Orthotopic bladder substitution: Surgical aspects and optimization of outcomes

Abstract Objectives Orthotopic bladder substitution (OBS) is a management option for urinary diversion in men and women undergoing cystectomy. The aim of the procedure is to provide a functional continent urinary reservoir of adequate capacity, compliance and low pressure. We have provided a narrative review of the existing literature and highlighted areas where improvement and standardization can be recommended. Methods Literature search included database search for publications from January 1970 to November 2020, using keywords including OBS, bladder reconstruction, neobladder, radical cystectomy, robotic cystectomy, intracorporeal neobladder, surgical technique, patient selection and outcomes. Results Due to various factors including indications, operative technique and risk of complications, OBS is an enormous undertaking and commitment for patients, surgeons and health professionals involved in the care pathway. The main considerations for patient selection, the technical elements of the procedure and the rationale behind these are discussed. Previously considered to be a choice for a select few, the inclusion criteria have expanded over the last decade. Similarly, surgical techniques including the choice and configuration of bowel segments, construction of anastomosis and nerve or organ sparing procedures have evolved over the years. Minimally invasive laparoscopic and robotic assisted surgery has added further perspectives to the existing literature on OBS. Understanding the principles of operative techniques and assessing the best evidence to influence patient management is crucial as it has a major impact on clinical outcomes. Peri‐ and post‐operative care, focused on the prevention of complications and morbidity, affects long‐term functional and oncological outcomes, which ultimately dictates the quality of life. Conclusions This concise overview of OBS literature highlights the importance of pre‐operative, peri‐operative, and post‐operative aspects with regards to the optimization of patient care. To achieve the best results, meticulous attention should be paid in all these areas, surgical and multi‐disciplinary. Patient education and counseling, with shared decision making are central to the success of the procedure.


| INTRODUC TI ON
The term orthotopic refers to a bladder substitute (neobladder) reconstructed in the same place as the native bladder, that is, in the pelvis. It is anastomosed to the native urethra, with a functional external urethra sphincter providing the continence mechanism. Orthotopic bladder substitution (OBS) was first described for male patients after radical cystectomy for cancer in 1913 by Lemoine using rectum. 1 Small intestine neobladder was first reported by Camey and Le Duc in 1979. 2 Use of an ileal segment is now the standard technique and radical cystectomy (RC) for bladder cancer is the main indication for OBS, which is less commonly performed for benign conditions including neurogenic bladder dysfunction. Patients requiring RC are often referred from the center of initial diagnosis to a tertiary center for oncological management. An understanding of pre-operative considerations, operative techniques, and post-operative care is essential for the optimization of patients undergoing neobladder reconstruction. We outline the fundamentals of OBS primarily in the context of radical cystectomy. The essential steps to prevent pitfalls from the beginning of the patient journey and to achieve long-term successful outcomes are discussed.

| ME THODS
A Medline database search using the following keyword search criteria was performed: OBS, bladder reconstruction, neobladder, radical cystectomy, robotic cystectomy, intracorporeal neobladder, surgical technique, patient selection, and outcomes. All publications from January 1970 to November 2020 were included and the literature search was confined to publications in English. An additional manual search of references in relevant published articles was performed.

| PRE-OPER ATIVE PL ANNING
Bladder substitution with intestinal segments is an option for continent diversion performed after cystectomy. The 2nd International Consultation on Bladder Cancer recommendations on the reconstructive options after RC (2012), have outlined criteria for patient selection with regards to renal function and risk of secondary tumor. 6 Current EAU or AUA guidelines do not specifically offer recommendations for patient selection for OBS and much of the evidence has evolved over the years. Indications include cancer, chronic inflammatory disease (tuberculosis, schistosomiasis, post-radiotherapy bladder contraction, bladder pain syndrome), and bladder dysfunction (neuropathic or idiopathic detrusor overactivity). OBS is very rarely performed for benign conditions and is mostly considered as a last resort when less invasive options have exhausted, in patients who wish to avoid an ileal conduit. The 2018-2019 Hospital Episode Statistics (HES) database for NHS England reported a total of 2,165 ileal conduit and 486 urinary diversion operations were performed with cystectomy that year, and only 46 were simple cystectomy (benign) procedures. 7

| Oncological factors
For OBS following radical cystectomy, oncological aspects such as a complete resection of the primary tumor, negative margins, and the absence of metastatic disease are important. Pre-operative transurethral biopsies from the prostatic urethra in males and bladder neck in females have a high negative predictive value, although studies show that they are not as accurate as intra-operative frozen sections. 8 Patients need clear counseling on the risk of developing secondary tumors in the urethra, which is 2.2% according to a systematic review by Fahmy et al. 9 Recent studies show that patients with positive biopsies have an increased urethral recurrence rate, but the cancer-specific survival is not reduced. 10

| Patient-related
Patient profile is of utmost importance and careful consideration of co-morbidities, performance status, life-expectancy, and cognitive ability is needed. There is no age limit at which OBS can be offered, and it has been suggested that elderly fit patients have similar outcomes to their younger counterparts. 11 There is no oncological compromise to women undergoing urethral-sparing cystectomy. 12 Adequate renal and hepatic function is an absolute prerequisite to reduce the risk of metabolic complications associated with the presence of bowel in the urinary tract. Previous significant bowel K E Y W O R D S bladder substitution, cystectomy, neobladder, orthotopic bladder substitute, urinary diversion | resection and severe inflammatory bowel disease predispose to the risks of Vitamin B12 deficiency, hyperoxaluria, and diarrhea, and hence are contra-indications. Well-informed motivated patients are ideal candidates as compliance with post-operative bladder training and a follow-up protocol is crucial.

| Functional considerations
Functional abnormalities of lower urinary tract including urethral strictures should be excluded. External urethral sphincter dysfunction and stress urinary incontinence are relative contraindications.
Pelvic irradiation is not considered an absolute contraindication; however, continence rates are lower (56%-76%). 13,14 The risks of 90-day post-operative complications are higher (77% vs. 52%) in non-neobladder UD with previous irradiation. 13 Late sequelae such as bowel stenosis, spontaneous neobladder perforation, and neobladder-vaginal fistula were seen in 40% of OBS patients in this study. Patients should be counseled that additional continence procedures may be required, with artificial urinary sphincter being placed in around 20% of such patients. 14 Prior radical prostatectomy is not a contraindication in men, especially if they have good continence pre-operatively. 15

| Other factors
All options for urinary diversion including ileal conduit should be discussed with the patient and shared decision-making should be implemented. Involvement of a specialist nurse early on in the management pathway is essential. Initiation of the Enhanced Recovery Protocol for RC has shown to reduce median LOS from 14 days to 7 days in the UK 16 and improved overall outcomes by earlier return to normality. 17 We have summarized the pre-operative factors to be considered prior to RC and OBS in Table 1.

| K E Y SURG I C AL PRIN CIPLE S
The main principle is to provide a continent urinary reservoir of adequate capacity, compliance, and low pressure. The advantages are continence (and the avoidance of a stoma bag), potential for spontaneous voiding and improved body image. 18 Careful dissection around the urethral margin to preserve the optimal length of urethra is necessary. Intra-operative frozen section is recommended to confirm negative margins. Prostatic urethral tumors are associated with an increased risk of secondary urethral tumors (12%-18%), 19 and multifocal disease and carcinoma-in-situ (CIS) is also reported to increase the risk of prostatic urethral tumor and secondary urethral tumors. These factors were previously considered a contraindication to OBS, but studies show that they do not appear to significantly increase the risk of secondary tumor. 9 If the distal urethral margin is negative intra-operatively, OBS can be performed. 20,21 The incidence of urethral tumors is low in women undergoing cystectomy (1.4%), lower than for men (5%). 9 Again, in appropriate cases, the suggestion is for frozen sections intraoperatively, and if negative, proceeding with OBS. 22,23 If a frozen section shows tumor at bladder neck in women, the risk of developing urethral recurrence is 50%. 22

| Choice of the bowel segment
Ileum is the most commonly used bowel segment as it has better compliance and less contractility as compared with colon or cecum. Ileal neobladder can obtain the same capacity as a colonic TA B L E 1 Factors to be considered for pre-operative planning for orthotopic bladder substitution neobladder, but ileal storage pressures are lower, 24 and there is less reabsorption of components from the urine due to mucosal atrophy over time, as compared to colon. Other segments of the intestine that have been used include ileum with cecum and or colon (Mainz pouch, Le Bag), right colon (Indiana, Goldwasser), and sigmoid. A meta-analysis of two trials suggested no difference in daytime or nocturnal continence rates between ileocolonic segments (using the Le Bag technique) or ileocaecal segments compared with and ileal segment (using the Studer technique). 25,26 Only one trial was identified that suggested ileal neobladder had lower rates of nocturnal incontinence, compared to ileocolonic segments, 26,27 the other study did not identify any differences. 25

| Techniques of bowel configuration
The chosen bowel segment is detubularized and the segments are

| Urethral and ureteric anastomoses
Anastomosis between the reconstructed bladder outlet and the urethra (preserving the sphincter) is created in a manner that it sits flat in the pelvis. A funnel-shaped outlet is not favored as it has risk of kinking and mechanical obstruction. This is especially important in women as urethral-pouch flexion can lead to chronic retention. 28 As described by Studer, the reservoir can be held in place by anchoring sutures to the Denonviller's fascia and pubo-prostatic ligaments. This allows for minimal tension on the membranous urethra and urethro-pouch anastomosis. The ureters are mobilized, and implantation is achieved by an end-to-side anastomosis either directly into the reservoir or into an afferent tubular limb as described by Studer. 29 Temporary ureteric catheters are inserted and brought to the abdominal wall to divert the urine and protect the anastomotic suture line from leaks. 30

| Anti-reflux mechanism
The question of whether reflux in a low-pressure reservoir such as OBS is clinically important has been debated. The WHO Consensus Group reported that reflux is not of clinical importance in OBS, but an anti-reflux mechanism is essential in continent cutaneous pouches. 3 Other studies indicated a trend toward an increased risk of stenosis (and subsequent upper tract deterioration) with anti-refluxing versus freely refluxing uretero-intestinal anastomotic techniques in OBS. 31,29 One study randomized ileal OBS patients to either anti-refluxing nipple valve or an isoperistaltic afferent ileal tubular segment for reflux | prevention. 29 After a median 45-57 months follow-up, there was no difference in the incidence of urinary tract infection (UTI), urinary incontinence, serum creatinine or functional reservoir capacity between the two groups. However, stenosis and upper tract deterioration were higher with the anti-refluxing technique (13.5% vs. 3% in the refluxing group). 29 When strictures do occur, they are associated with renal impairment. 31 Currently, oncological surgeons, who perform OBS, omit the formation of an anti-refluxing mechanism.

| Nerve sparing and organ sparing
Nerve-sparing in men is performed using the same technique as radical prostatectomy by dissection of the plane between the prostatic capsule and the neurovascular bundle. Nerve sparing can be unilateral on the non-tumor bearing side so that oncological safety is not compromised. In both male and female patients, preservation of autonomic innervation has a positive impact on continence with long term benefits. 32,33 Similarly, nerve sparing also prevents erectile dysfunction in men and loss of sexual function in women. 34,35 In women, genital sparing surgery is recommended as it is known to maintain continence and sexual function, 36 although further studies are required to assess its benefit over standard RC. 37 Preservation of the anterior vaginal wall has been shown to improve function, without compromising negative margins. 38 Prostate capsule and seminal vesical preserving procedures were previously discouraged due to poorer functional and oncological outcomes. 39

| Minimally invasive techniques
With the advent of minimally invasive and robotic-assisted surgery, the pyramid pouch, and the Y-pouch. 46 Whether intracorporeal approach has advantages in terms of post-operative recovery, is not fully established, reports have shown a longer learning curve and slightly higher risk of complications compared to extracorporeal diversion. 47,48 The currently ongoing iROC trial is a prospective RCT comparing outcomes of robotic cystectomy and intracorporeal diversion with the outcomes of open RC. 49 One study comparing open with robotic intracorporeal neobladders showed that short-term results for urodynamics and Health-related quality of life (HRQoL) score were similar, although daytime incontinence was worse for intracorporeal ONB. 50 The authors ascribed this to the shorter period of post-operative recovery in the robotic group.

| P OS T-OPER ATIVE C ARE AND COMPLIC ATIONS
In A systematic review of urinary diversions showed that OBS had lower postoperative morbidity (14%) and mortality (1%) as compared to ileal conduit (21% morbidity and 2% mortality rate), although this did not reach statistical significance. 52 It could be argued that these differences were due to selection bias involved in patients undergoing different types of urinary diversions. Overall early complications (within 30 days post-operatively) in ileal neobladders are reported in around 23%. 53 The MSKCC standardized reporting system 54 defines 11 categories of post-RC complications as summarized in Table 3.

| FOLLOW-UP AND LONG -TERM MANAG EMENT
The aim of follow-up is the early detection of metabolic com-

| Functional outcomes
From a reconstructive aspect, a focus on functional outcomes is necessary as continence and sexual function contribute hugely to quality of life. Across several studies, continence is not uniformly defined, and therefore continence rates are difficult to quantify mainly because of the heterogenicity of data. Overall continence rates are reported at around 85%. 59 Daytime continence rates are reported to be between 89% and 99%. 53 Toxin A have been tried. 65 Nocturnal continence takes longer to return, up to 24 months, and is reported to affect 74%-83%. 53,[60][61][62][63][64] Nocturnal incontinence occurs due to the absence of the physiological detrusor sphincter reflex, decreased tone of urethral sphincter, and uninhibited neobladder contractions at night. 66 Verapamil and oxybutynin have been shown to improve nocturnal continence rates. 67 Continence rates after robotic intracorporeal neobladder construction are similar with up to 88% overall continence in one series 68 and 87% daytime with 80% nocturnal continence in another large series. 69 Continence does appear to be maintained in the longer-term. In a study including three centers all performing ileal neobladders (Studer, Hautmann W Pouch or T pouch), at a mean follow-up of 48 months, daytime and nocturnal continence rates were 99% and 78%, respectively. 63 In the same patient group, follow-up for a mean of 88 months, 98% of patients were still achieving daytime continence and 76% were maintaining nocturnal continence. 53 Maintenance of continence in women after a median of 6.1 years follow-up remained good with 82.4% daytime continence and 76.5% nocturnal continence. 70 Of note, 58% of women in this study required periodic ISC. Women fare slightly less well overall than men, with daytime continence rates around 72%-87%, and nocturnal continence around 66%-85%. 12,23,38,70,71 Complete continence is reported in 57%, of the remainder using pads, 66% used 1-2 pads per day. 23 The 2012 Cochrane review of urinary diversion and bladder reconstruction identified studies indicating 0%-70% of patients who require ISC, while the remainder are able to empty the neobladder by abdominal straining. 27 Rates of ISC for the Studer neobladder are around 0%-21%. 53,62,72,73 In women, urinary retention (requiring ISC) is reported in 25%-50%. 12,23,60,74,75 Rates of erectile dysfunction in men without nerve-sparing have been reported to be around 35% at 12 months follow-up and are higher than that for ileal conduit (9.8%). 76 Women commonly encounter sexual dysfunction with reported dyspareunia (22%), reduced libido (37%), difficulty achieving orgasm (45%), and decreased lubrication (41%). 77 Reported studies show mixed results and as discussed above nerve-sparing and organ-sparing are beneficial. in non-ONB urinary diversion. 9 The authors concluded that muscle invasion, CIS, and prostatic stromal or urethral involvement at the time of RC have no significant effect on recurrence. There is some evidence that in male patients with symptomatic urethral recurrence, the survival rate is lower than those with no symptoms. 80 EAU guidelines suggest that recurrence is more common within the first few years and recommend 6 monthly CT scans for 3 years followed by annual imaging. ileal conduit shows that shared decision-making and goal concordance is necessary to achieve a low level of decision regret. 92 Thus, is it vital that treatment outcomes should be discussed with patients and the choice to proceed with OBS made in an informed manner.

| CON CLUS IONS
OBS is a valuable surgical option with the possibility of restoring the lower urinary tract function to achieve continence. This is important for patients undergoing RC as the "loss of an organ" is somewhat com- Above all, the type of urinary diversion should be acceptable to the patient whose main concern is cancer recurrence.