1. Introduction
Benign prostatic hyperplasia (BPH), which is a key cause of lower urinary tract symptoms (LUTS) in older men, affects approximately 210 million men worldwide [
1]. A study revealed that 50% of men developed pathological BPH at the age of 51–60 years [
2]. Moreover, BPH/LUTS prevalence is expected to increase sharply in the coming decades [
3]. The sequelae of BPH include decreased urinary flow and progression of voiding and storage symptoms, which eventually results in acute or chronic urinary retention (UR) [
4]. BPH with moderate-to-severe LUTS considerably affects all aspects of the quality of life of men as they age [
5]. A 50-year-old from the United States has an estimated risk of approximately 40% of undergoing therapeutic intervention (surgical or medical treatment) at some point during his lifetime [
6]. Accordingly, billions of US dollars are spent annually to treat BPH/LUTS [
7].
Both alpha-1 blockers and transurethral resection of the prostate (TURP) achieve favorable treatment outcomes in most patients with benign prostatic obstruction (BPO) [
8]. Alpha-1 blockers are used for first-line treatment of BPO in men with LUTS [
9]. In patients with unsatisfactory response to medication, TURP remains the dominant and definitive treatment for LUTS caused by BPH [
10]. Some studies have also reported that TURP achieves favorable outcomes even for BPH patients with comorbidities such as UR, type 2 diabetes, and stroke [
11,
12,
13]. Nevertheless, to the best of our knowledge, no studies have addressed the long-term sequelae for patients with “unfavorable” outcomes from either medical or surgical treatment. Therefore, we used Taiwan National Health Insurance Research Database (NHIRD) data to conduct a nationwide observational cohort study for investigating the correlation between the treatment outcomes of BPH/LUTS and lifelong health status, including urologic cancer incidence and geriatric adverse events.
4. Discussion
UR, Urinary tract infection (UTI), gross hematuria with bladder tamponade, and bladder stone formation are all possible sequelae of benign prostate obstruction (BPO) and are regarded as absolute indications of TURP [
20]. However, it is frustrating for both physicians and patients if the previously mentioned complications reoccur despite treatment, regardless of whether the treatment is in the form of a surgical or medical intervention. According to the literature, unfavorable events of TURP include UTI (1.7–8.2%), UR (3–9%), hematuria with clot retention (2–5%), urethral strictures (2.2–9.8%), and bladder neck contractures (0.3–9.2%) [
21]. The incidence of unfavorable events following treatment with alpha blockers varies among reports [
22]. Nevertheless, no studies have focused on whether these unfavorable events affect older adults during long-term follow-up.
Before comparing the clinical outcomes of the four cohorts, 1:1 propensity score matching [
23] was performed to ensure that the characteristics of both groups were similar and that more objective data could be obtained. Therefore, as detailed in
Table 2 and
Table 6, the distribution of parameters, including age, incidence of comorbidities, and Charlson comorbidity index, did not differ significantly between each two groups. The major finding of this research is that post-treatment AEs (whether following surgical or medical intervention) are significantly correlated with bladder cancer formation during lifelong follow-up. Bladder cancer is the ninth most common cancer worldwide, with an estimated 430,000 new cases in 2012 [
24]. Bladder cancer resulted in 170,000 deaths globally in 2011, which demonstrates an increase from the 114,000 deaths in 1990 of 19.4% after adjusting for the increase in the total world population [
25]. Data collected using the Taiwan Cancer Registry database suggest that the incidence of bladder cancer in the general population is approximately 0.21% [
26]. However, the patients included in our study exhibited a higher bladder cancer incidence compared with the Taiwan general population. Patients with post-treatment AE even had a greater risk of bladder cancer than those without AE. This phenomenon indicates that an unfavorable treatment outcome for BPO is associated with an increased incidence of bladder cancer.
Multiple factors are associated with bladder cancer development. However, smoking tobacco is the main known contributor [
27]. The number of cigarettes smoked, degree of inhalation, type of tobacco, use of filters, and smoking cessation all have significant relationships with bladder cancer development [
28]. In addition, common candidate genes or pathways, such as carcinogenic metabolizing genes, DNA repair genes, apoptosis-related genes, and microRNA-related genes, have been studied widely and can contribute to the risk of bladder cancer [
29]. Clinically, men with severe LUTS have a 64% higher relative risk of bladder cancer compared with men who report no LUTS. A recent study even revealed that patients with BPH who underwent TURP were at a higher risk of bladder cancer (HR = 6.17, 95%, CI = 3.68–10.3) than those who did not [
30]. The sequelae of unfavorable BPO treatment outcomes, such as high post-voiding residual urine volume, repeat UTIs, chronic bladder inflammation, and chronic UR, all increase urothelial exposure to carcinogens and, thus, increase the risk of bladder cancer [
31]. After chronic inflammation develops, it can mediate cancer pathogenesis by stimulating malignant cell growth, invasion, and metastasis through the recruitment of inflammatory cells and signaling molecules [
32]. Therefore, an unfavorable treatment outcome for BPO is associated with an increasing bladder cancer incidence.
Similar to bladder cancer development, that of prostate cancer is positively associated with chronic tissue inflammation and bacterial infection [
33]. Another study also reported that chronic tissue inflammation is associated with an increased risk of both prostate and bladder cancer, and a subgroup analysis by ethnicity suggested that the association was much stronger in Asian patients than in Caucasian patients [
34]. A study pertaining to microbiomes indicated a prevalence of pro-inflammatory bacteria and uro-pathogens in the urinary tract of men with prostate cancer [
35]. Urinary microbiomes influence chronic inflammation in the prostate and lead to prostate cancer development and progression [
35]. Nevertheless, the findings of our study suggest that an unfavorable treatment outcome for BPO is not associated with prostate cancer development. Our explanation for this phenomenon is that prostate cancer development is mediated in part by chronic inflammation as well as by genetics and exposure to toxins in the environment. Thus, compared with unfavorable BPO treatment outcomes, other factors such as age, race, family medical history, lifestyle, and presence of metabolic syndrome might be stronger contributors to prostate cancer development.
Another notable finding of this study is that the treatment outcome of BPO had a substantial impact on the health status of male patients. In the medication-only group, patients with AEs, despite regular alpha blocker treatment, had a higher risk of all-cause mortality. By contrast, patients with AE following TURP also had increased risk of hemorrhoids, hip fracture caused by accidental falls, and medication dependence (alpha blockers or antimuscarinic medications) during a three-year follow-up. Many patients have persistent voiding dysfunction after surgical treatment for BPO. Older age, history of diabetes, history of cerebrovascular accidents, and preoperative antimuscarinic drug use are possible risk factors of continuing medical therapy following TURP [
36]. We used 1:1 propensity score matching to eliminate the influence of the previously mentioned factors and concluded that the occurrence of AE within the six months following operation is also strongly associated with lifelong dependence on urologic medications.
This study has some limitations as a result of the NHIRD data structure. First, this database does not provide detailed personal information such as family cancer history, laboratory parameters, cigarette use, environmental toxin exposure, body mass index (BMI), and dietary habits, which are all confounding variables that influence prostate and bladder cancer development. Second, we used a strict criterion to divide our study population into two categories: patients with or without AEs. Thus, we could not assess how the duration, frequency, and severity of AEs affected treatment outcomes. Third, the use of laser prostatic vaporization or vapor-resection, which is not reimbursed by the Taiwan NHI, has only become increasingly common in the last decade [
37]. Thus, patients receiving prostate laser treatment were not included in this database. However, despite these limitations, we believe that this is innovative and valid research. This study confirmed that unfavorable treatment outcomes of BPH increase the incidence of bladder cancer and have negative health effects among older men.