Abstract
Objective: To investigate the efficacy of neoadjuvant novel hormonal therapy (NHT) combined with radical prostatectomy (RP) in patients with high-risk prostate cancer (HRPCa), and identify independent influencing factors for 3-year biochemical recurrence-free survival (BCRFS). Methods: A total of 420 patients with HRPCa treated between 2017 and 2022 were enrolled and retrospectively analyzed. All patients were divided into training (n=294) and validation (n=126) sets at a 7:3 ratio. Each cohort was further subdivided into the combination group and the RP-alone control group. Relevant clinical data were collected, and Cox regression analysis, nomogram construction and receiver operating characteristic (ROC) curve analysis were performed. Results: Baseline data were well balanced between the sets and the groups (all P>0.05). The combination group presented significantly lower positive surgical margin rate (8.7% vs 31.9%), lymph node metastasis rate (10.7% vs 27.8%) and 3-year biochemical recurrence (BCR) rate (12.0% vs 30.6%, all P<0.001), as well as longer BCRFS (34.81±3.27 months vs 33.14±5.67 months, P=0.002). No significant difference was observed in postoperative complication rate between the two groups (4.0% vs 6.9%, P=0.266). Preoperative prostate-specific antigen ≥28.285 ng/mL, Gleason score ≥8.5, positive surgical margin and lymph node metastasis were independent risk factors for BCR (all P<0.003). The area under the ROC curve of the combined prediction model was 0.881 in the training cohort and 0.876 in the validation cohort. Conclusion: NHT combined with RP can improve clinical outcomes of HRPCa without increasing postoperative complications. The four above-mentioned indicators can effectively predict the 3-year BCR risk of patients.
Keywords: Neoadjuvant novel hormonal therapy, radical prostatectomy, Gleason score, positive surgical margin, biochemical recurrence-free survival
Introduction
Prostate cancer is a common male malignant tumor. Among them, high-risk prostate cancer (HRPCa) has large tumor volume, aggressive biological behavior and high postoperative biochemical recurrence (BCR) risk, which has always been the core difficulty and research hotspot in clinical treatment [1,2]. At present, radical prostatectomy (RP) is the mainstream surgical treatment for HRPCa. Laparoscopic radical prostatectomy (LRP) has been widely applied due to its minimal invasiveness and rapid postoperative recovery [3]. However, LRP is technically demanding and accompanied by certain postoperative complication risks. Single RP treatment still has limitations such as high positive surgical margin rate and high lymph node metastasis risk, which lead to persistently elevated postoperative BCR rate and poor long-term therapeutic efficacy [4,5]. Therefore, exploring optimized treatment regimens to reduce recurrence risk and improve long-term prognosis is of great clinical significance.
Existing studies have confirmed that neoadjuvant hormonal therapy can expand surgical indications and improve postoperative pathological grading results [6,7]. In the treatment of prostate cancer, neoadjuvant novel hormonal therapy (NHT) combined with radical surgery can stably reduce androgen level, shrink tumor lesions, simplify surgical procedures and reduce surgical trauma, thereby optimizing survival prognosis and quality of life of patients [8,9]. Although several studies have focused on NHT combined with RP for HRPCa treatment, the clinical value of standardized novel NHT combined regimen, especially its influence on 3-year BCRFS and related risk factors, has not been fully clarified. In addition, the currently available clinical prediction tools for postoperative BCR risk in HRPCa patients are insufficiently accurate, which restricts the formulation of individualized treatment and follow-up strategies.
On this basis, this study retrospectively analyzed clinical data of HRPCa patients to explore the clinical application value of NHT combined with RP. By establishing training and validation cohorts, we identified independent risk factors for BCR and constructed a nomogram prediction model, so as to realize quantitative prediction of 3-year postoperative BCR risk. This study compensates for the research deficiency regarding the prognostic influence of novel neoadjuvant endocrine therapy on HRPCa, and provides objective evidence for clinical treatment selection and postoperative recurrence risk assessment.
Materials and methods
Patients’ selection
This study retrospectively collected clinical data of 465 patients diagnosed with HRPCa who were admitted to Baoji Gaoxin Hospital, Xianyang First People’s Hospital, China-Japan Union Hospital of Jilin University and Affiliated Hospital of Northwest University from May 2017 to May 2022.
Inclusion criteria: (1) Prostatic acinar adenocarcinoma confirmed by systematic prostate core needle biopsy; (2) Preoperative serum prostate-specific antigen (PSA) >20 ng/mL and biopsy Gleason score ≥8; (3) Complete preoperative abdominopelvic imaging examination combined with whole-body bone scan or prostate-specific membrane antigen PET-CT examination; (4) Newly diagnosed cases without previous anti-tumor treatment for prostate cancer; (5) Receiving standardized RP including laparoscopic, robot-assisted laparoscopic or open surgery; (6) Karnofsky Performance Status (KPS) score ≥80; (7) Complete clinical treatment data, perioperative pathological data and follow-up data.
Exclusion criteria: (1) Patients with severe cardiac, hepatic or renal insufficiency; (2) Combined with other malignant tumors; (3) Poor surgical tolerance or complicated conditions affecting surgical efficacy and prognosis; (4) Previous history of pelvic radiotherapy or systemic chemotherapy; (5) History of abdominopelvic and bladder surgery interfering with RP; (6) Incomplete clinical data or lost to follow-up.
The participant screening process is shown in Figure 1. Finally, 420 eligible patients were enrolled and divided into training and validation cohorts at a ratio of 7:3. The training cohort consisted of 294 patients (150 in the combination group, 144 in the RP-alone control group), and the validation cohort included 126 patients (61 in the combination group, 65 in the RP-alone control group). This study was approved by the Ethics Committee of Baoji Gaoxin Hospital.
Figure 1.
Flow diagram. Note: NHT: neoadjuvant hormonal therapy; HRPCa: high-risk prostate cancer.
Data extraction
Trained urological researchers independently extracted clinical data according to unified standard forms with consistent evaluation criteria. Any controversial data was reviewed and adjudicated by a senior chief urologist to ensure data authenticity and consistency. All data were imported into Excel database with double entry and logical error checking.
All patients in the control group received RP alone, while patients in the combination group received 3-month preoperative NHT intervention. The NHT regimen was as follows: oral enzalutamide 160 mg once daily combined with subcutaneous injection of luteinizing hormone-releasing hormone (LHRH) analogues (goserelin 3.6 mg or leuprorelin 3.75 mg) every 28 days. We collected baseline clinical data, postoperative pathological indicators, postoperative complication conditions and 3-year follow-up outcomes including BCR status and BCRFS, and verified the consistency of all follow-up records, pathological reports and laboratory results.
Outcome measures
Primary outcomes
Postoperative adverse events were recorded in detail, including anastomotic leakage, urinary leakage, erectile dysfunction and urinary incontinence.
All patients were followed up for 3 years after discharge to record the occurrence of BCR. BCR was defined as sustained postoperative serum PSA elevation ≥0.2 ng/mL without spontaneous decline during reexamination.
Secondary outcomes
Baseline clinical indicators including age, body mass index (BMI), comorbidities, educational level, prostate volume, maximum tumor diameter, TNM stage, preoperative PSA level and Gleason score were collected. Postoperative pathological indicators including positive surgical margin status and lymph node metastasis status were recorded within one week after surgery. Positive surgical margin was defined as tumor cells detected on the inked resection margin of postoperative specimens. Lymph node metastasis was confirmed by postoperative histopathological examination of resected pelvic lymph nodes.
Statistical analysis
Statistical analyses were performed using SPSS 20.0 software. The Shapiro-Wilk test was used for normality test. Normally distributed continuous data were expressed as mean ± standard deviation (x̅±sd), and compared by independent-samples t test. Categorical data were expressed as cases (percentage) and compared via chi-square test. Kaplan-Meier method was adopted for survival analysis, and the log-rank test was used for inter-group comparison. Variables with P<0.1 in univariate analysis were included in multivariate Cox proportional hazards regression model, and forward stepwise regression was employed for variable screening (inclusion α=0.05, exclusion α=0.10). Nomogram prediction models were constructed and visualized using R software. Receiver operating characteristic (ROC) curves were utilized to assess the prognostic value of independent prognostic factors, and the DeLong test was applied to compare the areas under the ROC curves (AUCs) across different prediction models. A two-tailed P<0.05 was considered statistically significant.
Results
Comparison of baseline data between the training and validation sets
There were no significant differences in age, BMI, hypertension, hyperlipidemia, educational level, prostate volume, maximum tumor diameter, TNM staging, PSA level and Gleason score between the two cohorts (all P>0.05, Table 1).
Table 1.
Baseline data of the training set and the validation set [n (%), x̅±sd]
| Training set (n=294) | Validation set (n=126) | t/χ2 | P | |
|---|---|---|---|---|
| Age (yr) | 56.34±4.53 | 56.41±4.56 | 0.145 | 0.885 |
| BMI (kg/m2) | 22.58±2.49 | 22.55±2.52 | 0.113 | 0.910 |
| Hypertension | 0.412 | 0.521 | ||
| Yes | 164 (55.8) | 66 (52.1) | ||
| No | 130 (44.2) | 60 (47.9) | ||
| Hyperlipidemia | 0.147 | 0.701 | ||
| Yes | 153 (52.0) | 63 (50.0) | ||
| No | 141 (48.0) | 63 (50.0) | ||
| Education level | 0.123 | 0.940 | ||
| High school degree | 31 (13.28) | 14 (11.1) | ||
| College degree | 153 (56.25) | 67 (53.2) | ||
| Bachelor degree or above | 110 (30.47) | 45 (35.7) | ||
| Prostate volume (ml) | 46.59±5.08 | 49.61±5.09 | 0.037 | 0.971 |
| Maximum tumor diameter (cm) | 3.17±0.12 | 3.18±0.15 | 0.632 | 0.528 |
| TNM staging | 0.559 | 0.576 | ||
| I-II | 130 (44.2) | 52 (41.3) | ||
| III-IV | 164 (55.8) | 74 (58.7) | ||
| PSA (ng/mL) | 27.28±1.52 | 27.16±1.45 | 0.752 | 0.453 |
| Gleason score | 8.47±0.56 | 8.42±0.51 | 0.861 | 0.390 |
Note: NHT: neoadjuvant hormonal therapy; BMI: body mass index; PSA: prostate-specific antigen.
Comparison of baseline data between the combination and control groups
No significant differences were found in all baseline clinical characteristics between the combination and control groups (all P>0.05, Table 2).
Table 2.
Baseline data of the two groups [n (%), x̅±sd]
| Combination group (n=150) | Control group (n=144) | t/χ2 | P | |
|---|---|---|---|---|
| Age (yr) | 56.27±4.98 | 56.40±4.01 | 0.245 | 0.806 |
| BMI (kg/m2) | 22.53±2.75 | 22.64±2.19 | 0.378 | 0.705 |
| Hypertension | 1.566 | 0.211 | ||
| Yes | 89 (59.3) | 75 (52.1) | ||
| No | 61 (40.7) | 69 (47.9) | ||
| Hyperlipidemia | 0.048 | 0.826 | ||
| Yes | 79 (52.7) | 74 (51.4) | ||
| No | 71 (47.3) | 70 (48.6) | ||
| Education level | 0.320 | 0.852 | ||
| High school degree | 17 (11.3) | 14 (9.7) | ||
| College degree | 76 (50.7) | 77 (53.5) | ||
| Bachelor degree or above | 57 (38.0) | 53 (36.8) | ||
| Prostate volume (ml) | 46.47±5.61 | 46.72±4.49 | 0.421 | 0.674 |
| Maximum tumor diameter (cm) | 3.18±0.16 | 3.19±0.13 | 0.587 | 0.558 |
| TNM staging | 0.006 | 0.939 | ||
| I-II | 66 (44.0) | 64 (44.4) | ||
| III-IV | 84 (56.0) | 80 (55.6) | ||
| PSA (ng/mL) | 27.10±1.58 | 27.31±1.38 | 1.212 | 0.227 |
| Gleason score | 8.42±0.57 | 8.48±0.55 | 0.918 | 0.359 |
Note: NHT: neoadjuvant hormonal therapy; BMI: body mass index; PSA: prostate-specific antigen.
Comparison of positive surgical margin rate, lymph node metastasis rate and 3-year BCR rate between the combination and control groups
The positive surgical margin rate, lymph node metastasis rate and 3-year BCR rate in the combination group were 8.7% (13/150), 10.7% (16/150) and 12.0% (18/150) respectively, which were significantly lower than those in the control group [31.9% (46/144), 27.8% (40/144), and 30.6% (44/144)]. Meanwhile, the combination group achieved longer BCRFS than the control group (all P<0.05, Table 3; Figure 2).
Table 3.
Incidence of adverse reactions in both groups of patients [n (%)]
| Combination group (n=150) | Control group (n=144) | t/χ2 | P | |
|---|---|---|---|---|
| Surgical margin | 24.818 | <0.001 | ||
| Positive | 13 (8.7) | 46 (31.9) | ||
| Negative | 137 (91.3) | 98 (68.1) | ||
| Lymph node metastasis | 13.951 | <0.001 | ||
| Yes | 16 (10.7) | 40 (27.8) | ||
| No | 134 (89.3) | 104 (63.2) | ||
| BCR in 3 year occurs | 15.201 | <0.001 | ||
| Yes | 18 (12.0) | 44 (30.6) | ||
| No | 132 (88.0) | 100 (69.4) | ||
| BCRFS (months) | 34.81±3.27 | 33.14±5.67 | 3.109 | 0.002 |
Note: NHT: neoadjuvant hormonal therapy; BCR: biochemical recurrence; BCRFS: biochemical recurrence-free survival.
Figure 2.
Kaplan-Meier curves for BCR in 3 year occurs in both groups of patients. Note: BCR: biochemical recurrence; BCRFS: biochemical recurrence-free survival; NHT: neoadjuvant hormonal therapy.
Comparison of postoperative complication rate between the combination and control groups
No significant difference was detected in the overall postoperative complication rate between the two groups (P>0.05, Table 4).
Table 4.
Incidence of adverse reactions in both groups of patients [n (%)]
| Groups | n | Anastomotic leakage | Urinary leakage | Erectile dysfunction | Urinary incontinence | Incidence of complications |
|---|---|---|---|---|---|---|
| Combination group | 150 | 3 (2.0) | 3 (2.0) | 0 (0.0) | 0 (0.00) | 6 (4.0) |
| Control group | 144 | 4 (2.8) | 3 (2.1) | 1 (0.7) | 1 (0.7) | 10 (6.9) |
| t | 1.238 | |||||
| P | 0.266 |
Note: NHT: neoadjuvant hormonal therapy.
Univariate analysis
Univariate analysis showed that age, BMI, comorbidities, prostate volume, maximum tumor diameter and TNM stage were not correlated with postoperative BCR (all P>0.05). By contrast, higher preoperative PSA level, higher Gleason score, positive surgical margin and lymph node metastasis were closely associated with increased BCR risk (all P<0.05, Table 5).
Table 5.
Univariate analysis of factors affecting BCR occurring in HRPCa patients [n (%), x̅±sd]
| BCR Group (n=62) | NBCR group (n=232) | t/χ2 | P | |
|---|---|---|---|---|
| Age (yr) | 56.32±4.59 | 56.34±4.52 | 0.031 | 0.975 |
| BMI (kg/m2) | 22.63±2.42 | 22.57±2.51 | 0.168 | 0.866 |
| Hypertension | 1.263 | 0.261 | ||
| Yes | 32 (51.6) | 132 (56.9) | ||
| No | 30 (48.4) | 100 (44.1) | ||
| Hyperlipidemia | 0.044 | 0833 | ||
| Yes | 33 (53.2) | 120 (51.7) | ||
| No | 29 (46.8) | 112 (48.3) | ||
| Education level | 1.091 | 0.580 | ||
| High school degree | 8 (12.9) | 23 (9.9) | ||
| College degree | 34 (54.8) | 119 (51.3) | ||
| Bachelor degree or above | 20 (32.3) | 90 (38.8) | ||
| Prostate volume (ml) | 46.77±5.02 | 46.54±5.11 | 0.316 | 0.752 |
| Maximum tumor diameter (cm) | 3.19±0.13 | 3.18±0.15 | 0.479 | 0.632 |
| TNM staging | 0.028 | 0.866 | ||
| I-II | 28 (45.2) | 102 (44.0) | ||
| III-IV | 34 (54.8) | 130 (56.00) | ||
| PSA (ng/mL) | 28.63±1.46 | 26.91±1.32 | 8.909 | <0.001 |
| Gleason score | 8.94±0.51 | 8.34±0.50 | 8.358 | <0.001 |
| Surgical margin | 43.883 | <0.001 | ||
| Positive | 31 (50.0) | 28 (12.1) | ||
| Negative | 31 (50.0) | 204 (87.9) | ||
| Lymph node metastasis | 20.949 | <0.001 | ||
| Yes | 29 (46.8) | 27 (11.6) | ||
| No | 33 (53.2) | 205 (88.4) |
Note: BCR: biochemical recurrence; HRPCa: high-risk prostate cancer; NHT: neoadjuvant hormonal therapy; BMI: body mass index; PSA: prostate-specific antigen.
Multivariate Cox regression analysis
Significant variables screened by univariate analysis were included in multivariate Cox regression model after grouping assignment according to cutoff values of PSA and Gleason score (Table 6). The results confirmed that preoperative PSA ≥28.285 ng/mL, Gleason score ≥8.5, positive surgical margin and lymph node metastasis were independent risk factors for postoperative BCR in HRPCa patients (Table 7).
Table 6.
Influencing factors assignment
| Influencing Factors | Assignment |
|---|---|
| Surgical margin | 0: Negative |
| 1: Positive | |
| Lymph node metastasis | 0: No |
| 1: Yes | |
| PSA | 0: <28.285 ng/mL |
| 1: ≥28.285 ng/mL | |
| Gleason Score | 0: <8.5 |
| 1: ≥8.5 |
Note: PSA: prostate-specific antigen.
Table 7.
Multivariate Cox regression analysis of factors affecting BCR occurring in HRPCa patients
| Factors | β | StdError | Wald x2 | P | HR | 95% CI | |
|---|---|---|---|---|---|---|---|
|
| |||||||
| Lower | Upper | ||||||
| Surgical margin: Positive | 0.868 | 0.282 | 9.449 | 0.002 | 2.382 | 1.370 | 4.143 |
| Lymph node metastasis: Yes | 0.838 | 0.279 | 9.016 | 0.003 | 2.312 | 1.338 | 3.996 |
| PSA ≥28.285 ng/mL | 0.899 | 0.287 | 9.838 | 0.002 | 2.458 | 1.401 | 4.312 |
| Gleason score ≥8.5 | 1.373 | 0.376 | 13.326 | <0.001 | 3.946 | 1.888 | 8.246 |
Note: BCR: biochemical recurrence; HRPCa: high-risk prostate cancer; PSA: prostate-specific antigen; 95% CI: 95% confidence interval.
Nomogram analysis
The nomogram constructed based on the above four indicators showed that all variables had good predictive efficacy for postoperative BCR risk in both training and validation cohorts (Figure 3A, 3B). Calibration curves verified favorable consistency between predicted value and actual outcome in both cohorts (training cohort: χ2=6.823, P=0.559; validation cohort: χ2=5.976, P=0.650, Figure 3C, 3D).
Figure 3.
Construction and diagnostic performance evaluation of the nomogram model: (A) Nomogram for training set; (B) Nomogram for validation set; (C) Calibration curve for validating the nomogram of training set; (D) Calibration curve for validating the nomogram of validation set. Note: BCR: biochemical recurrence; PSA: prostate-specific antigen.
ROC curve analysis
ROC curve analysis indicated that single clinical indicator had limited predictive value for 3-year BCR, while the combined prediction model possessed higher predictive accuracy in both cohorts (Table 8; Figure 4).
Table 8.
Results of ROC curves for assessing 3-year BCR occurrence based on various risk factors
| Training set | Validation set | |||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| AUC | 95% CI | Delong test | AUC | 95% CI | Delong test | |
| Surgical margin | 0.690 | 0.608-0.772 | <0.001 | 0.691 | 0.563-0.818 | <0.001 |
| Lymph node metastasis | 0.676 | 0.593-0.759 | <0.001 | 0.701 | 0.576-0.826 | <0.001 |
| PSA | 0.813 | 0.753-0.872 | 0.029 | 0.817 | 0.721-0.913 | 0.024 |
| Gleason score | 0.764 | 0.699-0.829 | 0.002 | 0.773 | 0.672-0.873 | 0.003 |
| Combine | 0.881 | 0.833-0.930 | - | 0.876 | 0.789-0.964 | |
Note: BCR: biochemical recurrence; PSA: prostate-specific antigen; AUC: area under the curve; 95% CI: 95% confidence interval.
Figure 4.
ROC curves predicting BCR in 3 year occurs for various risk factors: (A) Training set; (B) Validation set. Note: BCR: biochemical recurrence; PSA: prostate-specific antigen.
Discussion
HRPCa is characterized by strong invasive ability and high postoperative BCR risk. Most patients are diagnosed at high-risk stage without obvious early clinical symptoms, so its standardized treatment has always been a key research direction in urology [10,11]. RP is a standard surgical treatment for HRPCa, but single surgical resection cannot completely eliminate latent tumor lesions, easily leading to high positive surgical margin rate and lymph node metastasis, and further inducing postoperative BCR [12]. This study retrospectively analyzed real clinical data to explore the clinical effect of NHT combined with RP and identify independent prognostic factors affecting 3-year BCR.
This study confirmed that compared with single RP treatment, preoperative NHT combined with RP can effectively reduce positive surgical margin rate, lymph node metastasis rate and 3-year BCR rate, prolong BCRFS, and will not increase postoperative complication risks. This conclusion is consistent with previous clinical research results [13,14]. Mechanically, combined NHT regimen can effectively inhibit androgen signaling pathway, induce prostate cancer cell apoptosis, reduce tumor volume and invasiveness, and create favorable surgical conditions [15,16]. Reduced tumor burden can also decrease intraoperative tumor cell dissemination and residual lesions, so as to lower local recurrence and distant metastasis risks [17,18].
Multivariate Cox regression results verified that elevated preoperative PSA level, high Gleason score, positive surgical margin and lymph node metastasis are independent risk factors for postoperative BCR, which is consistent with previous research conclusions [19,20]. PSA level directly reflects tumor load; higher value indicates stronger tumor invasiveness and higher recurrence probability [21]. Gleason score evaluates tumor differentiation degree, and higher score represents higher tumor malignancy [22]. Positive surgical margin suggests incomplete tumor resection, and residual microscopic tumor lesions are the direct cause of sustained PSA elevation and BCR [23]. Lymph node metastasis implies the occurrence of early tumor lymphatic diffusion, accompanied by potential occult distant micrometastases, which greatly increases long-term recurrence risk [24].
The established nomogram prediction model has good stability and discrimination ability in internal and external verification. Single indicator has inevitable clinical limitations: PSA elevation can also be caused by benign prostatic diseases [25]; biopsy Gleason score is prone to sampling bias [26]; postoperative pathological margin evaluation cannot detect microscopic residual lesions comprehensively [27]; routine lymph node dissection cannot rule out occult micrometastases completely [28]. The combined application of four indicators can make up for the defects of single index evaluation, and comprehensively judge postoperative recurrence risk from tumor load, malignancy degree, local resection status and metastatic potential [29-31]. Clinically, for HRPCa patients with multiple high-risk recurrence factors, preoperative 3-month NHT combined with RP is recommended, and individualized postoperative follow-up and adjuvant treatment strategies should be formulated to improve longterm prognosis.
This study has several limitations. First, the follow-up period was limited to 3 years, and long-term survival outcomes were not observed, so the long-term safety and efficacy of this combined regimen still need further verification. Second, this study did not explore the optimal intervention cycle and different drug matching schemes of neoadjuvant therapy. Third, the prediction model failed to incorporate genetic molecular markers and emerging imaging prognostic indicators, which may affect its predictive efficiency. In the future, we will carry out prospective randomized controlled trials to further optimize the clinical application scheme of NHT combined with RP, and enrich predictive variables to improve the clinical application value of the nomogram model.
In conclusion, NHT combined with RP can significantly reduce positive surgical margin rate, lymph node metastasis rate and 3-year BCR risk in HRPCa patients, and prolong BCRFS without increasing postoperative complications. Preoperative PSA level, Gleason score, surgical margin status and lymph node metastasis status are reliable independent predictors of 3-year postoperative BCR. The nomogram model established based on the above factors is worthy of clinical popularization and application.
Disclosure of conflict of interest
None.
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