Summary

METHODS
This study comprises 131 patients with localized, locally advanced, and pelvic oligometastatic prostate cancer treated at our institution. All patients were treated with IMRT between February 2016 and August 2020. Urinary incontinence after the treatment was assessed retrospectively using a standardized follow-up program based on data available at our center. The urinary incontinence was scored using the CTCAE version 5.0 scoring system. In univariate analysis, the Mann-Whitney test was used to detect any association between penile bulb V50 doses and membranous urethral length on urinary incontinence.

RESULTS
Urinary incontinence after the treatment was reported in 17 of 131 patients. The average penile bulb V50 values of patients with incontinence were 28.66 gy and 26.8 in patients who did not have urinary incontinence. The mean membranous urethral length was 3.01cm in patients with incontinence and 3.34cm in patients without incontinence. Although these parameters have minimal difference in patients with and without incontinence, they are not statistically significant (p>0.05 all).

CONCLUSION
Radiation-induced urinary incontinence was not associated with the radiation dose of the penile bulb and membranous urethral length. However, further studies are essential.

Introduction

There are many known anatomical and physiological parameters related to urinary continence. Rehder et al.[2] described the effect of the penile bulb on urinary continence for the first time. This was based on the idea that physiological contraction of the bulbospongiosus muscle increases pressure in the bulb of the penis (as blood is not compressible) and consecutively leads to additional contraction of the urethral lumen. Based on this knowledge, a well-vascularized penile bulb is important to erectile function and urinary continence. There are several clinical studies that support this view.[3,4] These studies are about the relationship between continence surgery and male sexual function. No study has yet evaluated the penile bulb radiation dose effect on continence.

As we know, radiation treatment affects normal tissue vasculature near the target volume. We searched about the effect of this damage on the penile bulb and related urinary incontinence.

Methods

Patients
This retrospective cohort study was composed of 131 patients with localized, locally advanced prostate cancer and pelvic oligometastatic disease. We excluded extrapelvic-distant metastatic prostate cancer patients from the study. All patients were treated with radiotherapy between February 2016 and August 2020. Of the 131 patients, 30 were those who had undergone radical prostatectomy (salvage prostatectomy was excluded). Urinary incontinence that occurred after the treatment was evaluated. Radiotherapy was delivered using linear accelerators with 6 MV photons by intensity-modulated radiotherapy (IMRT). Patients were treated five times per week at doses ranging from 66 to 76 Gy at the planning target volume (PTV) using a standard 2 Gy per fraction. Six of the patients consisted of those treated with the hypofractionated regimen (2 Gy < per fraction). In the current patient cohort, 36.6% of patients had irradiated pelvic lymph nodes as part of therapy. Setup accuracy was verified during delivery by matching bony anatomy. Most patients with locally advanced prostate cancer received adjuvant hormonal treatment. Diabetes, hypertension, coronary artery disease, and peripheral artery disease were defined as "vascular diseases". Other diseases, such as endocrinological and rheumatological, were described as "other than vascular disease". These patient characteristics were retrospectively assessed from detailed patient charts (Table 1).

Table 1 Patient and treatment characteristics

Target and Organ at Risk Delineation
The high-risk clinical target volume (HR-CTV) consisted of the prostate with or without the SV, depending on the estimated risk of SV invasion. Due to the risk of locoregional metastases, pelvic lymphatics are included in the low-risk clinical target volume (LR-CTV). The full bladder was applied as part of the treatment planning. Patients were instructed to urinate and drink half or one liter of water one hour before the radiotherapy. The penile bulb contouring was done with the ESTRO-ACROP guidelines.[5] The bladder was created using the entire bladder. The trigone was defined as the triangle-shaped structure between the transition of the ureters in the bladder wall cranially and the transition of the urethra into the bladder wall caudally.[6] MUL was measured in the midline sagittal plane on CT-sim. On CT-sim with non-operated patients, MUL was considered to be the distance from the prostatic apex to the level of the urethra at the penile bulb (Fig. 1). With operated patients, MUL was supposed to be the distance from the bladder neck to the layer of the urethra at the penile bulb.[7]

Fig. 1. Sagittal view of the bladder (yellow), trigonum (green), membranous urethra (blue), penile bulb (purple), external and internal sphincters (pink, cyan).

Endpoints
The grade of urinary incontinence according to CTCAE v5.0 was evaluated retrospectively using available patient data between 2016 and 2020. Urinary incontinence grade 1 was defined as occasional leaking (e.g., with coughing, sneezing, etc.) when pads were not indicated, while grade 2 was defined as spontaneous leaking when pads were indicated. In addition, the operation intervention is only applied to grade 3. Urinary incontinence was evaluated for the first six months after treatment. Late urinary incontinence and recovery of incontinence were not evaluated.

Statistical Analysis
In univariate statistical analysis, the Mann-Whitney test was used to detect any association between penile bulb V50-V60 doses and membranous urethral length on urinary incontinence. Besides, the variables of age, comorbidity, operation, hormone therapy, bladder, and trigonum doses were compared to perform a univariate analysis. p value < 0.05 was considered significant. The statistical analysis was performed using IBM SPSS 22.0.

Results

Although there is minimal change in these parameters in patients with incontinence, they are not statistically significant (p>0.05 all). The variables of age, comorbidity, operation, hormone therapy, bladder, and trigonum doses were compared to perform a univariate analysis. The only association with incontinence was found with radical prostatectomy (p=0.021) (Table 2).

Table 2 Urinary incontinence related parameters

Discussion

There is an idea that physiological contraction of the bulbospongiosus muscle increases pressure in the bulb of the penis (as blood is not compressible) and consecutively leads to additional contraction of the urethral lumen. A well-vascularized penile bulb is an essential factor in this mechanism. Radiotherapy reduces the blood supply to these anatomic regions, and our study was based on this idea.

The proximal male urethral bulb is an integrated part of the urinary continence mechanism, especially during increased physical activity. Several clinical studies support this view.[3-5] However, these studies have demonstrated that urinary incontinence correlated with sexual function on surgical techniques. No study has yet evaluated the penile bulb radiation dose (sexual function) effect on continence. This study is the first on this aspect.

We have found no relation between urinary incontinence and penile bulb radiation doses. There could be several explanations for this result. The most important one is that we have a short period of follow-up time data retrospectively (six months), so there was no evaluation of late urinary incontinence and recovery. Just like the other factors, it should be kept in mind that penile bulb radiation dose may be associated with incontinence recovery. The second is that we do not use any side effect scoring questionnaires. The clinician"s patient records were used for grading urinary incontinence (CTCAE v5.0) retrospectively. This means there may be missing records.

Conclusion

Authorship contributions: Concept - M.A.; Design - M.A., Ş.D.; Supervision - M.A., Ş.D.; Materials - Ş.D.; Data collection and/or processing - Ş.D., M.E.Ş.; Data analysis and/or interpretation - Ş.D.; Literature search - Ş.D.; Writing - Ş.D.; Critical review - M.A., Ş.D.

Conflict of Interest: All authors declared no conflict of interest. Use of AI for Writing Assistance: Not declared.

Financial Support: None declared.

Peer-review: Externally peer-reviewed.

References

1) Schwartz K, Bunner S, Bearer R, Severson RK. Complications from treatment for prostate carcinoma among men in the Detroit area. Cancer 2002;95(1):82-9.

2) Rehder P, Staudacher NM, Schachtner J, Berger ME, Schillfahrt F, Hauser V, et al. Hypothesis that urethral bulb (corpus spongiosum) plays an active role in male urinary continence. Adv Urol 2016;2016:6054730.

3) Chung E, Wang J. The AdVance sling and male sexual function: A prospective analysis on the impact of pelvic mesh on erectile and orgasmic domains in sexually active men with postprostatectomy stress urinary incontinence. Sex Med 2022;10(4):100529.

4) Queissert F, Rourke K, Schönburg S, Giammò A, Gonsior A, González-Enguita C, et al. ATOMS (Adjustable Transobturator Male System) is an effective and safe second-line treatment option for recurrent urinary incontinence after implantation of an AdVance/AdVance XP fixed male sling? A multicenter cohort analysis. J Clin Med 2021;11(1):81.

5) Salembier C, Villeirs G, De Bari B, Hoskin P, Pieters BR, Van Vulpen M, et al. ESTRO ACROP consensus guideline on CT-and MRI-based target volume delineation for primary radiation therapy of localized prostate cancer. Radiother Oncol 2018;127(1):49-61.

6) Ghadjar P, Zelefsky MJ, Spratt DE, af Rosenschöld PM, Oh JH, Hunt M, et al. Impact of dose to the bladder trigone on long-term urinary function after high- -dose intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2014;88(2):339-44.

7) Lin D, O"Callaghan M, David R, Fuller A, Wells R, Sutherland P, et al. Does urethral length affect continence outcomes following robot assisted laparoscopic radical prostatectomy (RALP)? BMC Urol 2020;20:1-7.

8) Matsushita K, Kent MT, Vickers AJ, von Bodman C, Bernstein M, Touijer KA, et al. Preoperative predictive model of recovery of urinary continence after radical prostatectomy. BJU Int 2015;116(4):577-83.

9) Nguyen L, Jhaveri J, Tewari A. Surgical technique to overcome anatomical shortcoming: Balancing post-prostatectomy continence outcomes of urethral sphincter lengths on preoperative magnetic resonance imaging. J Urol 2008;179(5):1907-11.

10) Paparel P, Akin O, Sandhu JS, Otero JR, Serio AM, Scardino PT, et al. Recovery of urinary continence after radical prostatectomy: Association with urethral length and urethral fibrosis measured by preoperative and postoperative endorectal magnetic resonance imaging. Eur Urol 2009;55(3):629-39.

11) Schlomm T, Heinzer H, Steuber T, Salomon G, Engel O, Michl U, et al. Full functional-length urethral sphincter preservation during radical prostatectomy. Eur Urol 2011;60(2):320-9.