Oncological and functional outcomes of organ‐preserving cystectomy versus standard radical cystectomy: A systematic review and meta‐analysis

Abstract Introduction Radical cystectomy (RC) is historically considered the gold standard treatment for muscle invasive and high‐risk non‐muscle invasive bladder cancer. However, this technique leaves the majority of patients of both sexes with poor sexual and urinary function. Organ‐sparing cystectomy (OSC) techniques are emerging as an alternative to the standard procedure to preserve these functions, without compromising the oncological outcomes. We present a systematic review and meta‐analysis of the published literature. Methods MEDLINE, Embase and Web of Science were systematically searched for eligible studies on 6 April 2021. Primary outcomes studied were both oncological outcomes, specifically overall recurrence, and functional outcomes, specifically sexual function, and daytime and nighttime continence. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated. The PROSPERO registration reference number was CRD42018118897. Results From 13 894 identified abstracts, 19 studies (1886 male and 305 female patients) were eligible for inclusion in this review. These studies included patients who underwent either whole prostate, prostate capsule, seminal vesicle, nerve, uterus, ovary, vagina and fallopian tube sparing techniques. Four studies included only female patients. Thirteen studies reported oncological outcomes, and overall recurrence rate was similar between the two groups (five studies; OR 0.73; 95% CI 0.38–1.40, p = 0.34). Thirteen studies reported on male sexual function. In men, OSC had significantly greater odds of retaining potency (five studies; OR 9.05; 95% CI 5.07–16.16, p < 0.00001). Fourteen studies (13 on males and 1 female) reported urinary outcomes. In men, OSC demonstrated greater odds of daytime (seven studies; OR 2.61; 95% CI 1.74 to 3.92, p < 0.00001) and nighttime continence (seven studies; OR 2.62; 95% CI 1.76 to 3.89, p < 0.00001). Conclusion In carefully selected patients, OSC allows the potential to provide better sexual and urinary function without compromising oncological outcomes. There remains, however, a paucity of OSC studies in females. Further studies are required to make recommendations based on robust clinical evidence.


Conclusion:
In carefully selected patients, OSC allows the potential to provide better sexual and urinary function without compromising oncological outcomes. There remains, however, a paucity of OSC studies in females. Further studies are required to make recommendations based on robust clinical evidence.

| INTRODUCTION
Radical cystectomy is the gold standard surgical treatment for patients with muscle-invasive bladder cancer, or with non-muscle invasive bladder cancer but at high risk of progression, or after failure of intravesical Bacillus Calmette-Guérin (BCG) therapy. 1,2 In males, this operation involves removal of the bladder, prostate gland, seminal vesicles and neurovascular bundles ( Figure 1). In females, the radical surgery involves removal of the bladder, uterus, ovaries and anterior vaginal wall ( Figure 2). However, this en bloc removal of the organs results in debilitating sexual dysfunction with serious lifestyle implications in younger patients. [3][4][5] First described by Marshall and Whitmore in the 1940s, open RC was the primary surgical technique to treat muscle invasive bladder cancer-though it carried significant perioperative morbidity and mortality. 6 The advent of minimally invasive/laparoscopic cystectomy in the 1990s aimed to reduce adverse outcomes. Recent randomised control trials demonstrated fewer complications whilst achieving comparable oncological outcomes, though requiring longer operating times. 7 Owing to technological advancements, robotic-assisted RC has grown in popularity in high volume centres. Numerous studies highlight similar oncological outcomes and lower adverse outcomes, with the potential to improve surgeon precision and dexterity whilst reducing surgeon fatigue, though higher operating costs have restricted its widespread adoption. 8 Because of increasing awareness and concerns about functional implications of standard RC, there is growing interest in organ-sparing cystectomy (OSC) techniques. These techniques aim to maintain similar oncological outcomes to RC but with improvement in sexual and urinary outcomes. In males, prostate-sparing cystectomy was first described in 2002 and involves sparing the prostate gland, seminal vesicles, vas deferens and neurovascular bundles. 9 Alternative techniques include capsule-sparing cystectomy, where just the prostatic capsule is preserved after enucleating the inner part of the prostate gland. 10,11,12 In seminal vesicle-sparing cystectomy, the seminal vesicles, vas deferens and neurovascular bundles are preserved. 13,14 Lastly, in the neurovascular bundle-sparing cystectomy, the nerve bundles are preserved. 15 F I G U R E 1 Diagram of male pelvic anatomy 3 In females, organ-sparing techniques are less well described.
These have included sparing of the uterus, fallopian tubes, ovaries and anterior wall of the vagina. 16 Alternative techniques include vaginal-sparing cystectomy, where the anterior wall of the vagina is preserved, 17 and neurovascular bundle-sparing cystectomy. 18 Given the relative paucity of organ-preserving cystectomies, there is a lack of consensus in regard to the benefit of these techniques in the holistic management of bladder cancer patients. The aim of this systematic review is to provide an update of results on the role of organ-preserving techniques in the management of bladder cancer patients of either sex suitable for OSC.

| Search strategy
The protocol for this review has been published online in the PROSPERO database (CRD42018118897). 19

| Eligible study types
All study designs comparing the relevant interventions were considered for inclusion. Case series involving OSC were included if they involved over 50 patients. Studies reported in English, or any other language with an accessible English translation, involving human participants since 2000 were included.

| Eligible participants
The participants of interest were patients, male or female, with bladder cancer undergoing cystectomy for curative intent in the primary setting. The patients with bladder cancer, either muscle-invasive (MIBC) or high-risk non-muscle-invasive (NMIBC), and any stage up to T4 Nx/N1M0 undergoing cystectomy were included. Adjuvant treatments were permissible.

| Eligible interventions and comparators
The intervention of interest was pelvic OSC. For men, this included prostate-sparing, capsule-sparing, seminal vesicle-sparing and neurovascular bundle-sparing cystectomies. In women, this included uterussparing, ovary-sparing, vagina-sparing cystectomy and neurovascular bundle-sparing cystectomy. The comparator was standard RC, where pelvic organ sparing was not attempted.
We also included studies that compared individual organ-sparing techniques, without a comparison to standard RC, for example, a study comparing capsule-sparing cystectomy and seminal vesiclesparing cystectomy. As mentioned, we also included case series of a single technique if over 50 patients were included.

| Outcome measures
Primary outcomes of interest were both oncological and functional.
The oncological outcomes were assessed by reported positive surgical margins, local recurrence or metastatic disease (including site and time F I G U R E 2 Diagram of female pelvic anatomy 3 of diagnosis), summated overall recurrence, recurrence-free survival, progression-free survival disease-free survival and overall survival after 2 years. The data regarding adjuvant treatments and proportion of orthotopic neobladders were also collected.
The primary functional outcome was sexual function after surgery, as compared to preoperative status. In males, sexual function (potency) was assessed from subjective reporting on erectile function and questionnaires such as International Index of Erectile Function-5 (IIEF-5). We also planned to analyse fertility data, ability to achieve orgasm, and adjuvant treatments. For female patients, we extracted data pertaining to vaginal length, ability to have penetrative sex and the use of hormone-replacement therapy.
The secondary outcomes were measures of urinary function, including day and night continence (as measured by questionnaires), number of pads used and self-reported outcomes. Urodynamic study data were also extracted in patients who underwent orthotopic neobladder formation or other functional assessments.

| Assessment of risk of bias
This was dependent on the study design. The Cochrane Risk of Bias 2.0 tool was used to assess randomised-controlled trials (RCTs), 20 the risk of bias in non-randomised studies of interventions tool for nonrandomised comparative studies (ROBINS-I), and the Murad tool for single-arm case series. 21,22

| Subgroup analyses
Because of the nature of the intervention, male and female patients were assessed separately. We also performed subgroup analysis according to the type of OSC, the modality (robot assisted, laparoscopic and open) and according to differences in how functional outcomes were measured, for example, using questionnaires, subjective reports or other measures.

| Data analysis
A qualitative synthesis was performed, with discussion of possible explanations, and a subsequent summation in the conclusion. Metaanalysis was performed to compare local, metastatic, and overall recurrence rates; potency; and day and night continence at 12 months. Odds radios (OR) with 95% confidence intervals (95% CI) were calculated. In the presence of heterogeneity (I2 > 50%), a random-effect model was used. Otherwise, a fixed-effect model was used. Statistical significance was defined by p value of <0.05. Metaanalysis was performed using Cochrane RevMan (v.5.4, 2020; Cochrane Initiative). The quality of our effect estimates was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) rating system. 23 3 | RESULTS  Table 1 shows the study characteristics. Eighteen studies were observational. Eight of the studies were prospective, of which three were RCTs, 24,40,41 three were cohort studies 27,28,36 and two were case series. 35,42 Thirteen studies were retrospective, comprising 10 cohort studies 25,26,29,[32][33][34][37][38][39]43 and 3 case series. 9,30,31 The mean or median follow-up durations were reported in all but one study 41 (Table 1).

| Oncological outcomes
In total, only four studies included comparative data suitable for meta-analysis of oncological outcomes, which were divided into subgroups: local recurrence and metastatic disease. All three of the studies used in the meta-analysis of local recurrence were male only. 25,26,43 In contrast, one of the two studies used in the metaanalysis of metastatic disease included exclusively females. 33 The meta-analysis of local recurrence rates featured three studies, two analysing prostate-sparing techniques and the other nervesparing technique. 25,26,43 There were similar local recurrence rates between organ-sparing and RC papers (OR 0.73; 95% CI 0.34-1.55, The meta-analysis of metastatic disease featured two studies and showed similar rates of metastatic recurrence between OSC and RC (OR 0.68; 95% CI 0.30-1.19, p = 0.18). 33,43 In terms of metaanalysis of overall recurrence, when both local and metastatic data from these four studies were pooled, the overall recurrent rate was similar between organ-sparing and RC patients (OR 0.70; 95% CI 0.44-1.10, p = 0.12) 25,26,33,43 (Figure 4).

| Sexual outcomes
Male sexual function was evaluated in 13 studies, as highlighted in Table 6. 9,[24][25][26][27]29,31,32,36,38,[40][41][42] To assess potency, the primary functional outcome, seven studies used the IIEF-5 questionnaire. However, other means of assessing potency, such as the Erectile Hardness Score (EHS), Bladder Cancer Index (BCI) and a self-designed questionnaire were also used in one study each. Three studies did not explicitly state how patients' potency was assessed. 9,36,42 Of the aforementioned studies, only five had data suitable for comparison in a meta-analysis. All five studies analysed male patients only. Four of the studies compared nerve sparing 26,27,32,40 , whereas the fifth compared prostate sparing. 25 The patients undergoing an OSC had significantly better postoperative potency outcomes of 80.95-100% compared to 0-17% in the RC group. One study reported a reduction from preoperative potency to postoperative potency of 0.5% in nerve-sparing cystectomy compared to a greater reduction of 9.9% in standard RC. 40 The meta-analysis suggests organ-sparing techniques are associated with superior outcomes in terms of retaining potency (OR 9.05; 95% CI 5.07-16.16, p < 0.00001) ( Figure 5).  Three studies compared different organ-sparing techniques with regards to potency rates. The first two studies analysed capsulesparing and nerve-sparing cystectomies. 24,29 The second of these papers also compared these potency outcomes to a third cohort of patients undergoing seminal vesicle sparing. 29 (Table 6).

T A B L E 1 Baseline characteristics of all included studies
In total, seven studies reported on the use of adjuvant treatments to aid sexual rehabilitation. The percentage of patients who required treatment to restore sexual function ranged from 1 to 100%, as defined by the trialists. 24,26,29,31,36,38,40 All these patients were considered to have maintained potency status. There was no relevant data regarding patients' fertility or capability to orgasm ( Table 6).
As there was only one paper studying sexual outcomes in female patients, no meta-analysis could be performed. This study compared the postoperative sexual function in 13 females undergoing either a nerve-sparing or RC using the Female Sexual Function Index questionnaire. 37 Those who underwent a nerve-sparing cystectomy averaged a score of 22.3 compared to 11 for RC. There was no comment made towards patients' vaginal length, ability to have penetrative sex or use of hormone-replacement therapy (Table 7).

| Urinary outcomes
Fourteen studies analysed continence rates using several methods, including questionnaires such as the BCI, and number of pads. Twelve studies reported 100% of patients having orthotopic neobladder formation. 9,24,25,27,28,31,32,34,35,38,41,42 One study reported 86.4% of patients having an orthotopic neobladder and the remainder 13.6% of patients having an ileal conduit, with continence outcomes only reported in the patients with orthotopic neobladders. 26 One study did not specify the type of urinary diversion. 29  to measure continence and did not indicate whether this was daytime or nighttime continence 35 (Table 8).
Three studies examined the difference in continence rates between various types of OSC. 24   compared to a reduction of 28 AE 33 points in nerve-sparing cystectomy (p = 0.1). 24 The third study reported greater daytime and nighttime continence rates of 91.5% and 77.8%, respectively, in prostatesparing cystectomy compared to 52.2% and 21.1% in nerve-sparing cystectomy, respectively (p < 0.001) 38 (Table 8).
Only one study performed urodynamic assessment, showing better urodynamic outcomes in male patients who had nerve-sparing cystectomy compared to RC. The study observed a significantly longer functional urethral length of 34.8 mm in the nerve-sparing cystectomy group, compared to a length of 30.1 mm in the RC group. Furthermore, the study reported a greater maximum urethral pressure of 82.8 cm H20 in the nerve-sparing cystectomy group, compared to 77.9 cm H20 in the RC group. 27

| Risk of bias assessment
The data regarding the risk of bias assessment is detailed in Tables 9-11. Regarding the three RCTs included, risk of bias was rated as low risk in one study, 41 and there were some concerns with the other two studies 24,40 (Table 9). Moderate risk of bias was found for 12 of the non-randomised comparative studies, [25][26][27][28][29][32][33][34][35]38,39,43 with serious risk of bias found for one 37 (Table 10). Of the five case series included, there were some concerns with three, 9,31,37 whereas two were deemed low risk 30,42 (Table 11).

| Summary of findings
Based on the GRADE rating system of our meta-analyses, overall recurrence, daytime continence, and nighttime continence were assigned a low rating for quality of evidence. Potency was assigned a very low rating (  (Figures 4-7).

| Previous systematic reviews
Two previous systematic reviews comparing OSC with RC have been published, with both focussing on oncological and functional outcomes. One review compared the two techniques exclusively in men, 44 and the other exclusively in women. 45 The systematic review of male patients suggests that prostate-, capsule-, or nerve-sparing cystectomy can lead to superior sexual outcomes without jeopardising oncological outcomes. This review also notes limitations, such as moderate quality evidence, and the need for carefully selecting patients for OSC. 44 Selection criteria based on the age of the patient, type and position of bladder cancer, and family history of prostate cancer may influence the choice of prostate or capsule-sparing approaches.
The systematic review of female patients concluded that organsparing techniques were comparable to RC for oncological outcomes, with superior sexual and urinary function outcomes. However, this review comprised mostly small retrospective case series, with significant risk of bias and confounding. 45 Our present review provides a more up-to-date and detailed analysis of organ-sparing techniques in comparison with standard RC in both sexes. We include metaanalyses of both oncological and functional outcomes, excluding smaller single-arm studies and highlighting the need for more robust RCTs and female comparative studies.

| Oncological outcomes
There is no consensus over the best surgical approach to balance oncological and functional outcomes. Indeed, RC is performed in patients with no observable evidence of disease in the surrounding organs. 46 The disadvantage of RC in these patients is obvious: loss of sexual and urinary function is greatly associated with lower healthrelated quality of life. 3,5 There is a preconceived notion that if RC is not performed, there will be a higher risk of local recurrence or metastatic disease, most likely conferring reduced mortality. 44,45 Interestingly, our meta-analysis shows that there was no statistically significant difference in terms of overall recurrence between  When used in tangent with preoperative imaging methods such as magnetic resonance imaging (MRI), they may help guide bladder cancer risk stratification and the use of organ-sparing techniques.
Recent systematic review analysed the use of MRI as part of the Vesical Imaging Reporting and Data System (VI-RADS), which can be used to distinguish MIBC from NMIBC using multiparametric MRI, concluding that its use confers good performance and reproducibility. 49,50 Though, its application in organ-sparing risk stratification may be limited by its purported propensity to overstage bladder cancer in up to one third of patients. 51

| Functional outcomes
The rationale behind improved functional outcomes following OSC is that the sparing of nerves or various pelvic organs allows the preservation of neurovascular bundles that control potency and continence.
Erectile function in males is dependent on parasympathetic innerva-

| Limitations
OSC is an emerging technique in the treatment of bladder cancer. This systematic review provides an up-to-date analysis of this technique in both sexes from three important perspectives: oncological, sexual and urinary. However, this review does present with some limitations.
Firstly, the quality of the studies included were rated as either low or very low (Table 12). There were only three RCTs, and the majority of the studies are observational. Observational studies suffer from selection bias, and results often have to be used with caution.
Secondly, the reporting of outcomes between studies was inconsistent. In terms of oncological outcomes, there was incomplete reporting of overall survival, local and metastatic recurrence. Regarding functional outcomes, different methods were used to measure the same outcome, as evidenced through the use of both the IIEF-5, which measured multiple domains associated with sexual function and the EHS, which relied solely on self-reported erection strength.
There were inconsistencies with what each study defined as either continence or potency based upon the scoring questionnaires.
For example, some papers classed patients as potent when able to achieve an erection with the use of medication such as alprostadil, 36 whereas others defined potency as maintaining an erection without medication. 26 Furthermore, not all studies specified the exact criteria for defining potency or continence. 9,24 The studies in this review showed a lack of standardised followup duration. This may impact the present analysis of results because the data were recorded at different times. Furthermore, the lack of long-term follow-up limits the use of the meta-analysis in predicting any lasting effects of OSC.
There is a significant lack of female studies. This is likely because of the greater prevalence of bladder cancer amongst males when compared with females. 54  readmission after cystectomy than males because of complications. 55 Although a previous systematic review included 15 studies analysing OSC in females, these studies did not meet the inclusion criteria because of small sample sizes or being single-arm studies. 56 This review has also not discussed further complications of the surgery, for instance, the rate of bleeding, infection, bowel obstruction and urethral strictures. Analysing the rates of these complications, in the context of OSC and RC, can further provide a more detailed comparison of these two techniques, especially given the morbid nature of cystectomy.

| Recommendations
1. Based on the low quality evidence in this review, there is potential for OSC to be considered where possible, instead of RC, when deciding the surgical management of carefully selected bladder cancer patients in order to preserve sexual and urinary function.
Surgical planning may be aided by the use of preoperative imaging tools such as VI-RADS.
2. Future OSC RCTs, especially comparing oncological outcomes with standardised outcome reporting and long-term follow-ups, as well as female studies, are needed to add to the evidence base.
3. Research comparing single versus multi-organ sparing cystectomy and comparing different types of OSC will be beneficial.

| CONCLUSION
There is a potential advantage to OSC regarding sexual and urinary function with equivalent oncological outcomes in carefully selected men when compared to RC. Our results would benefit from more standardised functional outcome reporting, further study of oncological outcomes in robust RCTs and higher quality OSC studies in women.

ACKNOWLEDGEMENT
This work was supported and funded by King's College London [JISC].

CONFLICTS OF INTEREST
All authors declare no conflicts of interest as per the ICMJE COI.