Abstract
Purpose:
Despite robust 15-year cancer-specific survival for localized prostate cancer (CaP), long-term urethral complications after treatment are sparsely reported. Our objective is to assess the long-term incidence of urethral complications after CaP treatment.
Materials and Methods:
Men with the diagnosis of CaP from 2002 to 2021 in the Alberta Cancer Registry were evaluated for complications using the Discharge Abstract Database and the National Ambulatory Care Reporting System. Urethral complications were defined as development of stenosis, fistula, or a urethral procedure > 30 days after treatment. Patients were allocated into 8 treatment groups, radical prostatectomy (RP), external beam radiotherapy (EBRT), brachytherapy (BT), cryotherapy (Cryo), RP + EBRT, EBRT + BT, Cryo + EBRT, or medical treatment/observation (MT/O). Urethral complications were compared between groups using Cox regression.
Results:
A total of 47,387 patients were identified with a median age of 66 years (IQR 14). At a median follow-up of 79 months (25th percentile = 36, 75th percentile = 140), 3140 patients developed urethral complications. On multivariable Cox regression, age (P < .001), stage (P = .001), and treatment modality (P < .001) were independently associated with urethral complications. Most treatment modalities were associated with development of complications when compared with MT/O. The 15-year incidence of urethral complications was the highest for combined modalities. EBRT + Cryo (42%), EBRT + BT (26%), and RP + EBRT (22%) were at the highest risk while MT/O (8%) and RP (9%) were at the lowest. Complications after RP plateaued at 10 years, whereas other modalities continued to accumulate complications over time.
Conclusions:
Patients undergoing CaP treatment are at a risk of developing urethral complications in the long term regardless of treatment modality. However, combined modalities pose a heightened risk while observation and radical prostatectomy have the lowest with complications from surgery appearing earlier and stabilizing over time.
Key Words: population-based study, prostate cancer, urethral complications, radiotherapy
Prostate cancer (CaP) is the most common noncutaneous malignancy among men in North America.1 Treatments for CaP are highly effective at prolonging cancer-specific and overall survival. For example, 15-year cancer-specific survival for localized cancer is estimated to be > 95% irrespective of treatment modality.2 Twenty-year cancer-specific survival may be ∼70% to 80% for patients after radical prostatectomy (RP), brachytherapy (BT), or external beam radiotherapy (EBRT).3 With the majority of patients surviving 15 years and beyond, this has created one of the largest group of cancer survivors in western society, and patient counselling has shifted to weighing the trade-offs between benefits and harms of each available treatment.2,4 However, genitourinary complications beyond 10 years are sparsely reported and the full spectrum of long-term complications remain unclear.2,5,6 Erectile dysfunction and urinary incontinence are the most commonly reported adverse outcomes while urethral complications such as urethral stenosis and fistulae remain underreported despite the adverse impact on patient-reported quality of life.7,8 In the short-term, the incidence of urethral stricture or stenosis after single modality radiotherapy is reported to vary between 2% and 8% while after multimodality or high-dose treatment this figure can rise to 31%.9-12 With the increased use of combined radiotherapy and salvage local therapies, delineating urethral complications after treatment is highly relevant.13,14 While it is hypothesized that lower urinary tract complications after high-energy, ablative, or combined therapies increase over time, very few studies examine urethral complications after CaP treatment beyond 5 or 10 years.5,9,10,15 Our objective is to determine the relative difference of urethral complications in men undergoing different treatments for CaP using a large province-wide comprehensive database with up to 20 years of follow-up.
JU Insight
Study Need and Importance
Long-term survival for patients with localized prostate cancer (CaP) is robust. However, patient counseling regarding adverse events typically emphasizes erectile dysfunction, incontinence, and bowel toxicity. Urethral complications such as stricture can substantially impair patient-reported quality of life, but the long-term incidence remains poorly defined. This study evaluated the long-term incidence of urethral complications after CaP treatment.
What We Found
In this population-based cohort of 47,387 men with CaP from 2002 to 2021, 3140 developed a urethral complication during a median follow-up of 79 months. On multivariable Cox regression, increased patient age (P < .001), increased cancer stage (P = .001), and treatment modality (P < .001) were independently associated with a risk of urethral complications. At 15 years, complications were most frequent after combined modalities (Figure) including external beam radiotherapy (EBRT) plus cryotherapy (42%), EBRT plus brachytherapy (26%), and radical prostatectomy (RP) plus EBRT (22%). Risks were lower with observation/medical treatment (8%) and RP alone (9%) and intermediate after EBRT (14%), brachytherapy (13%), and cryotherapy (11%). Complications after RP plateaued early, whereas risks after radiation-based treatment continued to accumulate over time.
Limitations
Administrative data could not definitively establish a causal relationship between treatment and each urethral event, distinguish adjuvant from salvage therapy, or measure the full burden of repeat procedures. Care received elsewhere and differences in treatment era, selection, and follow-up may also affect estimates. Kaplan-Meier methods may overestimate absolute risk with competing mortality.
Interpretation for Patient Care
- Patients undergoing CaP treatment are at a risk of developing urethral complications in the long term regardless of treatment modality. Urethral complications should be discussed explicitly during shared decision-making and incorporated into survivorship planning. Patients receiving combined or radiation-based treatments warrant counseling about the heightened risk of delayed urethral morbidity while patients undergoing radical prostatectomy have the lowest risk with complications appearing earlier and stabilizing over time.
Figure.
Kaplan-Meier demonstrating the cumulative incidence of urethral complications among different prostate cancer treatment modalities. BT indicates brachytherapy; Cryo, cryotherapy; EBRT, external beam radiotherapy; Obs, observation; RP, radical prostatectomy.
METHODS
Study Population
We performed a population-based cohort study of all men > 18 years of age with the diagnosis and subsequent treatment of CaP from January 2002 to December 2021 included in the province-wide prospective dataset termed the Alberta Cancer Registry. The Alberta Cancer Registry holds a legal mandate to record all new cancer diagnosis and deaths in the province. Since 2005, it holds the highest certification status of the North American Association of Central Cancer Registries. Age at diagnosis and treatment, initial cancer stage, and subsequent medical diagnoses with treatments received were extracted. Patients were allocated into 8 different groups according to treatment modality: RP, EBRT, cryotherapy (Cryo), BT, RP + EBRT, Cryo + EBRT, and EBRT + BT. Patients who received 2 modalities were included in their group independent of chronologic treatment order. The last group comprised patients who did not receive any of the latter invasive interventions. This “medical” group received either observation and/or subsequent medical treatment with androgen deprivation therapy. This cohort was primarily used as a control group to evaluate the baseline incidence of urethral complications in patients without active or invasive treatment. Our objective was to evaluate relative differences in time-to-event outcome of urethral complications between treatment modalities. The study was approved by the provincial health research ethics board (HREBA.CC-22-0102).
Study Outcomes
The primary outcome was the development of a urethral complication > 30 days after treatment. This was defined as developing a urethral-related diagnosis in the electronic medical record or undergoing a urethral/bladder neck invasive procedure > 30 days after treatment. This information was searched for and extracted from the Discharge Abstract Database and the National Ambulatory Care Reporting System. The bladder neck codes were included because it likely refers to the vesicourethral anastomotic stenosis in the RP population. For urethral-related diagnosis, the Canadian Coding Standard 2022 (ICD-10-CA) was used. N34/N35 (urethral stricture) and N36 (other urethral disorders) were included (Supplementary Table 1, https://www.jurology.com). For the procedures, the Canadian Classification of Health Interventions 2022 was used. All procedures done to the bladder neck (PL35, PL50, PL59, PL72, PL80, and PL87) and to the urethra (PQ35, PQ50, PQ56, PQ57, PQ59, PQ77, PQ80, and PQ82) were considered. Prostatic procedures (Canadian Classification of Health Interventions code: QT) such as transurethral resection of the prostate or diagnostic procedures including cystoscopy were excluded as they are commonly acquired independent of CaP treatment. In addition, procedures related to prosthetic device insertion for erectile dysfunction or incontinence such as a penile prosthesis, male sling, or artificial urinary sphincter were excluded (PQ/PL 53, 54, and 55).
Statistical Analysis
For all 8 treatment modalities, Kaplan-Meier survival analysis was used to calculate the event-free survival, and cumulative event probabilities were derived as 1 minus the Kaplan-Meier estimates. The log-rank test was used to evaluate differences between modalities. The occurrence of subsequent multiple urethral procedures was not analyzed. Follow-up began 30 days after the final treatment constituting the treatment strategy. Patients were censored upon death or at the moment of the data extraction (July 2023). To focus on delayed urethral complications rather than peritreatment events, or intraoperative findings, follow-up began 30 days after treatment. Events occurring within the first 30 days were therefore not included in the analysis. Comparison of stage, type of intervention, and urethral diagnosis among treatment modalities was performed using χ2. Age at treatment was compared using Kruskal-Wallis test. We conducted a multivariable Cox regression including stage, age, and treatment modality as possible factors associated with development of urethral complications. The P values displayed for the overall variables represent omnibus test assessing the global contribution of the categorical covariate to the model. We used the software SPSS v.24 to evaluate the variables associated with urethral complications.
RESULTS
A total of 47,387 eligible individuals were diagnosed with CaP over the study period and were included in the analysis. The median age at diagnosis was 66 years while the cancer stage at the time of diagnosis is outlined in Table 1. Patients who did not develop the event of interest had a median follow-up of 79 months (25th percentile = 36, 75th percentile = 140). The median time between treatment for the patients who had a combination of modalities was 15 months (25th percentile = 6, 75th percentile = 36). There were 3140 patients who developed a urethral complication. Patient age at the time of treatment and cancer stage stratified by modality are demonstrated in Table 2. Procedures and diagnosis are detailed in Supplemental Table 2 (https://www.jurology.com) among the different treatment modalities. Type of intervention as well as urethral diagnosis differed between treatment approach (P < .01). Kaplan-Meier estimated probability of the event for every modality at 1, 5, 10, 15, and 20 years is depicted in Table 3. The 15-year incidences of urethral complications were the highest for combined modalities. EBRT + Cryo (42%), EBRT + BT (26%), and RP + EBRT (22%) were at the highest risk while medical treatment/observation (MT/O) (8%) and RP (9%) had the lowest, and EBRT, BT, and Cryo had a 15-year probability of 14%, 13%, and 11% respectively. The estimated incidence of 20-year complications was the highest for EBRT + Cryo (48%).
Table 1.
Clinical Characteristics of the Study Population Including Age, Stage, Treatment Modality, Diagnoses, and Interventions
| Clinical feature | Data value |
| N | 47,386 |
| Age at diagnosis, median (P25-P75), y | 66 (60-74) |
| Age at treatment, median (P25-P75), y | 67 (60-74) |
| Stage at diagnosis, No. (%) | |
| I | 5143 (11) |
| II | 19,848 (58) |
| III | 4777 (14) |
| IV | 4597 (13) |
| Treatment modality, No. (%) | |
| Medical/observation | 19,124 (40) |
| RP | 10,838 (23) |
| EBRT | 11,554 (24) |
| BT | 2281 (4.8) |
| Cryo | 821 (1.7) |
| Cryo + EBRT | 80 (0.2) |
| RP + EBRT | 2035 (4.3) |
| EBRT + BT | 653 (1.4) |
| Patients with urethral complication, No. | 3140 |
| Underwent intervention | 2531 |
| No intervention | 609 |
| Patients with urethral diagnosis, No. | 1974 |
| Urethral stricture/stenosis | 1603 |
| Other urethral disorders | 159 |
| Urethritis | 109 |
| Urethral fistula | 103 |
| Patients with interventions, No. | 2531 |
| Bladder neck—endoscopic/dilation | 718 |
| Bladder neck—surgery | 92 |
| Urethral endoscopic/dilation | 1544 |
| Urethral surgery | 177 |
| Fistula repair | 3 |
| Urethrostomy | 9 |
| Urethrectomy, partial | 54 |
| Urethrectomy, total | 13 |
| Urethroplasty | 98 |
Abbreviations: BT, brachytherapy; Cryo, cryotherapy; EBRT, external beam radiotherapy; P, percentile; RP, radical prostatectomy.
Table 2.
Patient Age, Cancer Stage, Interventions, and Number of Events Stratified by Treatment Modalities Features
| Treatment modality | N | Age, median (P25-P75), y | Cancer stage (%) | Presented with the event (N) | |||
| I | II | III | IV | ||||
| Medical/observation | 19,124 | 71 (63-79) | 29 | 48 | 3.4 | 20 | 880 |
| RP | 10,838 | 62 (57-66) | 8.2 | 66 | 23 | 2.3 | 869 |
| EBRT | 11,554 | 70 (64-75) | 5.4 | 59 | 13 | 23 | 702 |
| BT | 2281 | 64 (59-69) | 21 | 79 | 0.2 | 0 | 247 |
| Cryo | 821 | 71 (67-74) | 6.7 | 91 | 2.7 | 0 | 54 |
| EBRT + BT | 653 | 66 (61-70) | 15 | 66 | 17 | 1.1 | 31 |
| EBRT + Cryo | 80 | 65 (61-70) | 1.8 | 87 | 11 | 0 | 19 |
| RP + EBRT | 2035 | 61 (56-66) | 3.7 | 33 | 56 | 8.2 | 338 |
| P value | < .01a | < .01b | |||||
Abbreviations: BT, brachytherapy; Cryo, cryotherapy; EBRT, external beam radiotherapy; P, percentile; RP, radical prostatectomy.
Kruskal-Wallis test.
χ2 test.
Table 3.
Cumulative Incidence of Urethral Complications Among Different Treatment Modalities
| Treatment modality | N | 1 y | 5 y | 10 y | 15 y | 20 y |
| RP, percentage (95% CI) | 10,838 | 4.8 (4.4-5.2) | 8.0 (7.4-8.5) | 9.2 (8.6-9.8) | 9.8 (9.1-10) | 10 (9.6-11) |
| EBRT, percentage (95% CI) | 11,554 | 0.9 (0.7-1.1) | 4.4 (4.0-4.8) | 8.5 (7.8-9.2) | 12 (11-13) | 17 (15-18) |
| BT, percentage (95% CI) | 2281 | 0.7 (0.4-1.1) | 6.3 (5.2-7.3) | 10 (8.9-12) | 15 (13-17) | 18 (15-20) |
| Cryo, percentage (95% CI) | 821 | 1.0 (0.3-1.7) | 2.8 (1.6-4.0) | 6.2 (4.1-8.1) | 11 (7.8-14) | 16 (10-22) |
| EBRT + BT, percentage (95% CI) | 653 | 0.5 (0.1-1.0) | 4.4 (2.5-6.4) | 11 (6.3-16) | 25 (12-38) | 25 (12-38) |
| EBRT + Cryo, percentage (95% CI) | 80 | 1.3 (0.1-3.7) | 8.0 (1.9-14) | 15 (6.2-23) | 31 (18-45) | 52 (30-74) |
| RP + EBRT, percentage (95% CI) | 2035 | 5 (4.0-5.9) | 12 (11-13) | 17 (15-19) | 22 (20-24) | 25 (22-28) |
| Medical/observation, percentage (95% CI) | 19,124 | 1.6 (1.4-1.7) | 4.2 (3.9-4.6) | 6.3 (5.9-6.8) | 8.2 (7.6-8.8) | 9.4 (8.5-10) |
| Overall, percentage (95% CI) | 47,386 | 2.2 (2.1-2.4) | 5.6 (5.4-5.9) | 8.3 (8.0-8.6) | 11 (10-11) | 13 (12-13) |
Abbreviations: BT, brachytherapy; Cryo, cryotherapy; EBRT, external beam radiotherapy; RP, radical prostatectomy.
On Kaplan-Meier analysis (Figure), the occurrence of urethral complications differed among treatment groups (log-rank test P < .001). Descriptively, urethral complications after RP plateaued at 10 years, whereas other modalities continued to accumulate complications over the long-term. On multivariable Cox regression analysis (Table 4), each year of increasing age (HR 1.02, 95% C.I. 1.01-1.02; P < .001), stage (P = .001) at diagnosis, and treatment modalities (except for Cryo and EBRT + BT) were associated with development of urethral complications compared with medical treatment/observation. In particular, combined modalities such as EBRT + Cryo (HR 3.61, 95% CI 2.03-6.41; P < .001) and RP + EBRT (HR 2.97; 95% CI; P < .001) demonstrated the highest risk. Urethral complications after RP reached a plateau at 10 years, whereas other modalities continued to accumulate complications over the long-term.
Table 4.
Multivariable Cox Regression Model Examining Factors Associated With Urethral Complications
| Variable | HR | 95% CI | P value |
| Stage | .001a | ||
| I | Ref | ||
| II | 1.34 | 1.16-1.56 | < .001a |
| III | 1.27 | 1.06-1.53 | .01a |
| IV | 1.26 | 1.02-1.55 | .03a |
| Age (y) | 1.02 | 1.01-1.02 | < .001a |
| Treatment modality | < .001a | ||
| Medical therapy/observation | Ref | ||
| RP | 1.38 | 1.21-1.58 | < .001a |
| EBRT | 1.16 | 1.02-1.31 | .03a |
| BT | 1.82 | 1.54-2.14 | < .001a |
| Cryo | 0.94 | 0.68-1.29 | .68 |
| EBRT + BT | 1.25 | 0.84-1.86 | .27 |
| EBRT + Cryo | 3.61 | 2.03-6.41 | < .001a |
| RP + EBRT | 2.97 | 2.50-3.52 | < .001a |
Abbreviations: BT, brachytherapy; Cryo, cryotherapy; EBRT, external beam radiotherapy; Ref, reference; RP, radical prostatectomy.
Indicates P value < .05.
Figure.
Kaplan-Meier curve demonstrating the cumulative incidence of urethral complications among different prostate cancer treatment modalities. BT indicates brachytherapy; Cryo, cryotherapy; EBRT, external beam radiotherapy; Obs, observation; RP, radical prostatectomy.
DISCUSSION
With the majority of patients with localized CaP surviving 15 years and beyond, clinical emphasis has shifted from considering only oncologic outcomes to weighing the trade-offs between benefits and associated harms of each treatment.2 However, genitourinary complications beyond 10 years are sparsely reported, and the full picture of long-term harms remain unclear.5,6,9,10,15-17 While guidelines state that patients should be aware that all CaP treatments carry risk, the primary complications examined are urinary incontinence, sexual dysfunction, and bowel dysfunction.7 A retrospective analysis of 67,527 patients from the SEER (Surveillance, Epidemiology, and End Results) database estimated that patients undergoing radiotherapy had a lower estimated 10-year incidence of both erectile dysfunction and incontinence compared with RP alone but had higher rates of proctitis.15 The data also identified that combination therapies fare worse in every aspect. Using patient-reported outcomes, the CEASAR study examined similar adverse events using patient-reported outcomes.5 Among patients treated with favorable CaP, RP was associated with worse urinary incontinence at 10 years. On balance, based on these 3 measures alone, patients undergoing radiation would seem to have better functional outcomes with lower morbidity at 10 years. However, this may not represent the full spectrum of long-term adverse outcomes especially when considering urethral complications, and 10-year data may be insufficient for accurate patient counseling.9,10,15,16
The reported short-term incidence of urethral stricture or stenosis after radiotherapy varies broadly, and after multimodality or high-dose treatment, this figure can rise to 31%. Our population study helps resolves these discrepancies and provides needed insight regarding the real-world incidence of the long-term urethral complications of patients with CaP and the relative differences among treatment modalities. Data from this study emphasize that patients undergoing CaP treatment are at a risk of developing urethral complications in the long-term and risk differs by treatment modality. The 15-year risk of urethral complications was the highest for combined modalities including EBRT + Cryo, EBRT + BT, and RP + EBRT with an incidence of 42%, 26%, and 22%, respectively. However, EBRT + BT had no significant difference from observation despite the high cumulative incidence. This is likely explained by shorter follow-up for this group because of the more recent popularization of this approach. At the other end of the spectrum, observation/medical treatment (8%) and RP (9%) incurred the lowest risk of urethral complications. Other therapies such as EBRT, BT, and Cryo had an intermediate 15-year incidence of 14%, 13%, and 11%, respectively. During the first decade after treatment Cryo appears to exert the lowest risk, and subsequently over the second decade, this position becomes occupied by RP.
Urethral stricture of the anterior urethra and/or stenosis of the posterior urethra are the most common urethral complications after CaP treatment accounting for over 80% of complications identified in our study. Early evidence from the CaPSURE database examined the incidence of urethral stricture/stenosis in patients undergoing CaP with up to 4 years of follow-up.9 The authors estimated that the risk of urethral stricture 4 years after treatment varied between 1.1% and 8.4% with RP having the highest estimated incidence. By comparison, the risk of stricture with EBRT and BT were 1.7% and 1.8%, respectively, while combined radiotherapy had a 5.2% incidence. This study concluded that RP and combined radiotherapy had the highest risk of urethral complications after CaP treatment. In the short-term, these estimates are mostly concordant with our findings for the first 5 years after treatment with an incidence of 7%, 5%, and 6% for RP, EBRT, and BT respectively. However, our data identify that after RP complications plateau at 10 years, whereas other modalities continue to accumulate complications.
The bias incurred with short-term follow-up is apparent in a 2018 meta-analysis examining the risk of urethral stricture after prostate radiotherapy.10 With a median follow-up of 4 years, the authors estimated an incidence of 1.5%, 1.9%, and 4.9% after EBRT, BT, and combined radiotherapy, respectively. This underestimation is likely a function of short-term follow-up. Most studies examining urethroplasty for radiation-induced urethral stenoses consistently report that strictures are identified at a mean of 6 years or later after treatment.18,19 This delay emphasizes the need for comprehensive survivorship program after all CaP treatment modalities.16 In addition, the contemporary adoption of hypofractionation and high-dose rate brachytherapy has the potential to increase this risk of urethral stenosis.11,12
A more recent population-based study suggests a higher 5-year incidence of urethral stricture for radiotherapy compared with RP.15 This 2023 analysis from the SEER database reported a 5-year cumulative incidence of urethral stricture of 8.4% for EBRT, 5.4% RP, and 11.2% for RP combined with EBRT. This is consistent with our findings that ∼1/4 of patients undergoing RP + EBRT will develop urethral stricture. Estimates from Muise et al, also suggest that RP and radiotherapy have a similar incidence of urethral stricture at 10 years. These findings are similar to our 10-year stricture estimates of 9%, 9%, and 10% for RP, EBRT, and BT, respectively. However, our study demonstrates a divergence in this risk at 10 years with complication risk plateauing for RP and continuing to increase for both EBRT (13%) and BT (14%). The primary mechanism behind stenosis after RT is increased radiation dose to the prostatic apex and membranous urethra.20 Urethral stenoses after RT encompass a varied spectrum of pathology and are a unique treatment challenge because of associated progressive endarteritis, impaired tissue vascularity, and resultant fibrosis in the radiated field.8 Some stenoses may be focal and fibrotic, while others may have necrosis with involvement of bladder neck, dystrophic calcification, and secondary detrusor dysfunction.8,21,22 In addition, RT complications are typically multifocal and labor intensive with patients reported to require a mean of 7 procedures over their treatment course and ∼1/3 requiring urinary diversion.21,22 From a patient perspective, these complications have a substantial negative impact on quality life related to concurrent incontinence, voiding dysfunction, pain, sexual dysfunction, depressive symptoms, and often a poor awareness of these complications.8,23 With respect to RP, the risk of stenosis has likely changed over the last 20 years. Historically, the incidence of vesicourethral anastomotic stenosis after RP has been estimated to be 0.5% to 30%.24 However, more contemporary series have suggested a decrease with the advent of robot-assisted prostatectomy and increased surgeon experience.25,26 Thus, adoption of the robotic platform and concentration surgical cases in high-volume centers may contribute to a reduction in urethral stenosis after RP over time. Overall, year of treatment may affect the incidence of complications as treatment refinements occur.
Clinical Variables Associated With Urethral Complications
In our multivariable model, in addition to treatment modality, tumour stage and patient age at the time of diagnosis were found to be independently associated with development of urethral complications. All stages compared with stage I showed at least a 25% higher risk of developing complications. This could be partially explained by the need for more aggressive treatment (broader radiation templates, brachytherapy boosts, wider surgical margins, etc) in more locally advanced or aggressive tumors especially in those patients undergoing combined treatment. With respect to age, Elliott et al (2009) described age and obesity as predictors of urethral strictures after CaP treatment.9 We did not have access to BMI but were able to integrate age in our multivariable model. For radiated patients, this would support the contentious belief that age is associated with increased radiosensitivity.27,28 Our study suggests that age may play a role contributing to an increased risk of urethral complications independent of treatment modality and may warrant inclusion into pretreatment counseling.
Strengths and Limitations
One strength of this study is the single public health system which provides coverage to all residents. It is not legal to offer any care outside of the health authority if it involves any intervention that is covered under the health care system. This setting creates a captive study population and enabled us to ascertain the incidence of urethral complication with a lesser risk of bias. In addition, the provincial cancer registry has been in place for > 20 years which allowed us to determine these complications on a long-term basis. As a population study, the methodology has inherent pitfalls. We included patients diagnosed and treated in the province. Hence, we cannot fully account for patients who moved out of the province and underwent interventions elsewhere. However, both the Discharge Abstract Database and the National Ambulatory Care Reporting System employ national data which can capture out-of-province interventions. For procedures such as urethral dilation, there is the possibility that procedures performed by trainees emergently may not have been accounted for leading to a possible underestimation of the true incidence of these conditions. Another limitation is that we cannot attribute a cause-effect between the urethral pathology diagnosis/procedure and the CaP treatment. We were also not able to distinguish between adjuvant and salvage combined modalities. Patients who received combined treatment modalities were grouped independent of chronologic treatment order. This is unlikely to impact patients with combined radiotherapy or surgery with radiation given the rarity of RP after radiation in the study population. Because the study focused on the incidence of urethral pathology, we did not account for the total number of procedures performed. Individuals were censored once they had their first diagnosis or intervention related to the urethra or bladder neck and we were unable to account for patients undergoing multiple procedures.21 Kaplan-Meier methods were chosen to preserve consistency with previous analyses. However, because competing risk methodology was not explicitly incorporated, this may overestimate absolute event probabilities in the presence of competing mortality. This overestimation is balanced by the omission of patients with combination therapies that presented with a complication between treatments, which could underestimate the true incidence for this specific group. For example, patients ultimately receiving RP + EBRT generally had more advanced disease than those undergoing RP alone, and complications arising after RP but before radiotherapy would not have been counted within the surgery cohort. This may therefore have led to an underestimation of the burden of urethral morbidity among patients undergoing multimodal treatment. The magnitude of this potential bias cannot be determined from the available data. Regardless, this analysis provides much needed data regarding the long-term risk of urethral complications in a large, real-world, prospectively maintained data set.
CONCLUSIONS
In general, all patients undergoing CaP treatment are at a risk of developing urethral complications in the long term regardless of treatment modality. However, combined modalities pose a heightened risk of developing urethral complications while observation and radical prostatectomy have the lowest with complications from surgery appearing earlier and stabilizing over time.
Footnotes
Funding/Support: The Authors have no funding to disclose.
Conflict of Interest Disclosures: The Authors have no conflicts of interest to disclose.
Ethics Statement: The study was approved by the provincial health research ethics board (HREBA.CC-22-0102).
Author Contributions:
Data analysis and interpretation: Calvo, Rourke.
Critical revision of the manuscript for scientific and factual content: Calvo, Rourke.
Supervision: Rourke.
Statistical analysis: Calvo, Rourke.
Conception and design: Rourke.
Data acquisition: Calvo.
Drafting the manuscript: Calvo, Rourke.
Data Availability: The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
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