Clinical Impact of Long-term Neoadjuvant Hormone Therapy on Locally Advanced Prostate Cancer Treated with Radical Prostatectomy: A Retrospective Cohort Study

Technical Summary: Clinical Impact of Long-term Neoadjuvant Hormone Therapy on Locally Advanced Prostate Cancer

Problem Statement
Locally advanced prostate cancer (cT3–4N0M0) presents a significant clinical challenge due to frequent extracapsular extension and seminal vesicle invasion. While robot-assisted radical prostatectomy (RARP) is a standard treatment, surgery alone carries a high risk of positive surgical margins and postoperative biochemical recurrence. Neoadjuvant hormone therapy (NHT) has been utilized to reduce tumor volume and achieve pathological downstaging; however, its impact on biochemical recurrence and survival remains controversial. Consequently, NHT is not currently recommended as a standard preoperative treatment in clinical guidelines. A critical gap in knowledge exists regarding whether achieving a pathological complete response (pT0)—defined as the absence of residual cancer cells in the prostatectomy specimen after long-term NHT—correlates with improved oncological outcomes, specifically biochemical recurrence-free survival (BCRF).

Methodology
This study employed a retrospective, single-center cohort design at Saga University Hospital involving 51 patients with cT3–4N0M0 prostate cancer who underwent RARP between 2012 and 2024. These patients were selected from a larger cohort of 90 locally advanced cases, specifically those who received preoperative NHT.

The cohort was stratified into two groups based on pathological findings:

• pT0 Group (n=18): Patients with no residual cancer cells in the radical prostatectomy specimen.
• Non-pT0 Group (n=33): Patients with residual cancer cells.

Data Collection and Variables:

• NHT Regimens: Included Androgen Deprivation Therapy (ADT) alone, Combined Androgen Blockade (CAB), or ADT combined with an Androgen Receptor Signaling Inhibitor (ARSI).
• Variables Analyzed: Patient demographics (age, BMI, initial PSA), clinical T stage, biopsy Gleason grade group, NCCN risk classification, surgeon experience, NHT duration, preoperative PSA, perioperative outcomes (console time, blood loss, complications), and pathological outcomes (positive surgical margins).
• Endpoints: The primary endpoint was the comparison of BCRF between the two groups. Biochemical recurrence was defined as two consecutive postoperative PSA levels ≥0.2 ng/mL.
• Statistical Analysis: Continuous variables were compared using the Mann–Whitney U-test, and categorical variables using chi-square or Fisher's exact tests. BCRF was analyzed via Kaplan–Meier curves with log-rank tests. Univariate and multivariate Cox proportional hazards models were used to identify predictors of recurrence.

Key Results

• Treatment Characteristics: The pT0 group demonstrated a significantly longer median NHT duration (11 months) compared to the non-pT0 group (4 months; p < 0.00001). Furthermore, the pT0 group had a significantly higher proportion of patients receiving CAB (88%) compared to the non-pT0 group (52%; p = 0.0045). Preoperative PSA levels were significantly lower in the pT0 group (0.0015 ng/mL) versus the non-pT0 group (0.972 ng/mL; p < 0.00001).
• Perioperative and Pathological Outcomes: There were no significant differences in console time, estimated blood loss, or major complications between the groups. However, the pT0 group had a significantly lower rate of positive surgical margins (0%) compared to the non-pT0 group (24%; p = 0.0389).
• Oncological Outcomes: During the follow-up period, biochemical recurrence occurred in only 1 of 18 patients (5.6%) in the pT0 group, compared to 16 of 33 patients (48.5%) in the non-pT0 group. Kaplan–Meier analysis revealed significantly better BCRF in the pT0 group (log-rank p = 0.044).
• Predictive Analysis: In multivariate Cox proportional hazards analysis, achieving pT0 was identified as an independent predictor of reduced biochemical recurrence (Hazard Ratio [HR] 0.12, 95% CI 0.006–0.699, p = 0.0488). Similarly, a lower biopsy Gleason grade group (1–3 vs. 4–5) was an independent predictor of reduced recurrence (HR 0.24, p = 0.0441). NCCN risk classification and specific NHT regimens were not independent predictors in this model.

Significance and Claims
The authors posit that achieving a pathological complete response (pT0) following long-term NHT in locally advanced prostate cancer is not merely a pathological observation but a clinically meaningful indicator of favorable treatment response and prognosis. The study suggests that sufficiently prolonged and intensive endocrine treatment (specifically longer durations and CAB) can reduce tumor burden to a level that minimizes recurrence risk.

The paper claims that pT0 serves as a potential marker for patients who derive significant oncological benefit from the combination of long-term NHT and RARP. Unlike previous studies where short-term NHT (3–6 months) showed pathological improvements without clear survival benefits, this study highlights that longer durations (median 11 months) may be necessary to achieve pT0 and the associated reduction in biochemical recurrence. The authors conclude that while NHT is not yet a standard guideline recommendation, the achievement of pT0 supports the utility of surgery combined with neoadjuvant hormonal therapy for select locally advanced cases.

Limitations
The authors acknowledge the study's limitations, including its retrospective nature, single-center design, and small sample size (particularly the 18 patients in the pT0 group). They note that the observed benefits may be confounded by the longer NHT duration and higher CAB usage in the pT0 group. Additionally, the relatively short follow-up period necessitates longer-term studies to confirm the durability of these oncological outcomes.