The Impact of Palliative Transurethral Resection of the Prostate on the Prognosis of Patients With Bladder Outlet Obstruction and Metastatic Prostate Cancer: A Population-Matched Study

Objective: This study aimed to evaluate the survival outcomes of patients with bladder outlet obstruction (BOO) and metastatic prostate cancer (mPCa) after having a palliative transurethral resection of the prostate (pTURP) surgery. Methods: We identified patients with mPCa between 2004 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients who received pTURP and non-surgical therapy were identified. A propensity-score matching was introduced to balance the covariate. Kaplan–Meier analysis and COX regression were conducted to evaluate the overall survival (OS) and cancer-specific survival (CSS) outcomes. Results: A total of 36,003 patients were identified; 2,823 of them were in the pTURP group and 33,180 were in the non-surgical group. The survival curves of the overall cohort showed that the pTURP group was associated with worse outcomes in both OS (HR: 1.12, 95% CI: 1.07–1.18, p < 0.001) and CSS (HR: 1.08, 95% CI: 1.02–1.15, p = 0.004) compared with the non-surgical group. The mean survival time in the overall cohort of the pTURP group was shorter than the non-surgical group in both OS [35.13 ± 1.53 vs. 40.44 ± 0.59 months] and CSS [48.8 ± 1.27 vs. 55.92 ± 0.43 months]. In the matched cohort, the pTURP group had significantly lower survival curves for both OS (HR: 1.25, 95% CI: 1.16–1.35, p < 0.001) and CSS (HR: 1.23, 95% CI: 1.12–1.35, p < 0.001) than the non-surgical group. pTURP significantly reduced the survival months of the patients (36.49 ± 0.94 vs. 45.52 ± 1.23 months in OS and 50.1 ± 1.49 vs. 61.28 ± 1.74 months in CSS). In the multivariate COX analysis, pTURP increased the risk of overall mortality (HR: 1.19, 95% CI: 1.09–1.31, p < 0.001) and cancer-specific mortality CSS (HR: 1.23, 95% CI: 1.14–1.33, p < 0.001) compared with the non-surgical group. Conclusions: For mPCa patients with BOO, pTURP could reduce OS and CSS while relieving the obstruction.


INTRODUCTION
Prostate cancer is the most frequently diagnosed non-cutaneous cancer and the second leading cause of cancer-related mortality among men, globally, in 2020 (1,2). For localized disease, radical prostatectomy (RP) is one of the main treatments with an excellent long-time prognosis (3,4). However, RP has a low cure rate but a high complication rate for metastatic prostate cancer (mPCa). The majority of patients with mPCa will progress to having metastatic castration-resistant prostate cancer (mCRPC) within 2-3 years despite undergoing intensive androgen deprivation therapy (ADT) (5). Although novel androgen biosynthesis inhibitors such as abiraterone and enzalutamide have been introduced to prolong survival in mCRPC, most patients respond temporarily and soon develop resistance to the inhibitors, which results in the failure to control the tumor progression at the end (6,7). Hence once the disease enters a castration-resistant state, the patients are incurable by medicine along with therapy and under a substantially greater risk of mortality (1). According to previous literature, about 83.3% of patients with PCa also have bladder outlet obstruction (BOO) (1,8). Some of these patients have obvious lower urinary tract symptoms (LUTS) and some complications like persistent hematuria, urinary retention, high residual urine volume, bladder stones, etc. These symptoms have been increasingly troublesome for the patients and seriously affect their daily lives.
Patients with BOO who are medicine-failed or have absolute surgical indications are suggested to receive operation intervention, referring to the guidelines (9, 10). The transurethral resection of the prostate (TURP) has been the standard surgical treatment for benign prostatic hyperplasia (BPH) for many years (11). For patients with mPCa with serious BOO who have failed medical therapy and are unwilling to use a catheter for a long time, palliative TURP (pTURP) serves as an effective surgical choice to relieve BOO and improve symptoms (12,13). However, it creates a dilemma for urologists because it might potentially accelerate the tumor progression. Although several studies have investigated the effects of pTURP on mPCa (14)(15)(16), the longterm oncological data is still missing. In this study, we aim to evaluate the prognostic impact of pTURP on patients with mPCa.

Data Source
The data of this study were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2004, to December 31, 2016. Patients with mPCa were retrospectively identified within the SEER * STAT software. The general information and tumor information were collected.

Inclusion and Exclusion Criteria
Patients were considered eligible if they met the following criteria: (1) Patients were diagnosed with primary prostate cancer. (2) Prostate cancer was in the metastatic stage (T1-4N0-1M1). (3) Patients received pTURP or non-surgical treatments.
The following criteria were used for data exclusion: (1) Multiple tumors; (2) Patients received other surgical treatments besides pTURP; (3) Important information such as M stages, survival time, and survival status were incomplete or missing.

Variables and Main Outcomes
We collected the basic characteristics of the patients from the database. The variables involved age, year of diagnosis, race, marital status, tumor, nodes, and metastases (TNM) stage, tumor, prostate-specific antigen (PSA) level, Gleason score, metastasis sites. The main outcomes were cancer-specific survival (CSS) and overall survival (OS).

Statistical Analysis
A Chi-square test was adopted to assess the differences in the basic characteristics of the pTURP and non-surgical groups. Propensity-score matching was conducted to balance the covariates and generate a new cohort. The survival curves, mean survival months, and 1-, 2-, 3-, 5-, and 10-year survival rates were attained using the Kaplan-Meier analysis. Multivariate COX analyses were performed to evaluate the risk factors. The degrees of risk were presented by the hazard ratio (HR) with a 95% confidence interval (95% CI). P < 0.05 was defined as statistically significant. All analyses above were performed with the software SPSS 25 (IBM, Armonk, New York, United States) and Graphed Prism 7.0 (GraphPad Software Inc. San Diego, California, United States).

Patient Characteristics
A total of 36,003 patients with mPCa were identified; 2,823 of them received pTURP and 33,180 received non-surgical treatments. The median age was 72 (64-81) years old. After propensity-score matching, 1,942 pairs of patients were matched in the pTURP and non-surgical groups. There were no significant differences in the baseline characteristics between the two groups. The median age was 74 (65-82) and 72 (63-81) years in the matched pTURP and non-surgical groups in the matched cohort. The baseline characteristics of the patients in the overall cohort and matched cohort are presented in Table 1.

Survival Time and Survival Rates
In the overall cohort, the 1-year survival rates of the pTURP and non-surgical group were 71.6 vs. 69.1% in OS and 79.7 vs. 76.9% in CSS. The pTURP group was associated with similar 2-and   Table 2.
In the matched cohort, the OS and CSS of the pTURP group were consistently worse than the non-surgical group. Among the 1-, 3-, and 5-year survival rates, the CSS of the pTURP and nonsurgical group were 81. 8

Multivariate COX Analysis for OS and PCSS
The results of the COX analyses were showed in Table 3. With the non-surgical therapy group as the reference, the HR and 95% CI of the pTURP group for both OS and CSS were 1. 19

DISCUSSION
Most of the patients with the metastatic prostate disease will develop castration resistance, which means that they will face an unfavorable prognosis and survival (17). For patients with severe BOO and mPCa, whether or not to perform pTURP is a dilemma. Its benefits and harms need to be balanced for these patients. pTURP can relieve obstruction, improve lower urinary tract symptoms and the complications of BOO, and damage the primary tumor. But it may create a source for new metastasis like residual tumor and cancerous cell debris. The channel opened by pTURP operation may potentially promote the spread of tumor cells or tumor-promoting growth factors via the vascular passage (18). Additionally, the necessity of pTURP might imply a much severe condition of PCa, associated with hazardous complications such as a larger size of the tumor and a more aggressive or quick-spreading tumor (14). Poorly differentiated or aggressive prostate tumors are more likely to lead to invasive microvessel density and irregular vessel lumen (18)(19)(20).
Our results found that pTURP could significantly reduce the OS and CSS outcomes in both the overall and matched cohort. The mean survival time of the pTURP group was 36.49 vs. 45.52 months in OS and 50.1 vs. 61.28 months in CSS, compared with the non-surgical group in the matched cohort. This finding was consistent with several former retrospective studies. Choi et al. (14) reviewed 614 patients who received ADT, and pTURP showed notably lower survival rates among castration-resistant prostate cancer (CRPC)-free survival, OS, and CSS than the ADT only group. They specially regarded pTURP as an independent hazard factor of CSS with an HR and 95% CI of 2.543 (1.008-6.420). Pelletier et al. (21) found that the 5-year OS of patients after pTURP was only 16% (95% CI: 6.5-29.8). It was similar to the 18.7% of our 5-year OS results. Jin et al. (22) reported pTURP as an independent risk factor for the biochemical recurrence for prostate cancer, leading to significantly lower survival rates. Krupski et al. (16) also concluded that pTURP was an adverse prognostic factor even after the adjustment of the classical tumor characteristics. Note that studies also demonstrated that generally, the pTURP group had a larger prostate volume than the non-pTURP group before matching, which may contribute to the unfavorable prognosis in pTURP. Interestingly, the resection weight, resection time, and blood transfusion were tested not correlated with CSS (14,22).
There were also some opposite opinions. Qin et al. (23) analyzed the curative effect of complete androgen blockade (CAB) therapy only and pTURP+CAB combined therapy for patients with metastatic hormone sensitive prostate cancer (mHSPC). Their study revealed that pTURP was beneficial to both the OS (24.4 vs. 22.9 months) and CSS (24.4 vs. 24.1 months), resulting in a more prolonged and sensitive response to hormone therapy in mHSPC. Qu et al. (24) included 118 patients with mPCa; 110 of them were in the pTURP+ADT group. They reported that the 3-year CSS of pTURP + ADT group was higher than that in the ADT alone group (95.9 vs. 64.9%, p = 0.004). In their analysis, it was found that pTURP + ADT could improve the CSS outcomes when PSA ≥65 ng/mL, Gleason Score (GS) ≥8, and bone metastasis ≤5. As expected, pTURP could obviously improve LUTS symptoms in these patients. Crain et al. (12) reported that pTURP could be performed safely with significant improvement in the urinary symptoms and quality of life in mPCa patients. Moreover, Sehgal et al. (20) revealed that pTURP is a necessity for patients with PCa and high Gleason sum and the presence of retention, which showed an ideal 6month catheter free rate of 72%. Therefore, the application of pTURP in patients with mPCa and serious BOO should be comprehensively considered.
Even though our study analyzed a large sample of patients with long-time follow-ups, certain limitations still existed in our study. The limitations were as follows: (1) for patients with mPCa, medical treatments like ADT were essential factors for the control of disease progression. However, limited by the original data from the SEER database, this information was

CONCLUSION
For patients with mPCa and BOO, pTURP could reduce OS and CSS to a certain degree while relieving the obstruction. However, with the limitation of our study, more high-quality studies are needed for further evaluation.

DATA AVAILABILITY STATEMENT
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

AUTHOR CONTRIBUTIONS
KF, PS, and QD designed the protocol, extracted and analyzed the data, drafted the manuscript, revised the manuscript, approved the final manuscript, and supervised all stages of this study. JZ, LY, PL, and NL extracted and analyzed the relevant data, drafted the manuscript, revised the manuscript, and approved the final manuscript.