Pathophysiology and Repair of Post-Radiation Urethral Stricture Disease: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Javier C. Angulo.

Radiation therapy (RT) in the management of pelvic cancers remains a clinical challenge to urologists given the sequelae of urethral stricture disease secondary to fibrosis and vascular insults. The management of post-radiation urethral stricture consists of conservative, endoscopic, and primary reconstructive options. Endoscopic approaches remain an option, but with limited long-term success. Despite concerns with graft take, reconstructive options such as urethroplasties in this population with buccal grafts have shown long-term success rates ranging from 70 to 100%. Robotic reconstruction is augmenting previous options with faster recovery times. Radiation-induced stricture disease is challenging with multiple interventions available, but with successful outcomes demonstrated in various cohorts including urethroplasties with buccal grafts and robotic reconstruction.

  • :radiation injury
  • urethral stricture
  • reconstructive urology
  • wound healing

1. Introduction

About 192,000 cases of prostate cancer are diagnosed annually, with patients undergoing treatments such as prostatectomy, external beam radiation therapy (EBRT), and brachytherapy (BT) [1]. The Surveillance, Epidemiology, and End Results (SEER) database found that 13% of patients with prostate cancer opt for BT, 25% of patients opt for EBRT, and 38% of patients opt for prostatectomy [2]. As popular as these treatment modalities are, they present with significant side effects that can profoundly affect the quality of life of patients. Radical prostatectomy can result in urinary incontinence in 5–72% of patients [3,4][3][4]. Patients can elect to undergo different procedures to address this complaint, with the most frequent option being urethral slings (47.5%), artificial urinary sphincter (AUS) (35.3%), and the injection of bulking agents (17.2%) [3].
RT use in managing pelvic cancer has been shown to lead to multiple sequelae including radiation-induced stricture disease. This has created a complex urologic issue for urologists, notably reconstructive urologists, due to the increased rates of recurrence and complications after treatment of stricture disease, among other sequelae, after the application of ionizing radiation. The CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database analysis approximates that the likelihood of radiation-induced stricture is around 1.8% for BT and 1.7% for EBRT, while EBRT + BT combination therapy led to an overall likelihood of 5.2% [5].

2. Prevalence

Pelvic RT administered for rectal cancer can impact the bladder and urethra due to the short distance between these organs. Urinary adverse events (AE) are to be expected; however, there is a dearth of studies following potential urologic sequela [6]. Studies that tracked urinary AE revealed that about 4% of patients experienced severe AE [7]. When examining patients diagnosed with prostate cancer who solely received EBRT, a study performed by David et al. revealed a 28.4% 10-year cumulative incidence rate of hospital admissions due to urinary AE [8]. The absence of studies presents a potential future area of exploration and collaboration among diverse disciplines and specialties. Muise et al. conducted a review of a cohort of 67,527 patients diagnosed with prostate cancer; 72.62% received RT, 24.86% underwent a radical prostatectomy (RP), 4.94% underwent a RP followed by RT, and 0.46% received RT followed by RP. Within five years of completing treatment, 8.44% of those treated with RT developed urethral strictures, compared to the 5.35% diagnosed with strictures after RP [9]. When both modalities were used, the rates of urethral stricture were higher, with 11.22% of patients experiencing stenosis after salvage RT and 19.34% after salvage RP [9].

3. Stricture Etiology/Physiology

When the urethral lumen is subjected to repetitive damage, an atypical narrowing is formed due to these damages causing structural alterations to the supporting spongiosum and connective tissue underlying the urethral lumen [17,18][10][11]. As a result of these alterations, urine can extravasate into the neighboring spongiosum and trigger fibrotic changes. This process leads to the formation of a plaque which is classified as a stricture if it is circumferential [19][12]. The fibrosis present in urethral strictures demonstrates unique properties when compared to fibrosis in other areas of the body, such as a protracted healing process and involvement of much of the periurethral tissue [20][13]. In a study by Hofer et al., it was found that the parallels between urethral healing and dermal wound healing consisted of acute inflammatory, proliferative, and remodeling phases. These phases exhibited a 50% longer duration with cellular infiltration and cytokine changes that went beyond the injury site and affected a significant portion of periurethral tissue [20][13]. Important distinctions between urethral remodeling and dermal remodeling include differences in the length of the proliferative phase, which peaks at day 5 in dermal remodeling, while in urethral remodeling, students have demonstrated evidence of remodeling on day 10 [20][13]. Evidence from animal studies suggests strictures result from an increase in collagen and a decrease in smooth muscle content. This leads to compact, fibrotic, and poorly compliant tissue, although it is important to note that these findings have not been established in human studies [21][14]. Human studies have instead shown a decrease in the ratio of Type I collagen to Type III when comparing normal urethral spongiosum to urethral strictures [22][15]. Typical urethral spongiosum is composed of 75% Type I collagen and 25% Type III, compared to 16% Type I collagen and 84% Type III in the spongiosum of urethral strictures [22][15].

4. Radiation-Induced Changes in Urologic Tissue

RT causes unavoidable radiation injury to normal tissues, resulting in acute and late effects on parenchyma, stroma, and vascular structures. Effects that manifest within hours of exposure are characterized as acute changes and can consist of an increase in vascular permeability, lymphocyte adhesion and infiltration, and endothelial cell edema [26][16]. Effects manifesting months to years later are characterized as late changes and result from the reduction in stem cells or progenitor cells. Late effects include organ dysfunction, fibrosis, and necrosis [26][16]. Following RT, the urothelium exhibits parenchymal and epithelial changes such as cellular atypia, neoplasia, dysplasia, metaplasia, necrosis, and atrophy. One of the most notable and consistent delayed effects of RT is atrophy [27][17]. Delayed necrosis present in the acute phase is usually secondary to ischemia, leading to fissures in the epithelial lining. Fibrosis, the presence of fibrinous exudate, and atypical fibroblasts are stromal lesions that are commonly visualized in the lower urinary tract. Radiation-induced fibrosis and vascular insufficiency present as delayed effects. The extent of these sequelae is dependent on the surrounding tissues that are impacted and, in the case of blood vessels, is proportional to the size of the vessels impacted. Damage to small capillaries typically results in obliteration, as they are most radiosensitive leading to endothelial swelling and increased permeability, while damage to medium-sized vessels results in fibrinoid necrosis and thrombosis [28][18]. Damage to large vessels is rare. Radiation-induced endothelial apoptosis plays a prominent role in the series of acute vascular changes. Late-stage radiation changes produce vascular effects involving thickening of the basement membrane, scarring of surrounding tissues alongside the development of telangiectasias, and a decline in clonogenic capacity, which presumably contributes to the late-stage radiation response to typical parenchyma [29][19].

5. Pathways of Radiation-Induced Endothelial Cell Death

The behavior of endothelial cells when exposed to radiation has been extensively studied and understood. The macroscopic changes observed in acute radiation toxicity occur when irradiated endothelial cells undergo structural changes and produce a range of growth factors, chemoattractants, and biomarkers [26][16]. The prior literature has investigated different pathways involved in radiation-induced stricture formation; however, they are predominantly influenced by damage to the membrane and are mediated by ceramide production and acid sphingomyelinases (ASMases). Most studies exploring this pathway utilized single doses of radiation ranging from 10 to 20 Gy [6,26][6][16]. Ceramide activates the ceramide-activated protein kinase (CAPK) and the ceramide-activated phosphatase, leading to apoptosis through the activation of the MAPK8 pathway, the mitochondrial pathway, and the death receptor pathway [26,31,32][16][20][21]. The inhibition of protein kinase C (PKC) by ceramide-activated phosphatase is a critical step, given that PKC participates in antiapoptotic signaling and can impede sphingomyelin hydrolysis, thus obstructing the release of ceramide from cellular membranes [33,34,35][22][23][24]. Caspase 9 functions as an alternative activation pathway of caspases for apoptosis through mitochondrial proteins. This process is initiated by ceramides, as well. BCL-2-associated protein x (BAX) and BCL-2 antagonist of cell death protein (BAD) are proapoptotic proteins that promote apoptosis when CAPK is induced by ceramide [37][25]. When BAD binds to antiapoptotic proteins BCL2 and BCL2L1, cytochrome C is released and then caspase 9 is activated, which stops the suppression of apoptosis which is controlled by BAX [38,39][26][27]. Ceramide can be released through cell death or TNF receptor activation. This release leads to a direct apoptotic pathway using different adapter protein complexes including the TNFαR-associated death domain and the Fas-associated death domain [26][16]. The aforementioned domains start the induction of cytoplasmic promoters of cell death such as procaspase 8, which cleaves and activates effector caspases. Ceramide can also be released from radiation-induced DNA damage since the ceramide synthase can be activated by DNA double-strand breaks. This pathway would need de novo protein synthesis, which would result in slower kinetics over a longer period of time as a proapoptotic mechanism compared to the sudden release of ceramide once ASMase is activated [26][16]. The balance between pro- and anti-apoptotic signaling cascades and radiation dose determines the amount of endothelial cell apoptosis. For example, ionizing radiation does not lead to endothelial apoptosis directly from the mechanisms listed above, but it also activates anti-apoptotic pathways.

6. Cellular and Extracellular Components of Fibrosis

Fibrotic tissue changes are the result of the decreased decomposition and increased production of extracellular matrix (ECM) proteins, especially collagen, which can be caused by radiation exposure. The premature terminal differentiation of potentially mitotic progenitor fibroblasts into irreversible postmitotic fibrocytes can be activated by ionizing radiation [45,46,47][28][29][30]. Growth factors, tissue-specific collagen, cytokines, and matrix molecules are produced by these differentiated fibrocytes that are the main component of the fibroblast system [46,47,48][29][30][31]. This accumulation of postmitotic fibrocytes may explain why radiation results in an increased synthesis and extracellular deposition of collagen, which is remarkable for post-radiation fibrotic tissue. Cytokines are important in the mechanisms of radiation-induced injury. TGF-β1 is a cytokine responsible for the proliferation and differentiation of fibroblasts into postmitotic fibrocytes, which secrete collagens and other extracellular matrix proteins. TGF-β1 also controls extracellular matrix homeostasis, which is responsible for the increased production and decreased degradation of extracellular collagen molecules [26,27,28][16][17][18]. The activation of TGF-β1 and plasmin activator inhibitor 1 by radiation exposure plays a significant role in the process of fibrotic tissue changes. IL-17 is another cytokine that plays an important role in mediating the response of cells to radiation-related damage such as neutrophil recruitment [49,50][32][33]. Bessout et al. were able to show that IL-17 creation was increased in CD4 T cells in mice that had undergone colorectal irradiation [51][34]. Other cytokines that appear after irradiation are cytokines IL-1β and TGF-β [51][34]. They are involved in Th17 differentiation, a CD4 T cell which secretes IL-17 [51,52][34][35]. Excessive accumulation of ECM proteins such as collagen is the most commonly observed component of tissue fibrosis after radiation exposure, mainly through increased synthesis and decreased degradation. The reduced degradation of extracellular collagen that is newly synthesized and deposited can be attributed to the gene expression and production of tissue inhibitors of matrix metalloproteinases (MMP), which is mediated by TGF-β1 [55][36]. Another mechanism for fibrinolysis and ECM degradation regulation is the plasmin activator (PA) system. Plasmin can break down ECM through proteolytic activity and induction of latent MMPs [56][37]. The PA system is controlled by a group of PA inhibitors, and plasmin activator inhibitor (PAI-1) is the most significant. TGF-β1, TNF-α, and IL-1 are signaling molecules that can stimulate PAI-1 secretion.

7. Radiation-Induced Histologic Changes

Radiation causes a variety of histologic alterations including vascular modifications, fibrotic changes, cellular depletions, and inflammatory responses, which manifests progressively as the tissue gets further from the site of radiation exposure (Figure 1).
/media/item_content/202307/64bdca97789efjcm-12-03950-g001.png
Figure 1. Simplified model of the complex network of interacting processes and signals in the pathogenesis of radio-induced injury.

8. Pathogenesis of Radiation Strictures

The dynamics of typical cells during and after RT, especially in relation to the manifestation of stricture formation, is patient dependent and, as such, cannot be observed [67,68]. When examining the risk of stricture formation in BT versus EBRT, the ASCENDE-RT trial was able to discover an actuarial incidence rate of 5.2% in patients who underwent EBRT and 18.4% in patients who underwent BT [69,70]. However, combination EBRT + BT was the only risk factor that reliably demonstrated an elevation for the chance of stricture formation [12]. This implies that cumulative radiation dose is the most predictive factor of stricture formation rate. High-dose-rate BT and EBRT resulted in about a 9–21% risk of stricture formation, with conformal and intensity-modulated radiotherapy resulting in a 1.7–4% risk, the lowest possible incidence of stricture [5,11,12,13,14,16,71]. Meta-regression analysis and multivariable regression have not shown a connection among stricture formation and biological equivalent dose, despite the possibility that radiation dose schedules might elevate the chance of stricture formation [11,12,72,73]. The reason for this that inconsistency could occur because the interval of follow up across RT studies, endpoints, and terminology is not standardized. An example of this is that urethral strictures develop over a period of 2.2–3.4 years, and, as such, need long-term follow up to track the progression of formation [5,11]. The Common Terminology Criteria for Adverse Events version 3 mandates that a stricture requires urological intervention in order to be classified as a stricture. Diagnosing a stricture after RT is ultimately left to the provider’s preference.
When RT is administered after surgical intervention, there is a chance for a urethral stricture to develop. This probability does decrease as the amount of time between procedures increases [74]. When RT is applied before surgery, wound healing is disrupted due to damage to fibroblasts and their ability to create collagen, which increases the risk of stricture formation [75]. RT of the prostate is likely to increase the chance of stricture formation, especially in patients undergoing urethral instrumentation.
Radiation-induced strictures most commonly occur in the bulbomembranous region in patients that elect for primary RT and at the vesicourethral anastomosis (VUA) in patients electing for salvage or neoadjuvant RT. Urethral strictures form when the relative loss of normal cells is over a certain toxicity–specific threshold. Hughes et al. compared membranous urethral strictures in patients with and without radiation treatment for prostate cancer.
Simplified model of the complex network of interacting processes and signals in the pathogenesis of radio-induced injury.

8. Pathogenesis of Radiation Strictures

The dynamics of typical cells during and after RT, especially in relation to the manifestation of stricture formation, is patient dependent and, as such, cannot be observed [38][39]. When examining the risk of stricture formation in BT versus EBRT, the ASCENDE-RT trial was able to discover an actuarial incidence rate of 5.2% in patients who underwent EBRT and 18.4% in patients who underwent BT [40][41]. However, combination EBRT + BT was the only risk factor that reliably demonstrated an elevation for the chance of stricture formation [42]. This implies that cumulative radiation dose is the most predictive factor of stricture formation rate. High-dose-rate BT and EBRT resulted in about a 9–21% risk of stricture formation, with conformal and intensity-modulated radiotherapy resulting in a 1.7–4% risk, the lowest possible incidence of stricture [5][42][43][44][45][46][47]. Meta-regression analysis and multivariable regression have not shown a connection among stricture formation and biological equivalent dose, despite the possibility that radiation dose schedules might elevate the chance of stricture formation [42][43][48][49]. The reason for this that inconsistency could occur because the interval of follow up across RT studies, endpoints, and terminology is not standardized. An example of this is that urethral strictures develop over a period of 2.2–3.4 years, and, as such, need long-term follow up to track the progression of formation [5][43]. The Common Terminology Criteria for Adverse Events version 3 mandates that a stricture requires urological intervention in order to be classified as a stricture. Diagnosing a stricture after RT is ultimately left to the provider’s preference.
When RT is administered after surgical intervention, there is a chance for a urethral stricture to develop. This probability does decrease as the amount of time between procedures increases [50]. When RT is applied before surgery, wound healing is disrupted due to damage to fibroblasts and their ability to create collagen, which increases the risk of stricture formation [51]. RT of the prostate is likely to increase the chance of stricture formation, especially in patients undergoing urethral instrumentation.
Radiation-induced strictures most commonly occur in the bulbomembranous region in patients that elect for primary RT and at the vesicourethral anastomosis (VUA) in patients electing for salvage or neoadjuvant RT. Urethral strictures form when the relative loss of normal cells is over a certain toxicity–specific threshold. Hughes et al. compared membranous urethral strictures in patients with and without radiation treatment for prostate cancer.

9. Surgical Pitfalls and Options for Treating Radiation Strictures

In order to create a treatment plan for a patient with a suspected post-RT stricture, a complete workup is necessary including a physical exam, history of prior urological instrumentation, treatments, and incontinence, as well as diagnostic testing such as urodynamic studies and lab tests. Direct visualization of the stricture and assessment of adjacent tissue should be performed, with retrograde urethrogram (RUG) combined with voiding cystourethrogram (VCUG) used if the retrograde scope cannot pass through the stricture. Additional cross-sectional imaging modalities including CT scan and/or MRI may be required to assess associated pathology (i.e., presence and extent of calcified/necrotic prostatic cavity, or urethrosymphyseal or recto-urethral fistula). Treatment options for post-RT urethral stricture are conservative management (clean intermittent catheterization or chronic catheter placement), endoscopic management (dilation, direct visualization internal urethrotomy [DVIU]), and primary reconstructive options, with joint decision making to be performed between physician and patient based on oncologic and performance status, stricture location/length/number, bladder status, and current level of continence [78,79,80].
In order to create a treatment plan for a patient with a suspected post-RT stricture, a complete workup is necessary including a physical exam, history of prior urological instrumentation, treatments, and incontinence, as well as diagnostic testing such as urodynamic studies and lab tests. Direct visualization of the stricture and assessment of adjacent tissue should be performed, with retrograde urethrogram (RUG) combined with voiding cystourethrogram (VCUG) used if the retrograde scope cannot pass through the stricture. Additional cross-sectional imaging modalities including CT scan and/or MRI may be required to assess associated pathology (i.e., presence and extent of calcified/necrotic prostatic cavity, or urethrosymphyseal or recto-urethral fistula). Treatment options for post-RT urethral stricture are conservative management (clean intermittent catheterization or chronic catheter placement), endoscopic management (dilation, direct visualization internal urethrotomy [DVIU]), and primary reconstructive options, with joint decision making to be performed between physician and patient based on oncologic and performance status, stricture location/length/number, bladder status, and current level of continence [52][53][54].

10. Conservative Management

Patients who are not great candidates for surgery or do not want to undergo more invasive procedures can receive some level of relief from conservative management options for stricture disease. Surgery can carry significant side effects such as new onset or exacerbation of urinary incontinence, along with recurrence of stricture, not to mention the risk associated with general anesthesia [81][55]. Conservative management options include clean intermittent catheterization and endoscopic techniques. A study conducted by Rozanski et al., investigating 91 men with radiation-induced stricture disease treated with endoscopic management or clean intermittent catheterization, demonstrated that 80% of patients maintained stable uroflowmetry values, post-void residual measurements, and serum creatinine levels on conservative management over a median follow up of 15 months.
Additionally, it is important to acknowledge that not all urethral strictures in irradiated patients need to proceed with additional surgical intervention and depend on the balance between impacting bladder emptying and urinary incontinence. This is inherently dependent on an accurate functional and quality of life evaluation to select those patients that would benefit from interventions listed below [81][55]. It is important to accurately assess these metrics to decide who would benefit, as resulting incontinence can significantly impact quality of life and even operative measures to address resulting incontinence; male sling placement or artificial urinary sphincter patients have previously been demonstrated to have increased rates of complications in this previously irradiated patient population [82][56].

11. Endoscopic Management

Dilation and DVIU are endoscopic procedures that can be used in initial interventions for stricture disease; however, these measures have limited long-term success in patients with radiation-induced urethral strictures. A study by Merrick et al. revealed that among 29 patients who had undergone endoscopic treatment of their strictures, 31% needed multiple procedures to achieve patency, and 3 of the patients required suprapubic tube placement after developing recurrent strictures [14][45]. Similar findings from other publications revealed that nearly half of patients treated endoscopically needed subsequent interventions for stricture treatment. Notably, one study highlighted the significant risk of de novo incontinence associated with endoscopic approaches [13][44]. The pursuit of a more durable result following endoscopic management has led to the adjunctive use of injectable substances which may inhibit fibrosis and thus prevent recurrent stenosis. The injection of steroids and mitomycin C following DVIU have demonstrated patency rates of 83% and 90%, respectively [85,86,87][57][58][59]. Although these numbers must be considered in their proper context, as multiple procedures are often needed to achieve them, a sub-analysis of radiated patients shows significantly worse success rates, and mitomycin can have severe adverse events resulting in the need for cystectomy [87,88,89][59][60][61].

12. Reconstructive Techniques—Excision and Primary Anastomosis (EPA)

EPA for radiation-induced urethral strictures is typically performed via perineal access and tends to be more complicated compared to EPA performed on non-radiated urethral strictures for two main reasons: (1) the significant radiation-induced fibrosis which makes urethral mobilization difficult and (2) radiated fields have poor vascularity resulting in poor wound healing. The success rate of EPA, defined as not requiring additional procedures, for radiation-induced urethral stricture is reported to be 65–95% [90,91,92,93,94][62][63][64][65][66]. A multi-institutional retrospective study by Voelzke et al. identified the following factors, age, stricture length, and EBRT + BT, as associated with stricture recurrence after EPA [95][67]. One major limitation of the study is the heterogeneity in auxiliary surgical maneuvers (use of gracilis flaps, inferior pubectomy, crural separation) employed to complete the reconstruction, thus the effect of this excisional technique alone on the outcomes is difficult to ascertain.

13. Reconstructive Techniques—Buccal Mucosa Graft Urethroplasty

In the past, augmentation techniques were not performed on radiation patients due to concerns regarding the viability of the graft in such hostile environments. Recent studies suggest that augmented urethroplasties using buccal mucosa grafts (BMG), the most versatile grafts currently used in urologic practice, are a viable repair technique for post-radiation strictures and have outcomes similar to non-radiated patients in the short term and medium term [67][38]. Buccal mucosa grafts (ventral and dorsal onlays) have been used in several suggested approaches of augmentation urethroplasty which provide patients with outstanding outcomes with regard to postoperative patency rates; they have been documented to be from 71 to 75% and even 100% in one small series [83,92,96][64][68][69]. A study by Ahyai et al. on outcomes following ventral onlay BMG urethroplasty reported an overall success rate was 71% at a mean follow up of 26.5 months, and rates of de novo incontinence and erectile dysfunction were 10.5% and 6.3%, respectively [97][70]. Blakely et al. documented findings on three patients with membranous urethral strictures who had undergone dorsal onlay BMG urethroplasty after RT. The results showed that all patients were able to maintain patency with no instances of de novo incontinence during the follow up at 8 months [95][67]. A subsequent multicenter retrospective review by Policastro et al. of 79 patients with posterior urethral stenosis secondary to radiation therapy who underwent dorsal onlay buccal mucosal urethroplasty with a 3 cm mean stricture length demonstrated an 82.3% stricture-free rate at a mean 21 months of follow up, 8% de novo stress urinary incontinence, and 91% patient satisfaction [98][71].

14. Robotic Techniques

Robotic surgery has grown as a possible alternative to endoscopic management and open surgery in the treatment of radiation-induced urethral strictures. Open surgery for radiation-induced urethral strictures can lead to longer recovery times, additional interventions, and wound complications due to the hampered healing process present in irradiated tissue [101,102][72][73]. A review of open post-radiation urologic reconstructive procedures found a morbidity rate up to 54% [100,101][72][74]. In comparison, robotic surgery has been linked with reduced early postoperative morbidities for other major urologic procedures. This approach may translate to post-radiation reconstruction, potentially improving outcomes and decreasing morbidities [101,103,104][72][75][76]. Traditionally, open perineal surgery was used for the reconstruction of the posterior urethra, but this technique grew to be more challenging after RT since the natural planes of the tissue are eliminated and fibrosis is present [93,101][65][72]. In these circumstances, robotic surgery can improve visualization and improve dexterity in a tight working space around the bladder neck, allowing for the accurate placement of proximal sutures [101,105,106][72][77][78]. In patients undergoing a repair of vesicourethral anastomotic stenosis, robotic reconstruction of posterior urethral stenosis demonstrated a 100% patency rate. However, in two out of the seven patients, artificial urinary sphincter placement was needed [107,108][79][80]. A true assessment of the robotic approach for the repair of post-radiation stenosis is limited due to the exclusion of patients with a history of radiation in most of the current literature.

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