Abstract
Background/Aim: The impact of neoadjuvant chemohormonal therapy (NCHT) on biochemical recurrence-free survival (BRFS) in patients with very-high risk localized prostate cancer remains uncertain, particularly because previous studies have included heterogeneous populations with locally advanced disease. This retrospective study evaluated the clinical significance of NCHT in patients with strictly defined T2-T3a very-high risk disease.
Patients and Methods: A total of 49 patients treated between 2017 and 2024 were analyzed; 25 received NCHT consisting of androgen deprivation therapy and estramustine phosphate, while 24 underwent radical prostatectomy without NCHT. All patients received robot-assisted radical prostatectomy with extended lymph node dissection.
Results: Baseline characteristics and pathological outcomes were comparable between the two groups, with a median follow-up period of 19 months in the NCHT group and 29 months in the non-NCHT group. Kaplan-Meier analysis demonstrated no significant difference in BRFS between the groups (p=0.397). In multivariable Cox analysis, primary Gleason pattern 5 was the only independent predictor of BRFS (hazard ratio=3.72; 95% confidence interval=1.19-11.58), whereas NCHT did not confer an oncological benefit.
Conclusion: These findings suggest that for patients with very-high risk prostate cancer limited to T2-T3a disease, NCHT does not improve biochemical recurrence outcomes, and tumor biology–particularly primary Gleason pattern 5–plays a more decisive role in prognosis than neoadjuvant systemic intensification. While cytotoxic therapy combined with androgen deprivation remains of investigational interest, its utility in organ-confined but biologically aggressive prostate cancer appears limited based on current evidence. Further large-scale, prospective studies are warranted to clarify the optimal patient selection for neoadjuvant approaches.
- Localized prostate cancer
- robot-assisted radical prostatectomy
- chemohormonal therapy
- neoadjuvant therapy
Introduction
Prostate cancer (PCa) is the second major malignancy of males in developed countries (1). Prostate-specific antigen (PSA) surveillance contributes to early detection of PCa, and most PCa patients are diagnosed with clinically localized stage (2). Treatment options for localized PCa include surgery, irradiation, and ablation therapy (3). Robot-assisted laparoscopic radical prostatectomy (RARP) is standard management for localized PCa; however, “very-high risk” localized entities according to the NCCN guideline have shown high recurrence rates of up to 80% despite RARP allowing precise manipulation and extended resection (4).
To get over these meager outcomes, neoadjuvant therapy could be a potential approach (5). Androgen deprivation therapy is a conventional and manageable treatment for patients with prostate cancer despite their clinical stages. Patients with clinically significant prostate cancer can achieve a stable condition. Neoadjuvant hormonal therapy (NHT) has been tried for patients with high-risk factors since the open prostatectomy era (6). Most attempts have failed to show improved survival outcomes; therefore, no guidelines recommend NHT, even though it decreases the rate of positive surgical margins in RARP (7). Cytotoxic agents are crucial treatments for patients with resistance to both first-line hormonal therapy, including conventional and androgen receptor inhibitors, and those with high-volume metastatic disease. Because cytotoxic agents have a higher adverse event profile than hormonal therapy, only small or ongoing neoadjuvant trials, including those using docetaxel, have been reported (8). However, these results have not demonstrated consistent clinical benefit.
Estramustine phosphate sodium (EMP) is an anti-tumor drug that acts as both an antiandrogen and a cytotoxic agent against PCa and is administered as an easily accessible chemohormonal therapy (9). In several small studies, EMP has demonstrated improved oncological outcomes in patients with high-risk PCa before surgery (10). However, no successful therapeutic approach has been established for patients with very-high risk PCa. One concern about very-high risk is its unique classification in the NCCN guidelines, as its definition includes a diverse range of patients, from those with locally advanced stages to those with biologically aggressive diseases with micrometastasis (11). This variety may obscure the effectiveness of neoadjuvant chemohormonal therapy (NCHT) for patients with very-high risk PCa (12). Patients with clinically T3b or T4 prostate cancer may have non-organ-confined disease and may respond poorly to neoadjuvant therapy (13). The combination of a lower clinical T stage and biological high-risk factors may be a better candidate for NCHT, as PCa with aggressive histology might be more effectively managed by cytotoxic agents (14).
In this study, we aimed to compare the clinical implications of NCHT for very-high risk PCa with a T stage of T3a or lower in a retrospective cohort of 49 patients treated with or without NCHT in Japan.
Patients and Methods
Data collection and study cohort. This retrospective cohort study was approved by the review board of Asahikawa Medical University (ID: 22084 in the IRB of Asahikawa Medical University). Informed consent was obtained using the opt-out method, allowing patients to decline participation through publicly accessible information. The inclusion criteria were patients with very-high risk organ-confined T2 and T3a prostate cancer (the NCCN guideline version 2, 2021). We recruited 70 patients with very-high risk prostate cancer who received NCHT or not, treated between March 2017 and January 2024 at Asahikawa Medical University. We compared biochemical recurrence-free survival (BRFS) and patient characteristics between the groups. The clinical demographics of the patients, including age, tumor size, T category, Gleason score (per the 2004 World Health Organization classification), and performance status were investigated. All included patients had histologically proven prostate cancer and underwent magnetic resonance imaging to confirm a clinical T stage.
Study endpoints. The main objective was to evaluate BRFS in patients both with and without NCHT. The secondary objective was to examine the association between preoperative patient characteristics and BRFS. The risk factors related to BRFS were analyzed using the Cox proportional hazards regression model.
Neoadjuvant chemohormonal therapy. All patients with the very-high risk received a gonadotropin-releasing hormone antagonist or agonist as androgen deprivation therapy (ADT) and EMP (313.4 mg/day) as NCHT for six months before RARP.
Surgical procedure. The RARP was performed as follows. Six trocars were placed at the upper abdomen with Trendelenburg position (25°). All eligible patients underwent extended pelvic lymph node dissection (external iliac, internal iliac, common iliac, obturator, and presacral lesion).
Surveillance. The surveillance protocol varied depending on the policies set by each physician. The following determinations were made before starting treatment and repeated during therapy based on the decision of the attending physicians: complete medical history, physical examination, PSA, ECOG performance status (PS), complete blood counts with differential and platelet counts; biochemical profiles, including electrolytes, renal and hepatic function, coagulation parameters, pancreatic amylase, and lipase; and urinalyses. Radiological imaging was scheduled if metastatic disease had been suspected.
Statistical analysis. All patients were assessed for biochemical recurrence (BCR) by assaying for serum PSA level every three months during the first and second year after RARP and every six months during the third to fifth year. BCR was defined as a postoperative serum PSA level >0.2 ng/ml confirmed by a second consecutive measurement or the initiation of systemic treatment. In cases where the PSA level did not decrease below 0.2 ng/ml after RARP, the date of surgery was defined as the date of biochemical recurrence. Data are expressed as the median and interquartile range (IQR). A p-value less than 0.05 was considered statistically significant. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated from the Cox regression mode in both univariate and multivariable analyses. The data were statistically analyzed using EZR version 1.67 statistical software (Saitama Medical Center, Jichi Medical University, Saitama, Japan).
Results
Patient characteristics. In total, 70 patients with very-high risk PCa were included in the study cohort. Of those patients, 49 patients with T2 and T3a treated with or without NCHT were compared (Figure 1). The baseline patient characteristics for this cohort are shown in Table I. The median age at initiation of NCHT was 71 years (IQR=67-75), with a median PSA of 21.7 ng/ml (IQR=12.1-33.0). Twenty-five of 49 patients (51.0%) accomplished the total courses of NCHT, and 24 patients (49.0%) did not receive NCHT due to patient’s reason [10 (41.7%)], comorbidities [4 (16.6%)], and unknown reason [10 (41.7%)]. Eighteen patients (36.7%) were diagnosed with T2 and 31 with T3a (63.3%). Five patients (10.7%) had Gleason 6 or 7, and 44 (89.3%) had Gleason 8 or more. The patients with primary Gleason pattern 5 were 19 (38.8%). The baseline characteristics were not different between the groups (Table I).
Selection diagram of patients. Out of 70 patients with very-high risk prostate cancer, we selected 49 patients with T2 or T3a for this study. NHT: Neoadjuvant hormonal therapy; MRI: magnetic resonance imaging; NCHT: neoadjuvant chemohormonal therapy.
Patient characteristics treated with or without neoadjuvant chemohormonal therapy.
Outcomes of surgery. In all patients, the median console time was 232 min, with an IQR of 202 to 290 min. The median estimated blood loss was 84 ml, with an IQR of 3 to 295 ml. No significant differences were observed between the groups (Table II).
Clinical outcomes of robot-assisted radical prostatectomy.
Pathological findings. The surgical and pathological results are shown in Table III. There was no significant difference in the positive surgical margin (PSM) rates between the groups with or without NCHT (23.5% and 24.5%, respectively; p=0.454). Interestingly, nearly half of the patients exhibited more advanced stages, such as pT3b (32% in the NCHT group and 50% in the non-NCHT group) and pN1 (24% and 16%), compared to their stage before the initiation of management.
Surgical outcomes of pathology.
Biochemical recurrence-free survival. For all patients enrolled in the study, the median follow-up duration was 21.0 months (IQR=11.0-46.0 months). No patient died because of PCa during the follow-up duration. Nine patients (36%) developed BCR in the NCHT group, and the median time from RARP to BCR was not reached at the time of analysis. In contrast, 14 patients (58.3%) in the non-NCHT group developed BCR, with a median time from RARP to BCR 30.0 months. No significant difference in time-dependent BRFS was observed between the groups (p=0.397; Figure 2). The one and two years BRFS rates in the entire study population were 78.7% and 61.4% in the NCHT groups and 83.1% and 60.4% in non-NCHT group, respectively.
Kaplan-Meier curve of biochemical recurrence-free survival (BRFS) for patients with and without neoadjuvant chemohormonal therapy (NCHT) before robot-assisted laparoscopic radical prostatectomy (RARP).
Analyses of factors associated with biochemical recurrence survival. Multivariable analysis in all the patients revealed that primary Gleason pattern 5 (HR=3.72; 95% CI=1.19-11.58; p=0.022) was a statistically independent factor for predicting BCR in patients with PCa undergoing RARP (Table IV). NCHT did not affect BRFS in the very-high risk PCa with T2 or T3a.
Predictive clinical factors for biochemical recurrence-free survival in patients with very-high-risk prostate cancer analyzed by using univariable and multivariable Cox proportional hazard models.
Discussion
In this retrospective study, we compared the BRFS rates in patients with very-high risk PCa classified as either T2 or T3a treated with and without NCHT, consisting of ADT and EMP. Despite the use of NCHT, there was no difference in BRFS, with a median follow-up of 21 months. Primary Gleason pattern 5 was a significant factor associated with BCR.
Recent Japanese studies published in 2025 have also evaluated neoadjuvant chemohormonal approaches incorporating estramustine-based regimens; however, consistent survival benefits have not been demonstrated, which is consistent with our findings (10).
One of the major challenges in patients with very-high risk PCa, as defined by the NCCN guidelines, is aggressive tumor biology. This aggressive biology leads to a high likelihood of recurrence, metastasis, and cancer-specific mortality despite definitive local treatments such as surgery or radiotherapy (11). These tumors often present with features such as Gleason score ≥9, PSA >20 ng/ml, and T3b-T4 disease and are difficult to control with monotherapy (15). Previous studies indicate that 3- to 5-year BRFS rates range from 20% to 50%, depending on the cohort and the adjuvant therapies used (16, 17). Very-high risk patients have higher PSM rates, often reported between 25% and 40%, which correlates with worse recurrence risk (18). High rates of extracapsular extension, seminal vesicle invasion, and lymph node involvement are common, reflecting advanced disease at surgery. A recommended management by the NCCN for this entity is multimodal treatment, typically involving radiotherapy combined with long-term ADT (16). In selected cases, systemic intensification with novel androgen receptor signaling inhibitors, such as abiraterone, may also be considered (19). Radical prostatectomy should be only considered for carefully selected patients as part of a multimodal strategy, often followed by adjuvant or salvage therapies (20). Previous studies evaluating neoadjuvant hormonal therapy followed by robot-assisted radical prostatectomy in intermediate- and high-risk prostate cancer have reported improvements in pathological outcomes, although consistent survival benefits have not been demonstrated (21).
NCHT for very-high risk prostate cancer is an evolving approach with promising potential but still some uncertainties. Combining chemotherapy with ADT before surgery or radiation can be more efficient in reducing tumor burden. Early systemic control may help eradicate a micrometastatic disease that surgery alone cannot address. Some studies suggest improved pathological outcomes, which may also improve BRFS or progression-free survival. Data on survival benefits are currently limited and inconsistent. Large, randomized trials are currently underway or pending results (22, 23). Since optimal patient selection and timing remain unclear, NCHT is not yet universally adopted (7), and the standard of care remains ADT plus local therapy.
The failure of NCHT before RARP to consistently improve BRFS can be attributed to several factors. Very-high risk PCa often harbors aggressive, heterogeneous cancer cell clones (14). Even with chemohormonal therapy, resistant cancer cells may survive and later cause recurrence. The neoadjuvant phase is usually limited (e.g., a few months) (22), and this strategy may not allow sufficient time or dose intensity to eradicate micrometastatic disease or deeply infiltrating tumor cells (23). The systemic micrometastatic disease might not be fully controlled by neoadjuvant therapy alone, especially if distant metastases are already established but undetected. Surgery may remove the bulk tumor but cannot address residual systemic disease (24). If systemic therapy is not continued postoperatively (adjuvant), residual tumor cells can cause recurrence. The possibility of NCHT is still under debate because many proceeded studies had small sample sizes or heterogeneous patient populations. Additionally, variability in risk classification, therapy protocols, and follow-up duration may dilute the observed benefit. RARP, although minimally invasive, may face technical limitations in very-high risk cases, such as challenges in achieving wide negative margins, which can lead to local recurrence despite neoadjuvant chemotherapy. BRFS may be influenced by tumor biology unrelated to local control; some microscopic diseases can escape early therapy but become detectable later.
Study limitations. First, this study is significantly affected by biases in patient and treatment selection due to its retrospective design. Second, we found that a primary Gleason pattern of 5 was associated with poor BRFS rates. However, due to the non-randomized nature of the study, we did not measure or control for confounding variables, nor did we adjust for them using propensity score matching. Third, the limited sample size and follow-up period may increase error margins. To minimize biases related to confounders, we conducted a multivariable analysis that enhanced the reliability of our study.
Conclusion
NCHT before RARP did not improve BRFS in very-high risk prostate cancer patients with T2-T3a disease. Only primary Gleason pattern 5, not NCHT, independently predicted BRFS. NCHT’s role in this setting remains unproven.
Acknowledgements
The Authors are thankful to Fuyumi Onodera for her efforts in obtaining patient data.
Footnotes
Authors’ Contributions
Daiki Kikuchi: Data acquisition and analysis and manuscript drafting. Kazuyuki Numakura: Study planning, manuscript drafting, data acquisition, analysis, and critical revision of the manuscript. Kotona Miyauchi: Data acquisition. Noriyuki Abe: Data acquisition. Miyu Ohtani: Data acquisition. Shin Kobayashi: Data acquisition. Naoki Wada: Study design and critical revision of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.
- Received December 1, 2025.
- Revision received December 17, 2025.
- Accepted December 19, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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