. Patient summary: Treatment of high-risk prostate cancer is based on a multimodality approach that includes systemic treatments. The best treatment or therapy combination remains to be defined.

BRCA2 and Other DDR Genes in Prostate Cancer

“…No evidence has been produced to support a different ADT scheme in carriers, but since androgen deprivation seems to downregulate both homologous recombination (HR) [26] and non-homologous End Joining (NHEJ) [27,28], prolonged ADT or the addition of new androgen receptor signaling inhibitors (ARSI) such as abiraterone, enzalutamide, or apalutamide, might be of benefit for those carriers undergoing radiotherapy. Adjuvant chemotherapy with docetaxel following radiotherapy in unselected patients with high-risk disease improves relapse-free survival, but the benefit in metastasis free survival and overall survival is less clear [29]. Several trials are currently ongoing that would provide definite data on the impact of adjuvant chemotherapy or ARSI on metastasis free survival and overall survival.…”

Ten-year outcomes of high-dose intensity-modulated radiation therapy for nonmetastatic prostate cancer with unfavorable risk: early initiation of salvage therapy may replace long-term adjuvant androgen deprivation

“…The standard approach for unfavorable PCa is high-dose EBRT combined with long-term androgen deprivation therapy (ADT) for 2–3 years [1]. However, the optimal duration of ADT combined with high-dose EBRT remains unclear, because this evidence is based on results using 70 Gy or lower via three-dimensional conformal radiotherapy (3D-CRT) [2-6]. Up to now, no mature result of high-dose IMRT for unfavorable PCa is available from previous reports.…”

Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-risk Prostate Cancer—Results from the Prospective, Randomised, Open-label Phase III SPCG-13 Trial

“…Both RTOG trials had also much more aggressive tumors (see Table 5, GS distribution) than in our study explaining partly the difference in the outcome. Tosco et al published recently systematic review of therapeutic combinations with local treatments for high risk localized prostate cancer (26). They identified altogether 77 prospective trials.…”