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Current indications and results of orthotopic ileal neobladder for bladder cancer Expert Rev. Anticancer Ther. 14(4), 419–430 (2014)

Andrea Minervini*, Sergio Serni, Gianni Vittori, Lorenzo Masieri, Giampaolo Siena, Michele Lanciotti, Alberto Lapini, Mauro Gacci and Marco Carini Department of Urology, University of Florence, Careggi Hospital, Florence, Italy *Author for correspondence: Tel.: +39 055 417 645 Fax: +39 055 437 7755 [email protected]

During the past three decades, the reconstructive aspects of urologic surgery emerged and became a major component of our surgical specialty, and the most relevant developments have been observed in the field of urinary diversions. Health-related quality of life and self esteem have been improved following orthotopic bladder substitutions, which are actually the preferred method for continent urinary diversion. Patients with neobladders have enhanced cosmesis and the potential for normal voiding function with no abdominal stoma. Patient’s selection for orthotopic neobladder formation is mandatory as most of the surgical complications or consequences associated with a neobladder are correlated not only with surgical technique or management after surgery, but also with wrong patient’s selection. The principles of intestinal detubularization and reconfiguration to obtain spherical reservoir are the basis of continent urinary diversions and ileum seems to be preferable over any other segment. Nowadays, ileal neobladder is a widely adopted solution after cystectomy with a neobladder rate of 9–19% for population-based data with an increase to 39.1–74% for high-volume centers. However, controversies still exist in this urological field about the best candidates for neobladder construction, the best type of neobladder to offer, whether or not an antireflux uretero intestinal anastomosis should be used, the future of minimally invasive approaches, that is, robotic assisted cystectomy plus extracorporeal or intracorporeal neobladder, and last but very important, the functional results and the level of symptomsinduced distress and quality of life in the long term in patients with bladder cancer receiving an orthotopic bladder substitution. All these issues are discussed on the basis of the most recent published data. KEYWORDS: bladder cancer • erectile function • incontinence • long-term follow-up • lymph node dissection • orthotopic ileal neobladder • quality of life • radical cystectomy

Radical cystectomy (RC) is the gold standard surgical treatment for organ-confined invasive bladder cancer and for nonmuscle invasive bladder cancer at high risk of progression providing the best chances of survival [1]. Historically, RC was always followed by an external incontinent urinary diversion. Because of its impact on sexual function, urinary control and body image, RC plus incontinent external urinary diversion is one of the most traumatic cancer operations in terms of physical and emotional stress and alteration in lifestyle. Health-related quality of life (QoL) and selfesteem have been improved following orthotopic bladder substitutions, which are actually

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the preferred method for continent urinary diversion [2]. All parts of the small and large intestine as well as the stomach have been studied for orthotopic reservoir construction, but a comparison between all different gastrointestinal segments showed advantages for ileum over any other segment [3]. In 1951, Couvelaire reported the first human bladder substitution using an intact nondetubularized ileal segment sutured to prostatic urethra [4]. During the past three decades, the reconstructive aspects of urologic surgery emerged and became a major component of our surgical specialty, and it is not surprising that the most relevant developments have been observed in

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the field of urinary diversions. Bowel detubularization and reconfiguration were the basis for the recent advances achieved in this surgical field [5]. However, for many years, while orthotopic neobladder (ON) techniques were improving, the ileal conduit proposed by Bricker remained the standard urinary diversion [6]. While during the last two decades, several studies have shown a high conduit-related complications rate in longterm survivors [7], and therefore, nowadays, ileal ON is a widely adopted solution after RC with a neobladder rate of 9–19% for population-based data with an increase to 39.1–74% for high-volume centers [6,8]. Controversies still exist in this urological field about the best surgical technique for oncological radicality including the extent of lymph node dissection, the role of technical variations to preserve potency, the future of minimally invasive approaches, that is, robotic-assisted RC (RARC) plus extracorporeal (EC) or intracorporeal (IC) neobladder, the best candidates for ON construction, the best type of ON to offer, whether or not an antireflux uretero intestinal anastomosis should be used and last but very important, the functional results and the level of symptoms-induced distress and QoL in the long term in patients with bladder cancer receiving an orthotopic bladder substitution. Extirpative phase: RC plus lymph node dissection

Usually, RC is performed through a transperitoneal approach that allows a wide resection of perivesical tissues and the best local cancer control [9]. An extraperitoneal approach to RC and subsequent ileal ON has been proposed to minimize blood loss and infections, keeping the peritoneum closed, but requires careful selection of patients in order to not compromise the oncological outcome [10]. The risk is the incomplete tumor resection especially along the posterior bladder wall. RC in patients with bladder cancer includes regional lymph node dissection [11]. A standard pelvic lymph node dissection (PLND) should be always performed as it does not have an impact on the overall surgical morbidity. A standard PLND usually involves the removal of all nodal tissue cranially up to, and including, the common iliac bifurcation, with the ureter being the medial border, and including the internal iliac, presacral, obturator fossa and external iliac nodes [12]. The average number of nodes removed during standard PLND is 14 (which should be increased when performing a modified PLND to include presacral nodes) [13]. Extended bilateral PLND includes all lymph nodes in the region of the aortic bifurcation and common iliac vessels medially to the crossing ureters. The lateral borders are the genitofemoral nerves, caudally the circumflex iliac vein, the ligamentum lacunare and the lymph node of Cloquet [14,15]. A superextended lymphadenectomy extends cephalad to the level of the inferior mesenteric artery, but its oncological role is still debated [16]. There is evidence from retrospective studies that RC with extended PLND provides better staging and outcomes than a standard PLND. Extended PLND appears to provide survival and recurrence outcomes similar to those of a superextended template up to the inferior mesenteric artery. Complete 420

skeletonization in the extended lymph node dissection template is more important than nodal yield. This does not exclude the possibility that certain patient subgroups with suspicious nodes or after neoadjuvant chemotherapy may benefit from more extensive lymph node dissection [17]. No randomized clinical trials have yet defined the relationship between the extent of lymphadenectomy and disease progression or overall survival in patients with muscle-invasive bladder cancer. Two prospective multicenter studies are ongoing with the aim to evaluate the influence of different extension of pelvic lymphadenectomy (limited vs extended) on outcome of patients with bladder cancer (The Lymphadenektomie Eingeschra¨nkte vs Ausgedehnte study, ClinicalTrials.gov identifier: NCT01215071 and the SWOG S 1011 trial). Technical variations for potency preservation

The primary sources of symptom-induced distress in young patients undergoing RC and continent diversion are related to sexual dysfunction, namely decreased sexual potency, reduced sexual desire, reduced intercourse and orgasm frequency. The nerve-sparing cystoprostatectomy devised by Schlegel and Walsh in 1987 was proposed as an effective technique to preserve erectile function with an 83% potency rate [18]. However, the studies that followed have shown that even in the best surgical hands, potency maintenance is approximately 50% [19]. To improve patients’ QoL, prostate- and seminal-sparing cystectomies have been proposed by different authors with several techniques preserving a portion of the prostatic capsule, seminal vesicles and the vasa deferentia. There are two main techniques. First, transurethral prostate resection (TUR-P) can be performed as first step procedure 2 weeks before the main surgery. This allows to histologically rule out the presence of tumor at the prostatic urethra and to have the specimen analyzed for prostate cancer. Second, the internal part of the prostate is removed concomitantly with the open surgery either by TUR-P or as open procedure during cystectomy [20,21]. The results of several papers have confirmed the efficacy of this technique in preserving sexual function and its superiority to the nerve-sparing RC even if performed by experts in the field [20,21]. However, prostate- and seminal-sparing cystectomies have been criticized for the treatment of transitional cell carcinoma of the bladder by many authors for the substantial risk of distant metastases higher than the rate observed after RC [22,23]. Reported drawbacks and limitations of this surgical procedure include: modified PLND to preserve the tissue medial and posterior to the internal iliac artery (presacral tissue), in order to avoid damage of the nervi erigentes at their origin; preservation of the posterior perivesical tissue and nodes; hematogenous spread of tumor cells during TUR-P; urethral recurrence due to the preservation of the distal part of the prostatic urethra and adenocarcinoma of the prostate left in situ after surgery. Moreover, from a functional point of view, prostate- and seminal-sparing cystectomies have been associated with an increased risk of self-intermittent catheterization for the neobladder outlet obstruction caused by the prostatic tissue [24]. Expert Rev. Anticancer Ther. 14(4), (2014)

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Current indications & results of orthotopic ileal neobladder for bladder cancer

To overcome the negative aspects of the prostate-sparing approach, the use of potency-sparing cystectomy with complete prostate removal has been proposed [25,26]. This technique differs from prostate- and seminal-sparing cystectomies in two main aspects: the reservoir is anastomized to the urethral stump, thus avoiding the increased risk of chronic retention that is the main long-term functional complication of orthotopic urinary diversion, and there is no prostatic tissue left, thus considerably decreasing the risk of local recurrence from residual or regenerated urothelium of the prostatic fossa and eliminating the risk of prostate cancer. The pelvic plexus and nervi erigentes remain equally intact. Continence and potency rates are fully comparable to those of the cited series of potency-sparing cystectomy with partial prostate preservation. Minimally invasive approaches to RC & ON

The use of robotic-assisted laparoscopic surgical techniques in urology continues to increase. Although robotics have become the norm in a significant proportion of certain types of urooncological surgery, that is, prostatectomy and partial nephrectomy, its use in RC plus ON is still in its infancy. Basically, two techniques have been reported: RARC plus EC neobladder that is then anatomized inside the patient, with this latter stage being laparoscopic, robot-assisted; RARC plus IC neobladder by the robot-assisted laparoscopic route. Available data suggest that RARC can provide comparable oncologic outcomes to open RC despite the scarcity of level 1–2 evidence [27]. A recent systematic review and meta-analysis of comparative studies reporting early outcomes after RARC versus open RC included 13 studies with 962 cases (364 cases for RARC and 598 cases for open RC). The majority of series were from the USA and most of them included an EC reconstruction method for urinary diversion. In particular, pooled data indicated significantly lower overall perioperative complications, major complications, more lymph node yield, longer operative time, less estimated blood loss, lower perioperative transfusion, lower intraoperative transfusion and shorter length of stay in the RARC than the open RC group [28]. Short-term oncologic outcomes including lymph node yield and surgical margins as well as mid-term follow-up reported as recurrence rates and cancerspecific survival and overall survival showed equivalent results between RARC and open RC [29]. However, long-term followup, preferably from randomized trials, is needed prior to making any definitive conclusions regarding oncologic outcomes. Although RARC plus EC neobladder is the most widely adopted option in high-volume robotic centres, the very few reports presenting the results of RARC plus IC neobladder have demonstrated that, in their hands, excellent outcomes can be achieved; however, according to the most recent EAU guidelines, RARC plus IC neobladder must be regarded as an experimental procedure that should be undertaken only by expert hands [30–34]. Patients selection for ON construction

All patients who are eligible for RC should be considered possible candidates for an orthotopic diversion. Nevertheless, there informahealthcare.com

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are several contraindications. In fact, most of the surgical complications or consequences associated with ileal neobladder are correlated not only with the surgical technique or management after surgery, but also with wrong patient’s selection. Until the early 1990s, ON was considered contraindicated in females as the risk of urethral recurrence was considered higher due to the shorter urethral length. The first long-term data about the oncological safety of ON in females were reported in the mid-1990s. These studies represent the clinical and surgical basis to recommend ON as a possible option for urinary diversion also in females [35–37]. Absolute prerequisites for orthotopic bladder substitution are intact urethral function, absence of urinary stress incontinence and absence of tumor infiltration of the distal prostatic urethra in men or of the bladder neck in women. Patients with positive urethral margin at RC or with positive biopsies for invasive cancer or carcinoma in situ (CIS) from the prostatic urethra are not appropriate candidates because the risk of urethral tumor recurrence is considerably high [1,38]. Another absolute prerequisite determining successful outcome is that patients is represented by the intellectual and physical capacity to understand the new bladder voiding mechanism and to be able to catheterize the neobladder, if necessary. In some series, the need for clean intermittent catheterization at 5 year after orthotopic diversion has been reported in approximately 4–10% of male patients and 15–40% of female patients [39]. If these prerequisites are not given, then the ileal conduit is preferable. In patients with compromised renal function and serum creatinine >1.5–2 mg/dl, ON is considered an absolute containdication [40]. However, in cases of hydronephrosis due to tumor with significant creatinine increase, renal function may be reevaluated after upper urinary tract deobstruction by means of a percutaneous nephrostomy tube since sufficient kidney function may be recovered. Also severe hepatic dysfunction is a contraindication to ON because the absorption through the intestinal mucosa of ammonium can lead to hyperammonemia. Renal and hepatic insufficiency are considered contraindications because in these patients the metabolic consequences of continent urinary diversion cannot be compensated adequately. A severe inflammatory bowel disease (Chron’s disease) is a further contraindication to ON. Advanced age or prior radiation therapy is relative contraindications. Indeed, advanced age is not by itself a contraindication for neobladder, but older patients have a greater incidence of enuresis or nocturnal incontinence than younger patients. Physiologic rather than chronologic age must be taken into consideration [41]. In patients with prior pelvic irradiation, complications are likely to be more prevalent, but in theory if sphincter function is preserved, these patients can be managed by orthotopic reconstruction. The presence of positive pelvic nodes is not considered an absolute contraindication. Several studies have shown that in patients with node-positive disease, long-term survival can be achieved with a low incidence of pelvic recurrence rate (10–13%) through RC and PLND [42] and with a low risk of 421

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urethral recurrence, ranging from 1.1 to 2.5% [43,44]. Furthermore, it has been reported that in the presence of recurrent disease, most patients can achieve normal neobladder function even until death [44].

in the terminal ileum, vitamin B12 deficiency is more frequent in patients with >60 cm ileum resected or if the ileocecal valve and terminal ileum are resected [50]. Different techniques for ileal ON

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Principles for ileal ON construction

The aim of bladder reconstruction procedures is to develop a reservoir characterized by adequate capacity, low-pressure storage, high compliance, which consent adequate continence and voluntary expulsion of urine at convenient intervals and with a low capacity of reabsorption of hydrogen and chloride. Clinical evidences suggest that to obtain these features the reservoir must be spherical and made with small bowel [45]. Advantages of the spherical reservoir are: significant increase of reservoir capacity for a given length of bowel; slow increase in pressure during bladder filling at any degree of filling; absence of coordinated contractions due to the reconfiguration that renders the peristalsis of intestinal segment ineffective; the possibility to use the shortest length of bowel, which reduces the reabsorptive surface and the chance of diarrhea and vitamin deficiency to the minimum [45]. All parts of the small and large intestine as well as the stomach have been used for orthotopic reservoir construction but a comparison between all different gastrointestinal segments showed advantages for ileum over any other segment [3]. Metabolic consequences due to bowel wall secretion and urinary reabsorption from the intestinal reservoir can be best compensated in the terminal ileum compared with the proximal ileum, jejunum or colonic segments also for the mucosal atrophy that occur in the long term, in the terminal ileum, resulting in less reabsorption of hydrogen and chloride [46]. Moreover, the ileal segments have higher compliance than large bowel and store urine at lower pressure. In the literature, sigmoid neobladder is associated with a lower reservoir capacity, higher storage pressure, peak flow rate, a lower daytime and nighttime continence rate, higher risk of hyperchloremic acidosis in comparison to ileal neobladder [47]. The use of jejunum and stomach for neobladder reconstruction is not recommended [48,49]. Jejunal neobladders are characterized by high incidence of hypochloraemic and hyperkalaemic metabolic acidosis [48]. Gastric neobladders, in adult patients, are associated with high incontinence rates and electrolyte disturbances, such as hypochloremic alkalosis and higher pressure spikes because of spontaneous contractions related to their muscular nature, despite the detubularization [49]. Moreover, hematuria and dysuria, as consequences of urethral irritation by increased urine acidity, have been also reported. The length of ileum recommended for the reservoir is from 40 to 44 cm [50,51]. Excessive ileal length with creation of an over-sized neobladder must be avoided. Indeed, a larger neobladder can show a better postoperative continence with longer micturition intervals in the early phase; however, the advantages are only temporary and a floppy bag may develop with increased risk of chronically infected residual urine and the need for lifelong intermittent self-catheterization [51]. Moreover, as the absorption of vitamin B12 occurs primarily 422

Over the past 20 years, several orthotopic reconstruction techniques have been proposed by authors reporting their experience in tertiary referral centers. This suggests that there is still not an ‘ideal reconfiguration’. Many forms of ileal neobladder construction have been described using small bowel remodeled into various shapes such as U, crossfolded U, W, M, V, in a circular manner and with different approaches for the connection of the reservoir to the upper urinary tract. Here we will briefly review the two most popular reconfigurations presented in studies with long-term follow-up and the Padua ileal neobladder most popular in Italy. Studer ileal neobladder

The Studer neobladder with a long afferent, isoperistaltic tubular segment has become a popular orthotopic form of diversion [52]. Approximately 60–65 cm segment of terminal ileum dissected approximately 20–25 cm proximal to the ileocecal valve is used. The distal 40–45 cm segment is placed in a U shape, detubularized and the posterior wall edges are sutured. Then, the pouch is cross-folded and the anterior wall is sutured to create a spherical shape. The ureters are anastomized directly into the upper portion of the proximal intact 20–25 cm of ileal segment that serves as antireflux mechanism. Hautmann ileal neobladder

This ileal neobladder is an intentionally large capacity, spherical ileal reservoir constructed in an attempt to reduce nighttime incontinence [53]. It is created with 70 cm of detubularized ileum arranged into a W configuration with four limbs sutured to shape the posterior wall of the neobladder. Ureters are anastomized by direct refluxing or antirefluxing techniques to the superolateral posterior limbs of the diversion. The lateral limbs of the diversion are folded over to create the anterior wall of the neobladder. Many variations on this configuration, using also shorter ileal segment, have been described, including ileal S-pouch, J-pouch and the so-called chimney modification, in which a short segment of ileum is left at each superolateral corner for direct anastomosis to the ureters. Padua ileal neobladder

The Padua ileal neobladder is created with a 40 cm segment of terminal ileum opened entirely and reconfigured in a circular manner to produce a posterior plate that is then closed anteriorly [54]. The ureters, anastomized with the Le Duc antireflux technique in their initial experience, are usually now reimplanted with a simple end to side direct anastomosis. Considerations on the uretero ileal anastomosis

There are still controversies regarding the optimal mode of ureteroileal anastomosis in ON. Is any form of antireflux Expert Rev. Anticancer Ther. 14(4), (2014)

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Current indications & results of orthotopic ileal neobladder for bladder cancer

procedure necessary in patients with low-pressure intestinal reservoirs with no major coordinated contractions? Proponents of nonrefluxing techniques cite the harmful effects on renal function of recurrent pyelonephritis caused by reflux which appears especially during voiding due to a significant increase of intraluminal pressure [55,56]. Many antireflux techniques have been developed. The most commonly used are the Le Duc technique [57], the split-cuff ureteric nipple [58], the intussuscepted nipple valve as in the Kock pouch [59], the serous-lined extramural tunnel [60], the orthotopic T-pouch ileal neobladder [61] and a nonvalvular afferent isoperistaltic ileal segment [62]. The multiplicity of these techniques suggests that an ideal solution has not yet been found. Proponents of refluxing techniques cite the harmful effects on renal function caused by anastomotic strictures that, after nonrefluxing anastomosis, occur at an appreciatively higher rate than after direct anastomosis (9–20 vs 1–6%) [63]. At contrary, the benefits of reflux prevention are present for the continent cutaneous pouch requiring intermittent catheterization and for ureterosigmoidostomy, both usually with high reservoir pressures and bacteriuria. In conclusion, for patients undergoing large volume lowpressure continent diversion, the refluxing ureterointestinal anastomosis appears to be the technique of choice since this is technically easier to perform, is associated with a low stricture rate and preserves renal function in the long term [64]. The utility to use an efferent ileal segment to avoid reflux is not clear. In recent years, Thoeny and coworkers [65] reported the use of a 14–16 cm tubular afferent segment instead of the previously used 20 cm segment. Hollowell et al. reported results of a Hautmann ileal neobladder with chimney modification using the most proximal 8–12 cm as a short afferent limb [66]. Indeed, Minervini et al. reported the use of a short afferent limb 5–7 cm without detrimental effects on renal function in the long term [67,68]. General complications of ileal ON

RC and ileal ON construction represent a major surgery with potential relevant complications even in the most experienced hands. Complications of ileal ON may be divided into early and long-term complications (>90 days postoperatively) and may be classified as directly or not related to the neobladder itself. Early complications

In a contemporary, homogenous series of 1,013 patients who underwent RC and ileal ON, 587 (58%) experienced at least 1 complication within 90 days of surgery. Infectious complications were most common (24%) followed by genitourinary (17%), gastrointestinal (15%) and wound related (9%) [69]. Of the patients, 36% had minor (grade 1–2) and 22% had major (grade 3–5) complications. On univariate analysis, the incidence and severity of the 90-day complications rate correlate significantly with age, tumor stage, American Society of Anesthesiologists score and preoperative comorbidity. The 90-day mortality rate was 2.3%. informahealthcare.com

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Long-term complications

Most complications are diversion related. In a recent series of 923 patients [70] who underwent RC and ON, with a minimum follow-up of 90 days (median 72 months, range: 3–267), the overall long-term complication rate was 40.8%. Hydronephrosis, incisional hernia, ileus or small bowel obstruction and urinary tract infection were observed in 16.9, 6.4, 3.6 and 5.7% of the patients, respectively. Subneovesical obstruction occurred in 3.1% of cases and was due to local tumor recurrence in 1.1%, to neovesicourethral anastomotic stricture in 1.2% and to urethral stricture in 0.9%. Overall, 307 of 923 required long-term bicarbonate substitution. Rare complications included cutaneous and intestinal neobladder fistulas, neobladder perforation and necrotizing pyocystis [70]. Long-term results of ON

Good long-term results after RC and ileal ON requires the meticulous postoperative surveillance of patients. Continuous monitoring of the upper excretory tract must be carried out to identify and correct possible stenosis of the ureters that are the most important cause of functional renal deterioration [68]. Meticulous surveillance of the maximum voided volume, bacteriuria and postvoid residual urine volume is necessary to identify and correct any possible stenosis of the urethroileal anastomosis that is the most important cause of reservoir decompensation and voiding dysfunction [68]. Moreover, blood gases examination must be carried out regularly for the early detection of metabolic abnormalities although in patients with neobladder made with shorter (40–45 cm) intestinal segments of ileum, metabolic acidosis and hyperchloremia are unusual if the kidney functionality is preserved. Renal function

Urinary diversion following cystectomy must be safe for the upper urinary tract. Only a few studies on ON have evaluated renal function during follow-up, and the comparison among these studies is difficult because of the heterogeneity of clinical reports. Furthermore, the assessment of renal function in most studies relied on suboptimal endpoints, such as creatinine and/or radiologic studies, which are inexact determinants of overall renal function and usually underestimate the decrease of the glomerular filtration rate (GFR) in the elderly patients. Moreover, the functional status of the upper urinary tract before urinary diversion is a valuable information that is often lacking in clinical reports. To better examine the morphological and functional outcome of the upper urinary tract, renal scintigraphy and total and separate GFR must be utilized. Long-term renal function in patients with ON can be influenced by several factors including ureteral obstruction, urethral stenosis, urinary tract infection and reflux. The most frequent cause of renal function impairment is represented by ureteroileal anastomotic strictures that, after nonrefluxing anastomosis, occur in an appreciatively higher rate than after direct anastomosis (9–20 vs 1–6%) [62,63]. Overall, long-term maintenance of upper tract function in bladder substitution has been demonstrated for the vast majority of patients (73–96.2%), with rising serum 423

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creatinine levels observed in 3.8% of the cases after a 5-year follow-up [64–66]. Minervini et al. evaluated morphological alterations of the upper urinary tract and renal function in 70 W-shaped neobladder without antireflux mechanism using renal scintigraphy, ultrasonography and total and separate GFR. For comparative purposes, a control group of patients without nephrourological diseases was evaluated in a similar manner [64]. No statistically significant difference between the GFR of patients and controls was demonstrated. The authors concluded that renal deterioration after ON without antireflux mechanism is minimal at 10-year follow-up and a ureteroileal stenosis is the greatest cause of postoperative renal deterioration [64]. Voiding function

Voiding function is fundamental in patients with ON, and QoL in these patients, compared with that of patients with alternative forms of diversion, can be better only if voiding function is preserved. Continence

After discharge, patients receive the instruction to void every 3 h during the day and twice during the night. Continence rates improve throughout follow-up since the neobladder capacity increases over time and usually it needs at least 8 months to mature and achieve its final functional capacity [71,72]. A neobladder filling capacity of 300–500 ml is usually recommended for a mature ON [51]. Various factors influence continence such as correct timing in voiding during the day and night, the pressure generated inside the reservoir that should be low and depends on the size and configuration of the ileal segment, in accordance with the La Place law, and completeness of voiding. Preservation of the distal urethral sphincter and its innervation are of paramount importance to maintain continence and additional factors may play a role as urethral length and sensitivity, absence of bacteriuria, patient age and mental status [3]. Long-term follow-up studies have shown that daytime and nighttime continence rate can be achieved in 75–95% and in 50–85% of the patients, respectively [1,73,74]. Incontinence rates correlate positively with patient age and tend to increase slightly especially from 6 to 12 years after surgery. Madersbacher et al. reported that, at 5 years after surgery, the 19% of patients, aged 70 years [71]. Apoptosis in the rhabdosphincter with reduction of sphincter length, of maximum urethral closure pressure and decrease of the membranous urethra innervation with age are responsible for this phenomenon [72,75]. Nerve sparing and especially prostate-sparing cystectomy may protect against incontinence [19–23]. Indeed, in the study by Madersbacher et al., daytime continence rate was significantly higher in men submitted to nerve sparing versus no nervesparing cystectomy [71]. Also postvoiding residual urine and positive urinocultures are predisposing factors for incontinence; patients voiding without significant residual urine and with negative urinocultures had significantly better continence especially by night than men with significant post voiding residual urine or positive urinocultures [71]. 424

The ON was regarded as contraindicated in females until the early 1990s due to concerns about the increased risks of urethral recurrence and postoperative urinary incontinence. After the description by Colleselli et al. of the morphology and nerve supply of the female urethral sphincter, and as the result of a better understanding of the risk factors of urethral tumor involvement, orthotopic diversion in women has been routinely applied in referral centers since the mid-1990s [76]. Diurnal and nocturnal continence rates ranging from 72 to 95% and from 66 to 86%, respectively, have been reported [76]. Preservation of the urethral support mechanism, as well as rhabdosphincter and its autonomic nerve supply, improves continence and voiding through an effective active relaxation of the proximal urethra and prevention of urethral kinking during voiding [77]. Urinary retention

The rate of catheterization for elevated postvoiding residual urine volumes or urinary retention range in male patients between 4 and 25% [78]. The use of excessive ileal length (>60 cm) with creation of an oversized neobladder [79], elongated bladder outlet kinking especially in obese patients [50] and cicatricial stenosis of urethroneovesical anastomosis [63,67] are responsible for post voiding residual urine and urinary retention. Also an inability to sustain abdominal straining, as well as in case of abdominal or inguinal hernias, produces elevated post voiding residual urine and the risk for urinary retention [51]. Urinary retention is more common in women with long-term rates of 21–61% and the pathogenesis is not completely established [77]. Some authors postulated that urinary retention in women is due to changes in the urethral innervation or the inability to relax the pelvic floor. On the other hand, most investigators believe that the primary cause of hypercontinence is a falling back of the pouch into the pelvic cavity with the formation of a ‘pouchocele’ that leads to angulation and obstruction of the urethroileal anastomosis [76,77,80]. Video urodynamics has showed pelvic floor reconstruction after cystectomy increases the back support of the neobladder, which may result in a significant decrease in urinary retention [81]. Urinary tract infection

Bacteriuria is frequent in ON, and 3–34% of patients have positive urine cultures. Nevertheless, rarely bacteriuria is symptomatic with signs of systemic infection [82]. There are several causes of bacteriuria. The absence of the prostate with its antibacterial secretions and the lost inhibitory action of bowel epithelium against the bacterial adherence are important factors, but more important is the presence of residual urine that provokes elevated bacterial colonization. The presence of positive urine cultures correlates directly with postvoid residual urine. Recurrent urinary tract infection and the presence of postvoid residual urine represent two indicators to identify urethroileal anastomosis strictures [82]. Patients with complete or nearly complete emptying have a much lower rate of bacteriuria. Therefore, complete and regular emptying represent an important defense mechanism against Expert Rev. Anticancer Ther. 14(4), (2014)

Current indications & results of orthotopic ileal neobladder for bladder cancer

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urinary tract infection. It has been debated whether asymptomatic bacteriuria in patients with ileal neobladder should be treated or not. Some authors suggest that prophylactic antibiotics are recommended in patients with recurrent urinary tract infection, but the majority of authors do not consider it necessary to treat a positive urinary culture in the absence of specific voiding symptoms [82]. Sexual function

Severe erectile dysfunction after RC is a well-known complication. A nerve-sparing technique may preserve erectile function in 13–50% of the cases [18,19]. It is also possible to combine ileal neobladder with prostate capsule-sparing cystectomy that increase the rates of potency preservation up to 80–100% [20–24]. Sexual dysfunction is a very important problem also in females after RC. For oncological safety, RC in women traditionally includes the removal of the bladder, urethra, uterus, the proximal third of vagina and ovaries. This procedure has a negative impact on sexual function and on general QoL for the injuries to the neurovascular bundles, located on the lateral walls of the vagina damaged by removal of the urethra and anterior vaginal wall, and the concomitant devascularization and denervation of the clitoris [83,84]. The most common symptoms reported by these patients include diminished sexual desire, decreased vaginal lubrication, dyspareunia and diminished ability or inability to achieve orgasm [85]. The preservation of the urethra with clitoral neurovasculature, and of anterior vaginal wall, as much as possible, with tubular reconstruction, can improve postoperative sexual function in sexually active women with ileal neobladder [86]. Overall, both in male and in female patients, ON avoids the disadvantages of the ileal conduit as the presence of stoma, the possibility of urinary leakage from the stoma and, as a result, the emanation of unpleasant smell, may make the patients reluctant to engage in sexual activity even when the erectile function was preserved. Long-term survival

The primary aim of bladder replacement is to improve patients’ QoL. Ileal neobladder does not compromise the quality of cystectomy itself and does not have a major impact on cancer control and on survival endpoints if nerve-sparing surgery is attempted when oncologically indicated [9]. Yossepowitch et al. reported survival, local recurrence and urethral recurrence rates after cystectomy in 214 patients who underwent ON for bladder cancer and in 269 treated with an ileal conduit and showed no differences in cancer-specific survival between the two cohorts when adjusting for pathological stage [9]. Patterns of relapse in 62 of the 214 patients with a neobladder (29%) included local recurrence in 23 (11%), distant recurrence in 19 (9%) and combined local and distant recurrence in 18 (8%) [9]. Urethral recurrence was rare (2%) [9]. Urethral recurrence is a rare event and occurs between 2 and 5% of patients. The highest risk is present in patients with multifocal primary tumors or concomitant CIS [87]. Hautmann et al. analyzed the impact of ON in a series of informahealthcare.com

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923 patients with a median follow-up of 72 months (range: 3–267) [70]. The overall survival rate and complications rate were similar to those of patients with similar characteristics treated with ileal conduit diversion [88]. The significant increase in survival rate of patients treated with an ileal neobladder reported in some studies [87,89] is not due to the surgical choice itself but to the capacity of an ileal neobladder treatment plan to decrease physicians and patients reluctance to perform a timely cystectomy in younger patients who have less comorbidities and greater probability of organ confined tumor [9]. QoL, general remarks

RC is a traumatic event associated with significant changes in urinary and sexual activity, psychosocial function and overall wellbeing. The influence of these specific symptoms on emotions and social activities in the individual patients varies, and the evaluation of the level of distress caused by this symptom (in other words, the relative importance of sources of symptom-induced distress) more than the symptoms itself is to be considered as an important concern after any bladder cancer treatment. The use of validated instrument to record possible changes in urinary and sexual activity, psychosocial function and overall well-being is mandatory to compare the QoL outcomes after different urinary diversion. To date, health-related QoL assessment in patients with bladder cancer has primarily been accomplished through either generic or cancer-specific validated instruments. Several validated questionnaires have been proposed to asses QoL after RC and urinary diversion. All questionnaires must be selfadministered during a scheduled follow-up visit. An effective measurement must consider at least three categories of QoL: the general health status; the physical and mental health in patients with oncologic disease; the organ-specific function (urinary and sexual) after local treatment. The following validated questionnaires are the most accurate to assess the overall health and QoL after cystectomy and urinary diversion: Short Form-12 (SF-12, the short version of the SF-36 questionnaire) [90], the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C-30 (cancer generic) [91], The EORTC QLQ-BLM-30 (cancer-specific bladder muscle invasive) [92] and the Functional Assessment of Cancer Therapy for Bladder Cancer (Bladder and Vanderbilt Cystectomy Index): functional assessment of cancer therapy (FACT) Bladder and Vanderbilt Cystectomy Index that use the 28 items of the FACT General as the core set of items, with addition of new subscale items specific to bladder cancer diagnosis and treatment [93]. QoL in males

In male patients, the radical treatment of muscle-invasive bladder cancer involves a reduction in many aspects of the QoL. Some of these are related to the cystectomy itself, such as the erectile dysfunction and physical and psychological consequences related to the diagnosis and treatment of the disease, including also the anxiety/depression for the fear of recurrences. Other aspects are related to the type of urinary diversion chosen, as 425

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the management of the micturition itself and potential complications. In this broad group, most common urinary incontinence, urinary retention requiring self-catheterization, urinary infection, subjective reduction of attractiveness, bowel symptoms (as frequent defecation, urgency, fecal leakage, constipation, abdominal pain) and fatigue, can affect QoL in different degrees according to the specific diversion [8]. No randomized controlled studies have investigated QoL after RC and ON. Such studies are desirable but difficult to conduct. Several studies are available in literature, but only a minority is prospective, and all are limited by several biases, the most recognized of which is the lack of a universal definition of the term ‘health-related QoL’. Thus, the term may differ between cultures, countries and, consequently, study groups. Moreover, in different studies, the health-related QoL is investigated using different methods (structured face-to-face interview, telephone interview, postal questionnaire surveys), the questionnaires chosen are heterogeneous and not always validated and many patients do not return the questionnaires creating a bias of recruitment. For all these reasons, there is currently a low-level evidence on this topic. For sure, patients with neobladders have enhanced cosmesis and the potential for normal voiding function with no abdominal stoma; nevertheless, the assumption that ON provides better QoL than ileal conduit diversion is still debated [94]. The superiority of ileal neobladder has been demonstrated by Hobisch et al. [95] and by Erber et al. [96]. In these studies, patients with neobladder scored significantly better in all functional domains: physical, emotional, cognitive and social than patients with conduits. Hobisch et al. also reported that 36% of the patients with conduits would recommend the operation to a friend, while this percentage went up to 97% for those with ON [95]. Henningsohn et al. evaluated distressful symptoms, well-being and QoL in 101 recurrence-free ON patients and found them to be similar to those seen in a matched control population of the same geographical area (n = 147) (level of evidence: 3) [97]. The instrument used was a validated, detailed questionnaire comprising 137 questions about physical and psychological well-being, anxiety and depression level, subjective attractiveness, urinary, sexual and bowel symptoms. Compared with controls, patients with neobladders had significantly more often erectile dysfunction (94 vs 48%), urinary leakage at least once monthly (18 vs 5%), postvoid residual urine (100 cc or more) with need of selfcatheterization (26 vs 0%) and urinary tract infections (14 vs 6%). Nevertheless, no difference between groups resulted in scores related to the psychological well-being, the subjective QoL, anxiety and depression. Male patients with ON felt as attractive as controls, and distressful bowel symptoms were slightly higher in patients versus controls (14 vs 9%) [97]. Other studies comparing ON patients with different types of urinary diversion (ileal conducts, continent and incontinent cutaneous diversions) were unable to confirm superiority of one type of reconstruction with regard to health-related QoL, while all showed preserved well-being with any type of derivation, despite the presence of erectile dysfunction and different degree of 426

urinary and intestinal disorders [98]. These results were also confirmed in a recent study by Philip et al. who observed no significant difference in health-related QoL indices in ON patients compared with a cohort of age-similar patients treated with ileal conduit, even if the first group had significantly better physical function, more active lifestyle and lower reduction of subjective attractiveness [99]. QoL in females

Several trials are based on the data from both men and women taken together, whereas only a few studies have evaluated the QoL, after RC and urinary diversion in female patients, only. The major limitation of these scientific reports are the small samples of women recruited, the absence of an adequate disease-free follow-up time and the use of few and not validated questionnaires. Gacci et al. compared life quality of women undergoing to three different types of urinary diversion after RC: cutaneous ureterostomy, Bricker’s ileal conduit and VIP ON with the use of three different validated questionnaires: the EORTC-QLQ-C30, the EORTC-QLQBLM30 and the FACT-BL [100]. Only women undergoing to cutaneous ureterostomy had a worse QoL for the deterioration of both the physical and emotional perception of their body image [100]. Expert commentary

According to National Comprehensive Cancer Network guidelines and the European Association of Urology guidelines, RC is the standard treatment for localized muscle-invasive bladder cancer and high-risk nonmuscle-invasive cancers resistant to endovesical chemotherapy, regardless of gender [1]. In relation to female concerns about the increased risks of urethral recurrence and postoperative urinary incontinence, for many years, the orthotropic neobladder was largely limited to male patients [76]. Only approximately 20 years ago, with a better understanding of either the anatomy of the female rhabdosphincter and the natural history of bladder cancer in women, such as with the developing of frozen section, urethra-sparing cystectomy and orthotopic urinary diversion was performed largely in females with muscle invasive bladder cancer [84,101]. However, to obtain good results, ON should be performed in selected patients observing determinate principles. The reservoir should be detubularized and reconfigured, the ileum should be preferred whenever possible. Reflux prevention is not a major concern and it does not justify the use of an antireflux mechanism that is associated with a high rate of anastomotic strictures. Satisfactorily long-term functional outcome requires not only a careful selection of patients but also a meticulous postoperative surveillance. It is necessary to continuously monitor the upper urinary tract and maximum voided volume, bacteriuria and postvoid residual urine to identify ureteroileal and urethroileal anastomotic strictures and therefore to preserve renal function and neobladder function in the long term. ON, combined with nerve-sparing surgical technique, allows patients to live with no abdominal stoma and urinary bags with a good voiding function and, in some cases, with an acceptable sexual activity. We believe, like others, that until a better solution is devised, orthotopic reconstruction remains the best option for patients requiring RC. Expert Rev. Anticancer Ther. 14(4), (2014)

Current indications & results of orthotopic ileal neobladder for bladder cancer

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Five-year view

What changes might we expect over the next 5–10 years with regard to orthotopic bladder reconstruction? Certainly, in the future, RARC with totally IC urinary diversion will continue to evolve with technology driving new techniques such as robotic instruments that aid retraction, suturing and closure of the neobladder, or indocyanine green fluorescence, a useful tool that enables the surgeon to identify the mesenteric vessels prior to forming a urinary diversion [102]. Therefore, it is possible that within 5–10 years, the majority of centers will offer a minimally invasive RC plus IC ON to selected patients. Recent advances in the fields of microfabrication, biomaterials and tissue engineering have provided new opportunities for developing biomimetic and functional tissues with potential applications in replacing the bladder [103]. Various populations of either embryonic or adult stem cells and progenitor cells have been studied as useful cell sources for the tissue engineering, but the future of tissue engineering technology for replacing human bladder will depend on the future development and improvements of bladder preserving therapies for bladder cancer such as chemotherapy, radiotherapy and their combination. The larger will be the need for RC in the future, the stronger will be the

Review

energies and efforts of biomedical industries and national health systems to develop a total prosthetic bladder. RC plus continent urinary diversion is the method of choice in a large number of patients today but, within 5–10 years, multimodal bladder preservation strategies might become an alternative to RC in selected patients with single lesion; no extravesical extension; no associated CIS; no hydronephrosis; negative lymph nodes at CT or MRI and radicality of the transurethral resection [104,105]. Acknowledgements

The authors would like to thank R Minervini, former chief of the Urology Unit at the University of Pisa, Italy, with a strong experience in the field of orthotopic neobladder for his valuable comments that significantly contributed to the manuscript development. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • All patients who are eligible for radical cystectomy should be considered possible candidates for a neobladder. • Patient’s selection is mandatory as most of the surgical complications or consequences associated with ileal neobladder are correlated not only with surgical technique or management after surgery, but also with wrong patient’s selection. • The principles of intestinal detubularization and reconfiguration to obtain spherical reservoir are the basis of continent urinary diversions. • All parts of the small and large intestine have been used for orthotopic reservoir construction, but ileum seems to be preferable for lower filling pressures than large bowel and because ileal resection may well have less malabsorptive impact than resection of the ileocecal segment. Also, the risk of acidosis may be less with ileum than with colon. • The refluxing ureterointestinal anastomosis is the technique of choice since it is technically easier to perform, with a low stricture rate and preserves renal function in the long term. • Erectile dysfunction after radical cystectomy is a well-known complication. One measure to avoid this devastating complication is to perform nerve-sparing surgery that preserves erectile function in 13–50% of cases. Prostate capsule-sparing cystectomy further increase the potency rate to 80–100%. • Satisfactorily long-term functional outcome requires not only a careful selection of patients but also a meticulous postoperative surveillance. • The use of validated instrument is mandatory to compare the quality of life outcomes after different urinary diversions. • Patients with neobladders have enhanced cosmesis and the potential for normal voiding function with no abdominal stoma; nevertheless, the assumption that orthotopic neobladder provides better quality of life than other type of diversion that use the intestine is still debated.

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