Pitcher pot neourethral modification of ileal orthotopic neobladder achieves satisfactory long‐term functional and quality of life outcomes with low clean intermittent self‐catheterization rate

Abstract Objective To describe a decade of our experience with a neo‐urethral modification of ileal orthotopic neobladder (pitcher pot ONB). Multiple investigators have reported similar modifications. However, long‐term longitudinal functional and quality of life (QOL) outcomes are lacking. Methods Prospectively maintained hospital registry for 238 ONB patients comprising a mix of open and robotic surgery cohorts from 2007 to 2017, and minimum of 2 years of follow‐up was retrospectively queried. QOL was evaluated using Bladder Cancer Index (BCI). Longitudinal trends of QOL domain parameters were analysed. List of perioperative variables that have a biologically plausible association with continence, potency, and post‐operative BCI QOL sexual, urinary, and bowel domain scores was drawn. Variables included surgery type, Body Mass Index (BMI), T and N stage, neurovascular bundle (NVB) sparing, age, and related pre‐operative BCI QOL domain score. Prognostic associations were analysed using multivariable Cox proportional hazard models and multilevel mixed‐effects modeling. Results The study comprised 80 and 158 patients who underwent open and robotic sandwich technique cohorts, respectively. Open surgery was associated with significantly higher “any” complication (40% vs 27%, P‐value .050) and “major” complication rate (15% vs 11%, P‐value .048). All patients developed a bladder capacity >400 cc with negligible post‐void residual urine, and all but one patient achieved spontaneous voiding by the end of study period (<1% clean intermittent self‐catheterization [CISC] rate). By 15 months, QOL for all three domains had recovered to reach a plateau. About 45% of patients achieved potency, and the median time to achieve day and night time continence was 9 and 12 months respectively. Lower age and NVBs spared during surgery were found to be significantly associated with the earlier achievement of potency, day and night time continence, as well as better urinary and sexual summary QOL scores. Conclusions Pitcher pot neobladder achieves satisfactory long‐term functional and QOL outcomes with negligible CISC rate. Results were superior with incremental nerves spared during surgery.


| INTRODUC TI ON
Bladder cancer has the second-highest incidence rate among all genitourinary malignancies. 1 Radical cystectomy remains the standard treatment for the muscle-invasive disease. A systematic review by the ICUD-SIU International Consultation on Bladder Cancer concluded in favour of orthotopic neobladder (ONB) to have a better quality of life (QOL) in comparison to other forms of urinary diversion (UD) in the short and medium-term. 2 However, most studies analysing QOL were cross-sectional, with scarce longitudinal data.
We preferred Studer neobladder (SN) in the initial years due to the simplicity of design. 3 However, the inability to make the ONB reach the urethral stump in few patients prompted us to modify SN by creating a neourethra using a part of the ileum, thus aiding anastomosis without tension by providing extra length. 4 The final appearance resembled an Indian earthenware container called a "pitcher pot." The ease of neourethral anastomosis helped when we innovated the technique to reduce the length of surgical incision to 8-12 cm (mini-lap radical cystoprostatectomy). 5 Ultimately, pitcher pot ONB became our default preference in every case irrespective of any consideration about the mesentery's length.
However, theoretical concerns existed about the possibility of an "accordion" or "concertina" effect whereby the neourethral tube could kink, leading to bladder outlet obstruction. Here we describe a decade of our experience with "pitcher pot" ONB, emphasising longterm functional and QOL outcomes, including complications.

| MATERIAL S AND ME THODS
Ours is a tertiary level regional cancer center, and a prospective registry of all surgical cases is maintained. Treatment protocols, including indications and contraindications to ONB, follow the National Comprehensive Cancer Network (NCCN) guidelines. 6 We do not fashion neobladder in those with locally advanced tumours and restrict neoadjuvant chemotherapy to those with suspected T 3 or N1 disease on pre-operative imaging. Adjuvant chemotherapy was given Since 2011 performing cystectomy robotically became our preferred approach unless the patient picked open mini-lap radical cystoprostatectomy surgery due to cost constraints. The "sandwich technique" for fashioning ONB was performed, where cystectomy was performed robotically, and the specimen was delivered via a small periumbilical incision which was also used to fashion the ONB extracorporeally. The robot was docked to complete the vesicourethral anastomosis. Recently, we have even begun to fashion this neobladder completely intracorporeally; however, a detailed description of the technique and outcomes is part of a separate manuscript.

| Follow-up schedule
The patient was discharged with maintenance antibiotics for 30 days.
Following suture removal and review of histopathology to assess the need for any adjuvant chemotherapy on the 14 day, patients were instructed to report initially after 6 weeks of surgery. Subsequent visit schedule was once every 3 months for the first 2 years; every 6 months for the next 3 years; and then annually once afterwards. Imaging and laboratory workup for any metabolic abnormalities at each visit followed NCCN guidelines. For the first 2 years, complete blood count, a comprehensive metabolic panel with liver and kidney function tests (including electrolytes), and blood gas analysis were performed every 3-6 months. In the years 2 through 5, the frequency of tests was reduced to once every 6 months, and vitamin B12 level was assessed in addition. After year 5, the frequency of tests was reduced to once per year. Routine urodynamic studies were not performed; however, all patients were taught positive life style changes such as pelvic floor exercises, drinking habits, maintaining healthy weight, renewed instructions on voiding techniques, and time intervals (especially at night time using an alarm clock). Any recorded complication was graded by Clavien Dindo classification; further dichotomized as major (≥3a) or minor (<3a). 7 QOL was assessed at each visit using Bladder Cancer Index (BCI), which is a disease-specific responsive instrument during surgery were found to be significantly associated with the earlier achievement of potency, day and night time continence, as well as better urinary and sexual summary QOL scores.

Conclusions:
Pitcher pot neobladder achieves satisfactory long-term functional and QOL outcomes with negligible CISC rate. Results were superior with incremental nerves spared during surgery.

K E Y W O R D S
neobladder, quality of life, radical cystectomy, robot-assisted radical cystectomy, urinary bladder neoplasms, urinary diversion, urinary incontinence JAIPURIA et Al.

| 293
applicable to the entire spectrum of localized bladder cancer. 8 It was initially described in 2007 and comprehensively summarized "urinary," "bowel," and "sexual" health domains of QOL via 36 items subdividing each domain into "function" and "bother" subdomains. The final score of each main domain or subdomain ranges from 0 to 100, with a higher score implying better QOL. Patients self-administered the questionnaire at each visit (including first pre-operative visit). In case of difficulty with language or interpretation, they were aided by a trained nurse practitioner with English as a native language.
With institutional ethics committee approval, we retrospectively collected data from prospectively maintained surgical registry for all male patients with localized bladder cancer who underwent The patient was defined to be day and night time "continent" when he reported "total control" in response to items 26 and 27 of BCI, which assess "what response best describes your urinary leakage while awake" and "sleeping during past 4 weeks" respectively.
The patient was defined to be "potent" if his response to item 56 of BCI assessing "ability to function sexually during the last 4 weeks" was at least "fair." We aimed to determine secular longitudinal trends of outcome parameters and uncover prognostic associations between them and biologically plausible perioperative variables.

| S TATIS TI C AL ME THODS
Quantitative data with non-parametric distribution are presented as median (interquartile range [IQR]), whereas standardized BCI scores are presented as mean (standard deviation [SD]). Count data are summarized as numbers (proportion).
For multivariable analysis, a list of perioperative variables having a biologically plausible association with continence, potency, and post-operative BCI QOL domains was drawn including type of surgery, Body Mass Index (BMI), T and N stage, neurovascular bundle (NVB) sparing status, age, and related pre-operative BCI QOL domain score. Charlson Comorbidity Index score was omitted as ONB was not offered to patients with significant comorbidities, and age remained the only factor contributing to higher scores, which was already accounted for.

| Analysis of potency and continence
Cox proportional hazard models were used for multivariable analysis of the achievement of day and night time continence. Firth's penalised maximum likelihood survival analysis was performed for multivariable analysis of potency as a dependent outcome to overcome the problem of non-convergence of maximum likelihood estimate. 9

| Analysis of BCI QOL domains
Two-level (time as level 1, patients as level 2) random intercept mixed effect (maximum likelihood random-effects type) multivariable model with each BCI QOL domain as the dependent outcome was created, with the same set of perioperative factors as independent variables (treated as fixed effects) as mentioned previously.
The entire data set was used for analysing secular trends of BCI QOL domain scores, serum creatinine, bladder capacity, and PVRU. For multivariable and multilevel analysis, we restricted the dataset to the first 2 years of follow-up as outcomes plateaued beyond that time. It was almost universal to see patients miss some scheduled follow-up visits over the extended study duration. Such events were mostly noted after the second year of follow-up and were considered "missing at random" during the first 2 years for analysis. Descriptive statistics were analysed using MedCalc v15.8. Mann-Whitney U-test was used for comparison of quantitative data, except for normally distributed BCI QOL domain scores which were analysed using t-test (with Welch correction assuming unequal variances). Between-group comparison for count data was made using Chi-square or Fisher's exact test (if columns had less than five patients) as appropriate. Stata SE v14.2 was used for multilevel modeling; remainder analysis, including graphing, was done using the R program (v3.6.1). α < .05 was set as significant before-hand. Table 1

| Potency, urinary continence, and reservoir functional outcomes
Supplementary Figure B depicts the cumulative probability curves for achieving potency, daytime and night time continence for the entire study cohort restricting the sample to the first 24 months (as recovery beyond this time frame was rare). For the overall group, the median time to achieve day and night time continence was 9 (95%CI 9-12) and 12 (95%CI 12-15) months respectively. Four (<2%) patients did not achieve continence, and 130 (55%) patients didn't achieve potency. Supplementary

| Multivariable mixed effect multilevel models for QOL outcomes
Supplementary

| Complications
Supplementary  and osmotic shift of water into concentrated urine within the reservoir. As innervation plays a crucial role it is not surprising that others have also found any degree of nerve sparing to be associated with improved night time continence, which improves further with time. 11 Better functional outcomes translate to better urinary and sexual domain summary QOL scores.

| Maneuvres to resolve short mesentery and experience of others with neourethral modification
Short mesentery is an occasional concern needing surgeons' attention while forming orthotopic neobladder. Some maneuvres to resolve it are common knowledge such as reducing the Trendelenburg tilt (during robotic surgery) and deeper incision in the distal mesentery of the isolated bowel limb. 12 Further options include step ladder peritoneal cuts drawing from the experience of gastrointestinal surgeons. 13 We described the creation of a neo-urethra to resolve Chandra et al. modified the Padua neobladder to construct an offset neourethral opening, which "facilitated ease in reaching the native urethra (even in obese individuals) and made a dependent funnel that promotes better bladder emptying. 16 The bladder neck contracture rate was 2% in their series of 160 patients. Giampaolo et al. modified the SN to create a conical distal part that eased the urethroneovesical anastomosis and reduced anastomotic tension, which they hypothesized reduced the anastomotic stricture rate to 2.7% in their series of 36 patients. 17 Despite all efforts, if mesentery still does not allow an ileal neobladder then sigmoid neobladder can be considered which may provide a better chance at spontaneous voiding, though at the cost of lower patient satisfaction. 18

| Voiding
Though the initial drive to innovate pitcher pot neobladder was Explaining CISC has ceased to be a part of our routine care protocols since over a decade now. Similar excellent spontaneous voiding rates have been described with all neourethra type modifications of the neobladder. However, an 8.8% dysfunctional voiding rate (independent of physical obstruction to bladder outlet) necessitating CISC has been described by others for SN. 19 A recent series has reported a CISC rate of 22% with SN necessitated by "bladder overdistension, deteriorating renal function, or recurrent urosepsis despite timed voiding". 20 Nerve-sparing and younger age have been found associated with improved CISC rates. 21  SN. 23 Resecting such folds are safe, and the surgeon should limit oneself to resecting the mucosal layer only, aiming to achieve an unobstructed passage. With due diligence, spontaneous voiding can be achieved, and bladder perforation is not yet reported. 23,24 It is essential to understand that pitcher pot modification does not need an additional length of the bowel to be sacrificed, but only requires central 5 cm portion to be fashioned into a neourethral stump. Hence, it does not predispose patients to any higher risk of metabolic dysfunction than the conventional SN.
We observed a lower "major" and "any" complication rate with robotic surgery, and all neobladders were fashioned via a sandwich approach. Literature comparing both approaches' complications is controversial; however, a recent review noted a trend toward lower complications with robotic surgery. 25  It remains conjectural if robotic surgery also allows a better urethral anastomosis.

| Limitations
We have not directly compared pitcher pot with SN and, thus, our results should not be concluded to be superior by indirect comparison of historical data. Further, patients in our cohort are relatively younger though we equally offered ONB to all patients less than 70 years of age. BCI has to be self-administered, but many patients were not native English speakers. We tried to reduce the interviewer bias by ensuring that an independent trained nurse practitioner specialising in rehabilitating patients with urinary diversions and postprostatectomy urinary incontinence administered the questionnaire.

| CON CLUS ION
Pitcher pot ONB achieves satisfactory long-term functional outcomes with negligible CISC rate. Patients achieved urinary domain QOL scores similar to pre-operative levels by the end of one year.
Sparing of NVBs was found to be the most substantial modifiable

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interest.

I N FO R M E D CO N S E NT
Informed consent was obtained from all individual participants included in the study.