Persistent bothersome urinary frequency following stereotactic body radiation therapy for clinically localized prostate cancer: rationale for prophylactic β3-agonist in men with elevated baseline international prostate symptom scores

Introduction: Stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer has been associated with prolonged acute obstructive and irritative lower urinary tract symptoms (LUTS). Prophylactic alpha-adrenergic antagonists have been used therapeutically to prevent obstructive symptoms in patients undergoing prostate SBRT, however irritative symptoms may be better addressed with beta 3-adrenergic receptor agonists, which are shown to be safe and effective in men with overactive bladder (OAB).

Objective: This study retrospectively examines the pattern of bothersome urinary frequency associated with SBRT to determine which patients would have potentially benefitted from prophylactic beta 3-adrenergic receptor agonist.

Methods: Patients with clinically localized prostate cancer who underwent prostate SBRT (n=1676) were followed for 3 months post-treatment to evaluate for bothersome urinary frequency, which was assessed by question 4E on the EPIC-26. Answers to question 4E and tamsulosin usage were recorded at regular follow-ups to assess, and demographic factors as well as baseline prostate volume, alpha-adrenergic antagonist usage and IPSS score severity were used as modifiers.

Results: Using the IPSS questionnaire to determine baseline LUTS, most patients reported moderate urinary symptoms (53%), followed by mild (34%) and severe (13%). Patients endorsed increased irritative LUTS at 1-month post-SBRT, with similar rates of frequency at 3 months compared to baseline. Patients with moderate and severe urinary symptoms per the baseline IPSS were more likely to endorse bothersome urinary frequency at one month post SBRT (EPIC-26 Q4E; OR 2.58 and 10.2 respectively) compared to those with mild symptoms. No significant differences were found in urinary frequency between patients who used and did not use an alpha antagonist at baseline.

Conclusions: Bothersome post-SBRT urinary frequency persists 1-month post-SBRT. Baseline LUTS predicts bothersome post-treatment urinary frequency. Prophylactic alpha-adrenergic antagonists do not protect against bothersome acute urinary frequency. This paper makes the case that urinary frequency may be better addressed with a prophylactic beta-3 agonist, like vibegron, which is designed to treat storage-related LUTS concerns.

Introduction

Stereotactic body radiation therapy (SBRT) is an increasingly popular intervention for the treatment of clinically localized prostate cancer (1–3). As more patients are choosing this convenient mode of treatment, it becomes imperative that potential side effects are well understood in order to guide symptom management. Lower urinary tract symptoms (LUTS) is a general term that includes the categories of obstructive (e.g., retention and hesitancy) and irritative (e.g., frequency, urgency, and urge incontinence) (4). Previous research has demonstrated an increased prevalence of acute LUTS in men undergoing prostate SBRT for up to 3 months post-treatment (5, 6). Prophylactic alpha-adrenergic antagonists are typically used as standard of care to treat obstructive symptoms, either prophylactically or at the earliest sign of symptoms (6–8). Irritative symptoms, however, may be better addressed by alternative strategies (5).

Irritative voiding symptoms are a common problem of aging (9). In men > 70 years old, the prevalence is greater than 20% (10). An enlarged prostate may increase the risk of bothersome irritative voiding symptoms (6, 11). Anti-cholinergic medications may relieve symptoms but are commonly discontinued due to bothersome dry mouth and/or constipation (12, 13). Beta-3 agonists are a newer effective medication class for overactive bladder (OAB) with an improved side effect profile and adherence (14). Beta-3 agonists relax bladder smooth muscle which increases storage capacity and prolongs intervals between voiding (15). In men with BPH and OAB, treatment beta-3 agonists did not adversely affect voiding parameters (16, 17).

The aim of this study was to retrospectively examine the pattern of bothersome urinary frequency in patients with clinically localized prostate cancer undergoing SBRT from the first day of treatment up to 3 months post-treatment. Additionally, we wished to evaluate the impact of baseline patient characteristics on post-SBRT bothersome urinary frequency, specifically at 1-month post-SBRT when we expect urinary frequency to be the most pronounced.

Methods

Patient selection

The Medstar Georgetown University Hospital Internal Review (IRB) approved this single institution retrospective study (IRB 09-510). Patients eligible for study inclusion had localized prostate cancer treated with SBRT. All patients provided informed consent prior to treatment. Baseline urinary symptoms (QOL) was assessed using the International Prostate Symptom Score (IPSS) with higher values (range 0-35) indicating more severe LUTS (18). An IPSS of 0–7 is mild, 8–19 is moderate and 20–35 is severe LUTS. Patients were eligible if they had localized prostate cancer treated with SBRT and completed the EPIC-26 Questionnaire. For this analysis, patients who did not complete the EPIC-26 at 1-month post-SBRT were excluded. No additional exclusions were made based on prior surgery or comorbidities.

SBRT treatment planning and delivery

SBRT was delivered utilizing the CyberKnife robotic radiosurgical system (Accuray, Inc., Sunnyvale, CA, USA). Fiducial placement, treatment planning magnetic resonance imaging (MRI), and computed tomography (CT) simulation procedures have been previously described (2, 6). The clinical target volume (CTV) was defined as the prostate and proximal seminal vesicles to the point where the proximal seminal vesicles separate. The CTV was expanded 5 mm in all directions except 3 mm posteriorly to generate the planning target volume (PTV). Patients were treated to a prescription dose of 35-36.25 Gy to the PTV delivered in five fractions over two weeks based on treatment planning. The prescription isodose line was limited to ≥ 75% to restrict the maximum prostatic urethra dose to 133% of the prescription dose. Critical structure dose constraints were previously detailed by Chen et al.² For structures relevant to genitourinary toxicity, the maximum allowable dose was 37 Gy to both the bladder and the membranous urethra. Urinary symptoms were managed with alpha-antagonists and/or short steroid tapers. Patients were treated with tamsulosin 0.4 mg until moderate urinary symptoms abated. The standard protocol for a steroid taper was Decadron 4 mg in the morning for a week followed by 2 mg in the morning for a second week.

Follow-up and statistical analysis

Patients completed the Expanded Prostate Cancer Index Composite (EPIC)-26 on the day of the first SBRT fraction and during routine follow-up one month and three months after the completion of SBRT (19). The EPIC-26 is a validated tool that measures associated bother with treatment related symptoms. Bothersome urinary frequency was assessed before and after treatment based on the patient reported response to Question 4e on the EPIC 26 (“How big a problem, if any, has the need to urinate frequently during the day been for you the last 4 weeks?”). Patients were seen at 1 month, 3 months, then at 6 months intervals for a year, then yearly for the rest of their lives.

To statistically compare changes between time points, the levels of responses were assigned a score, and the significance of the mean changes in the scores was assessed by paired t test. Wilcoxon Signed-Rank Test and chi-square analysis were used to assess differences in health-related quality of life (HRQOL) scores in comparison to baseline. Paired t-test was used to assess significance of the change in scores. The minimally important difference (MID) to assess for clinically significant change in HRQOL from baseline was set as half a standard deviation (SD). All analyses were performed using R statistical software.

Covariates were selected if they were statistically significant in univariate analysis and/or clinically relevant. For example, baseline AUA severity was included given its strong association with urinary frequency (p < 0.001) and clinical importance. Risk group was also included, since it was statistically significant in the univariate analysis (p = 0.04 for intermediate vs. low). Other variables (age, race, prostate volume, alpha antagonist use) were excluded as they were not significant in the univariate analysis and lacked strong clinical justification in this setting.

Results

Baseline demographic and clinical patient characteristics are presented in Table 1. 1676 patients with localized prostate cancer were treated with prostate SBRT and followed for 3 months to evaluate acute toxicities. For this study, we limited the analysis to the 1078 patients who completed the EPIC-26 questionnaire at 1-month post-SBRT. The median patient age was 70 years old (IQR: 66-75). 58% self-identified as white and 35% as black. The median prostate volume was 39 cc, obtained through transrectal ultrasound (IQR: 28 –53). Using the D’Amico risk classification, 21% of patients were low risk, 66% of patients were intermediate risk, and 13% patients were high risk. The majority of patients were treated with 36.25 Gy in 7.25 Gy fractions. Baseline IPSS scores show that most patients had mild to moderate lower urinary tract symptoms with a high rate of alpha antagonist usage (72%) prior to receiving SBRT.

Table 1

Table 1. Demographic and clinical characteristics of patients who did 1 month of follow-up.

When looking at urinary frequency with question 4 on EPIC-26, patients endorsed increased urinary frequency at 1-month post-SBRT (mean of 2 on 4-point scale), with similar rates of frequency at 3 months compared to baseline (mean of 1 on 4-point scale; Figure 1). Patients with moderate and severe urinary symptoms per the baseline IPSS were more likely to endorse bothersome urinary frequency at one month post SBRT (EPIC-26 Q4E; OR 2.58 and 10.2 respectively) compared to those with mild symptoms (Tables 2, 3). No significant differences were found in urinary frequency between patients who used and did not use an alpha antagonist at baseline (Table 2).

Figure 1

Figure 1. Mean scores for urinary frequency, assessed by Question 4e on the EPIC-26 (“How big a problem, if any, has the need to urinate frequently during the day been for you the last 4 weeks?”). Scores range from 0 (no problem) to 4 (big problem).

Table 2

Table 2. Univariate logistic regression model predicting the risk of reporting urinary frequency in EPIC Q4-E.

Table 3

Table 3. Multivariate logistic regression model predicting the risk of reporting urinary frequency in EPIC Q4-E.

Discussion

Alpha-adrenergic antagonists have been routinely used therapeutically as well as prophylactically for radiation-related urinary symptoms and, more recently, were shown to be well-tolerated in patients undergoing SBRT (6–8). Alpha-adrenergic antagonists are designed to address the “voiding” category of LUTS by inducing smooth muscle relaxation in the prostate and bladder neck, thus reducing urinary obstruction (11). The “storage” category of LUTS may be better addressed with beta 3-adrenergic receptor agonists, medications designed to treat overactive bladder without as many anticholinergic side effects as antimuscarinic medications (12, 14). While our study does not specifically measure the efficacy of beta 3-adrenergic receptor agonists in men undergoing SBRT for prostate cancer, it provides a rationale for the future study of these medications in this patient population.

Mirabegron, a type of beta 3-adrenergic receptor agonist, has been shown to be effective in treating male patients with overactive bladder with minimal effects on urodynamics (16, 20). Adding mirabegron to an alpha-adrenergic antagonist improved frequent urination compared to an alpha-adrenergic antagonist alone (21). However, elevated blood pressure is common in elderly prostate cancer patients and blood pressure elevation is a known side effect of mirabegron (22).

Another beta 3-adrenergic receptor agonist, vibegron, was found to be effective and safe as an add-on therapy in men already receiving an alpha-adrenergic antagonist presenting with persistent storage symptoms (2). There has not yet been a study that examines the safety and utility of beta 3-adrenergic receptor agonists in treating LUTS in patients undergoing SBRT for prostate cancer. Importantly, vibegron does not increase blood pressure or interact with alpha-adrenergic antagonists, but it will be important to show low rates of acute urinary retention (2).

A prior study utilizing the EPIC-26 in the context of patients undergoing SBRT for prostate cancer found a 20% increase in the number of men who endorsed bothersome urinary frequency 1 week after the completion of treatment compared to pretreatment (3). This study highlights the prevalence of urinary frequency in men undergoing stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer. Our findings indicate that SBRT treatment primarily exacerbates urinary urgency and frequency within the first month post-treatment, with a significant improvement by three months. This temporal pattern suggests that the acute effects of SBRT on the bladder may be distinct from more chronic prostate cancer treatments and may be particularly amenable to targeted interventions.

The analysis of IPSS symptom scores revealed that patients with moderate and severe urinary symptoms at baseline were more likely to report significant urinary urgency (IPSS Q4; ORs 2.69 and 5.72, respectively) and frequency (EPIC-CP Q4E; ORs 2.58 and 10.2, respectively) post-treatment. The relationship between baseline symptoms and post-treatment urgency and frequency reinforces that pre-existing voiding or storage dysfunction may serve as a risk factor for increased symptom burden after SBRT. The higher risk of urgency in those with moderate-to-severe baseline symptoms suggests that these patients may require closer monitoring and more aggressive symptom management strategies, including potential pharmacologic interventions.

While alpha-adrenergic antagonists such as tamsulosin have been widely used in SBRT patients to alleviate obstructive voiding symptoms (6, 7), our study did not find any protective benefit of baseline alpha-adrenergic antagonist usage in preventing urinary frequency. This is consistent with the literature suggesting that alpha-adrenergic antagonists are more effective in managing obstructive voiding dysfunction (e.g., weak stream, incomplete emptying), rather than storage symptoms, such as urgency and frequency (4–8). The lack of a protective effect from alpha antagonists further supports the hypothesis that medications targeting the beta-3 adrenergic receptor, which modulate bladder storage function, may be more appropriate for addressing storage-related LUTS in SBRT patients.

Beta-3 adrenergic receptor agonists, such as vibegron, have been shown to be safe and effective in improving symptoms of overactive bladder (OAB), including urinary urgency, in men (10, 11). Given that SBRT-related urinary urgency and frequency appears to peak at one month post-treatment, our findings suggest that the early addition of a beta-3 agonist in men at high risk for storage LUTS could provide a beneficial prophylactic strategy. This approach could be particularly valuable for patients with moderate to severe pre-treatment LUTS, as they appear to be more vulnerable to post-SBRT storage symptoms. Additionally, the lack of a significant difference in urinary frequency and urgency between patients who used and did not use an alpha antagonist suggests that addressing storage symptoms may require a different pharmacologic approach than the current standard of care in SBRT patients.

Our study has several strengths, including its large sample size (n=1078) and the use of validated questionnaires (IPSS and EPIC-26) to assess patient-reported outcomes. However, there are also several limitations to consider. First, the retrospective design of the study limits our ability to establish causal relationships between SBRT and the onset of urinary urgency. Additionally, because our cohort did not include patients who received other forms of radiation therapy or surgical interventions, the generalizability of our findings may be restricted to SBRT-treated individuals. Further, we assessed symptom severity using patient-reported outcomes rather than data obtained by urodynamic studies, which may provide a more comprehensive and objective understanding of the mechanisms underlying SBRT-induced LUTS.

Conclusion

Our study demonstrates that urinary frequency is a common and significant side effect of stereotactic body radiation therapy (SBRT) in men with localized prostate cancer, particularly during the first month following treatment. Urinary symptoms appear to be most pronounced in patients with moderate to severe urinary symptoms at baseline, highlighting the need for tailored management strategies. The lack of a protective effect from alpha-adrenergic antagonists necessitates further research into whether alternative therapeutic strategies, such as beta-3 adrenergic agonists, may offer a more effective approach for managing storage-related LUTS in this patient population. Future prospective studies are needed to confirm these findings and evaluate the clinical benefit of beta-3 agonists in preventing or alleviating SBRT-induced urinary urgency and frequency.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by The Medstar Georgetown University Hospital Internal Review Board (IRB 09-510). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

JZ: Methodology, Investigation, Formal analysis, Writing – original draft, Writing – review & editing. MK: Writing – original draft, Formal analysis, Investigation, Writing – review & editing. EL: Writing – original draft, Writing – review & editing. TO: Writing – original draft, Data curation, Writing – review & editing, Formal analysis. KG: Formal analysis, Writing – original draft, Writing – review & editing, Investigation. AZ: Writing – original draft, Formal analysis, Writing – review & editing. MD: Writing – review & editing, Writing – original draft. DK: Writing – original draft, Formal analysis, Writing – review & editing. SS: Writing – review & editing, Writing – original draft. RH: Writing – original draft, Writing – review & editing. SC: Methodology, Writing – original draft, Data curation, Formal analysis, Investigation, Conceptualization, Supervision, Writing – review & editing, Project administration.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by The James and Theodore Pedas Family Foundation. SC and DK acknowledge the grant R01MD012767 from the National Institute on Health Disparities.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declare that no Generative AI was used in the creation of this manuscript.

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References

1. van As N, Griffin C, Tree A, Patel J, Ostler P, van der Voet H, et al. Phase 3 trial of stereotactic body radiotherapy in localized prostate cancer. New Engl J Med. (2024) 391:1413–25. doi: 10.1056/NEJMoa2403365

PubMed Abstract | Crossref Full Text | Google Scholar

2. Chen LN, Suy S, Uhm S, Oermann EK, Ju AW, Chen V, et al. Stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer: the Georgetown University experience. Radiat Oncol. (2013) 8:58. doi: 10.1186/1748-717X-8-58

PubMed Abstract | Crossref Full Text | Google Scholar

3. Kishan AU, Dang A, Katz AJ, Mantz CA, Collins SP, Aghdam N, et al. Long-term outcomes of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer. JAMA Net Open. (2019) 2. doi: 10.1001/jamanetworkopen.2018.8006

PubMed Abstract | Crossref Full Text | Google Scholar

4. Abdelmoteleb H, Jefferies ER, and Drake MJ. Assessment and management of male lower urinary tract symptoms (LUTS). Int J Surg. (2016) 25:164–71. doi: 10.1016/j.ijsu.2015.11.043

PubMed Abstract | Crossref Full Text | Google Scholar

5. Danner M, Hung MY, Yung TM, Ayoob M, Lei S, Collins BT, et al. Utilization of patient-reported outcomes to guide symptom management during stereotactic body radiation therapy for clinically localized prostate cancer. Front Oncol. (2017) 7:227. doi: 10.3389/fonc.2017.00227

PubMed Abstract | Crossref Full Text | Google Scholar

6. Repka MC, Guleria S, Cyr RA, Yung TM, Koneru H, Chen LN, et al. Acute urinary morbidity following stereotactic body radiation therapy for prostate cancer with prophylactic alpha-adrenergic antagonist and urethral dose reduction. Front Oncol. (2016) 6:122. doi: 10.3389/fonc.2016.00122

PubMed Abstract | Crossref Full Text | Google Scholar

7. Prosnitz RG, Schneider L, Manola J, Rocha S, Loffredo M, Lopes L, et al. Tamsulosin palliates radiation-induced urethritis in patients with prostate cancer: results of a pilot study. Int J Radiat Oncol Biol Phys. (1999) 45:563–6. doi: 10.1016/S0360-3016(99)00246-1

PubMed Abstract | Crossref Full Text | Google Scholar

8. Merrick GS, Butler WM, Wallner KE, Lief JH, and Galbreath RW. Prophylactic versus therapeutic alpha-blockers after permanent prostate brachytherapy. Urology. (2002) 60:650–5. doi: 10.1016/S0090-4295(02)01840-X

PubMed Abstract | Crossref Full Text | Google Scholar

9. Wein AJ, Rovner ES, Staskin DR, Andersson KE, and Ouslander JG. Definition and epidemiology of overactive bladder. Urology. (2002) 60:7–12. doi: 10.1016/S0090-4295(02)01784-3

PubMed Abstract | Crossref Full Text | Google Scholar

10. Milsom I, Stewart W, and Thüroff J. The prevalence of overactive bladder. Am J Manag Care. (2000) 6:S565–73.

Google Scholar

11. Eapen RS and Radomski SB. Review of the epidemiology of overactive bladder. Res Rep Urol. (2016) 8:71–6. doi: 10.2147/RRU.S102441

PubMed Abstract | Crossref Full Text | Google Scholar

12. Veenboer PW and Bosch JLHR. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol. (2014) 191:1003–8. doi: 10.1016/j.juro.2013.10.046

PubMed Abstract | Crossref Full Text | Google Scholar

13. Song YS, Lee HY, Park JJ, and Kim JH. Persistence and adherence of anticholinergics and beta-3 agonist for the treatment of overactive bladder: systematic review and meta-analysis, and network meta-analysis. J Urol. (2021) 205:1595–604. doi: 10.1097/JU.0000000000001440

PubMed Abstract | Crossref Full Text | Google Scholar

14. Mostafaei H, Salehi-Pourmehr H, Jilch S, Carlin GL, Mori K, Quhal F, et al. Choosing the most efficacious and safe oral treatment for idiopathic overactive bladder: A systematic review and network meta-analysis. Eur Urol Focus. (2022) 8:1072–89. doi: 10.1016/j.euf.2021.08.011

PubMed Abstract | Crossref Full Text | Google Scholar

15. Radomski SB. Update on medical therapy for male LUTS. Can Urologic Assoc J. (2014) 8:S148. doi: 10.5489/cuaj.2310

PubMed Abstract | Crossref Full Text | Google Scholar

16. Nitti VW, Rosenberg S, Mitcheson DH, He W, Fakhoury A, and Martin NE. Urodynamics and safety of the β₃-adrenoceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. J Urol. (2013) 190:1320–7. doi: 10.1016/j.juro.2013.05.062

PubMed Abstract | Crossref Full Text | Google Scholar

17. Staskin D, Owens-Grillo J, Thomas E, Rovner E, Cline K, and Mujais S. Efficacy and safety of vibegron for persistent symptoms of overactive bladder in men being pharmacologically treated for benign prostatic hyperplasia: results from the phase 3 randomized controlled COURAGE trial. J Urol. (2024) 212:256–66. doi: 10.1097/JU.0000000000003999

PubMed Abstract | Crossref Full Text | Google Scholar

18. Barry MJ, Fowler FJ, O’Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK, et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol. (1992) 148:1549–57. doi: 10.1016/S0022-5347(17)36966-5

PubMed Abstract | Crossref Full Text | Google Scholar

19. Wei JT, Dunn RL, Litwin MS, Sandler HM, and Sanda MG. Development and validation of the Expanded Prostate Cancer Index Composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology. (2000) 56:899–905. doi: 10.1016/S0090-4295(00)00858-X

PubMed Abstract | Crossref Full Text | Google Scholar

20. Warren K, Burden H, and Abrams P. Mirabegron in overactive bladder patients: efficacy review and update on drug safety. Ther Adv Drug Safe. (2016) 7:204–16. doi: 10.1177/2042098616659412

PubMed Abstract | Crossref Full Text | Google Scholar

21. Nakai Y, Tanaka N, Asakawa I, Miyake M, Anai S, Torimoto K, et al. Mirabegron reduces urinary frequency and improves overactive bladder symptoms at 3 months after 125I-brachytherapy for prostate cancer: an open-labeled, randomized, non–placebo-controlled study. Urology. (2022) 161:87–92. doi: 10.1016/j.urology.2021.12.018

PubMed Abstract | Crossref Full Text | Google Scholar

22. Leong DP, Cirne F, and Pinthus JH. Cardiovascular risk in prostate cancer. Cardiol Clin. (2025) 43:83–91. doi: 10.1016/j.ccl.2024.09.003

PubMed Abstract | Crossref Full Text | Google Scholar