Prostate cancer (PCa) is one of the most common genitourinary malignancies and the second leading cause of cancer mortality in men worldwide (1), and approximately 15% present with high-risk localized disease in newly diagnosed PCa (2). To date, no consensus is available on the optimal treatment strategies for men with high-risk localized PCa (3) and these patients suffer an increased risk of biochemical recurrence and cancer-related death following radical prostatectomy (RP). The multimodal therapy strategy including systemic and local therapies has been raised for years and the majority of urologists are inclined to perform radical prostatectomy plus extended pelvic lymph node dissection or external beam radiotherapy plus androgen deprivation therapy (ADT) (4).

Administration of neoadjuvant hormone therapy (NHT) before RP can reduce positive surgical margin (PSM) rate, prostate volume, and pathologic stage, whereas survival benefits such as biochemical recurrence-free survival (BRFS) or overall survival (OS) are not observed (5). Although numerous prospective and retrospective studies aim to find a better prognosis associated with NHT, the European Association of Urology notes that evidence of neoadjuvant ADT is weak and has limited recommendations for initiating NHT before surgery. Hence, for improving oncological outcomes, chemotherapy, which is widely used in leukemia and other solid tumors (6, 7), has been administrated in men with metastatic PCa and shown to prolong survival in advanced PCa (8, 9). In addition, some clinical trials have preliminarily revealed that neoadjuvant chemohormonal therapy (NCHT) was well tolerated and showed acceptable therapeutic effects (10–12).

Based on these findings, a growing number of investigators were committed to exploring the significant differences between NCHT and NHT or RP alone recently, especially in survival analysis. However, because of the lack of high-level evidence, namely multicenter randomized controlled trials (RCTs) and meta-analyses, the present guidelines make strong recommendations difficult. In this meta-analysis, we aimed to evaluate the perioperative and survival outcomes of NCHT prior to RP, and provide the available evidence for supporting the potential advantages of NCHT.

The definition of high-risk localized PCa is PSA level>20 ng/mL or Gleason score≥8, scilicet International Society of Urological Pathology (ISUP) grade 4–5 or clinical stage≥cT2c (3, 23). Currently, there is still no consensus on optimum therapeutic strategies for high-risk PCa, not to mention very high-risk PCa, which was proposed by Sundi et al. (24) and characterized with higher metastasis risk and cancer-specific mortality. In addition to the recommended options in predominant international guidelines, since docetaxel was found to be significantly superior in terms of survival benefits in metastatic castration-resistant prostate cancer (25), chemotherapy, especially docetaxel, attracted extensive attention. The CHAARTED and STAMPEDE trial demonstrated the efficacy of docetaxel for metastatic hormone-sensitive prostate cancer with acceptable adverse events in 2015 and 2016 (8, 9), respectively. Furthermore, a meta-analysis showed that additional chemotherapy to ADT could significantly improve progression-free survival in high-risk PCa (26). These findings made it logical to examine chemotherapy earlier in the process of PCa and we believed that NCHT could be considered as a part of multi-modal therapy based on this study.

Previous papers elucidated that decreased prostate volume after NHT might prompt surgeons to dissect smoother (27, 28), thereby resulting in lower operative difficulty theoretically, whereas controversy still exists regarding the advantages of NHT in optimizing surgical variables, including operation time and hemorrhage. In NCHT, despite the analysis of the two mentioned variables was absent in this study because of limited data, Nosov et al. (17) and Pan et al. (20) found no significant difference in operation time and blood loss between NCHT and RP alone group, namely NCHT did not increase the surgical difficulty. Of note, PSM plays a crucial role in predicting biochemical recurrence (29) and NCHT could improve the pathological outcomes of high-risk PCa in our study, such as reducing PSM and increasing the rate of pathological downstaging, which was consistent with a latest meta-analysis for NHT (30).

In general, patients and urologists may be more concerned with life expectancy. Administration of NHT before RP was evaluated in different RCTs showing no satisfactory effect on survival (14, 31, 32), which was also acknowledged in a systematic review (33). With regard to the reasons, neoadjuvant ADT cannot block the production of adrenal and intratumoral androgens to stop the sustainability of androgen receptor signalling (34). Moreover, the duration of follow-up and NHT was insufficient, and numerous subjects were enrolled in the early to middle stages of the disease, weakening the effects of NHT. On the contrary, the prevalent pharmaceuticals used in NCHT can restrain cancer cell proliferation and induce apoptosis by targeting microtubules or DNA (35). Patients receiving neoadjuvant docetaxel and/or estramustine phosphate demonstrated a significant improvement in BRFS and OS as expected (P=0.008 and P=0.02, respectively), which was the firm superiority compared to NHT.

Due to the lack of records of adverse events in the RP alone group (not placebo), we cannot conduct a meta-analysis about safety. Nonetheless, there was no significant difference in early and late postoperative complications between the NCHT plus RP and RP groups (17). The current included literature also revealed that the most common adverse events were neutropenia, fatigue, hot flashes, and other gastroenterological reactions (20–22). No chemotherapy-related deaths were observed and the rates of grade 3 and 4 adverse events were comparable to the patients undergoing ADT plus radiotherapy (36). Therefore, it is reasonable to assume that chemotherapy before RP is well tolerated (35).

Though the eligible studies possess a low risk of bias and most findings are positive, the heterogeneity is definitely present and some factors may be involved. First, the different definitions of high-risk PCa were utilized and Pan et al. even performed interventions on patients with very high-risk PCa (20). Second, the included studies implemented follow−up schedules in a different manner, and BRFS was defined as a serum PSA level >0.2 ng/mL with a diverse time interval. Additionally, Grasso et al. considered that the capacity to find significant differences was associated with methodology immensely, and study design and sample size are two of the most important elements (37), which may explain why sample size, region, and study design were the main sources of high heterogeneity in LNI and BRFS. However, no study was responsible for the heterogeneity under the sensitivity analyses.

Unfortunately, our work is limited by a small number of studies, especially published multicenter, prospective trials, hence our results may be affected by future papers. On the other hand, the application of the random-effect model was to reduce but cannot eliminate the influence of heterogeneity. Besides, other survival outcomes (cancer-specific survival and metastasis-free survival) are not analyzed, which may provide more clinically meaningful information.

The results of our meta-analysis suggest that NCHT may improve pathological outcomes, manifesting as depressed PSM and SVI rates, and elevated pathological downstaging rate. More importantly, prolonged BRFS and OS are available following NCHT plus RP and further large-scale RCTs are necessary to offer more powerful evidence.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

QG, HX, and ZW contributed to conception and design of the study. DY, ZF, ZC, JiX, and YZ were in charge of data collection. SZ, JuX, and BS performed the statistical analysis. QG wrote the first draft of the manuscript and HX plus ZW edited the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

This study was funded by the National Key Technology R&D Program of China (nos. 2018YFC2002204) and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (JX11213894).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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