Comparison of the Safety and efficacy of enucleation of nonmuscle-invasive bladder cancer versus transurethral resection of nonmuscle-invasive bladder cancer: a systematic review and meta-analysis

Purpose: Transurethral resection of bladder tumor (TURBT) via a wire loop has been regarded as a standard procedure dealing with nonmuscle-invasive bladder cancer (NMIBC) for a long time, and en-bloc resection of bladder tumors (ERBT) is a promising alternative to conventional transurethral resection of bladder tumor. Methods: We performed a systematic review and meta-analysis based on randomized controlled trials (RCTs) and non-randomized controlled trials(nRCTs) and some retrospective studys which were searched and sreened. A systematic search up to the 1st of March 2019 was conducted in the following databases: PubMed, Web of Science,the Cochrane Central Register of Controlled Trials and Embase. Data such as resection techniques, morbidity, specimens’ quality, and recurrence were collected from the manuscripts. Results: Sixteen studies were included in this systematic review finnally.No statistical difference is detectded between the two techniques regarding operative time,the 2-year recurrence-free survival and the occurrence of ureterostenosis.Analysis of some complications showed that ERBT was better than TURBT for NMIBC, including obturator nerve reflex, cystic stimulation rate, bladder perforation, operation time,duration of catheterization, postoperation duration of postoperation bladder irritation and length of hospital stay. In addition, detrusor miss rate is lower in ERBT group,the 1-year and 3-year recurrence-free survival improved in the ERBT group than in the TURBT group. Conclusions: This systematic review and meta-analysis suggests that ERBT technique is a feasible, safe procedures that may provide an alternative treatment for NMIBC.


Introduction
Bladder cancer is the ninth most common cancer and the fourteenth lethal cancer worldwide [1] . It is defined as an international public health problem for high recurrence rate, high economic costs and high mortality [2] . Approximately 75% of patients diagnosed bladder cancer present with non-muscle-invasive bladder cancer (NMIBC), including mucosa (Ta), submucosa (T1) and carcinoma in situ [3] . A standard procedure of nonmuscle-invasive bladder cancer is transurethral resection of bladder tumor (TURBT), and it's necessary, however, to improve the performance of TURBT because of the residual tumor rates (up to 33%) and recurrence rates (up to 75%) after TURBT [4] . With the technological advances achieved in endourology, technique of en-bloc resection of bladder tumors (ERBT) is popularized and mastered by clinicians gradually since its first report by Ukai and colleagues in 2000 [5] . Two decades witnessed the publishment of several literatures pertaining to this very technique by using various instruments. However, it still remains a matter of debate about the safety and efficacy of ERBT, mainly in that most studies comparing ERBT to TURBT were, instead of RCT, nonrandomized controlled trials (NRCTs) and retrospective studies. In addition, inadequate sample sizes and data obtained from a single center were not capable of providing a convincing conclusion. Consequently, a systematic review and meta-analysis were applied to validate differences between the intraoperative and postoperative situation of both procedures.

Literature Search Strategy
Literature was searched by two reviewers (Ting Huang and Qing Yang) independently up to 21st March 2019. We searched Web of Science, the Cochrane Central Register of Controlled Trials and Embase without publication date restrictions. The article language was restricted to English. The following search terms and words were used: "bladder tumor", "bladder cancer", "bladder carcinoma", "transurethral resection", "TURBT", 4 "resection of bladder tumor", "resection of bladder tumor", "en bloc resection" and "enucleation".

Inclusion and Exclusion Criteria
Studies were included only if the following criteria were fulfilled: (1) studies that compared the safety and efficacy of ERBT with traditional TURBt in adult patients diagnosed as non-muscle-invasive bladder cancer; (2) the study was an RCT or a controlled clinical trial, including nRCT and retrospective studys; (3) the primary outcomes of retrospective studies were reported include complications, duration of catheterization, hospital stay, recurrence rate, detrusor miss rate, and at least three of the primary outcomes were included.
The exclusion criteria were as follows: (1) studies that did not compare ERBT with traditional TURBt; (2) The study was not an RCT or CCT; (3) studies that cannot find full text or did not provide the sufficient date.

Data extraction and outcome of interest
After being reviewed by two searchers (Ting Huang and Qing Yang), data wanted from these studies was extracted and filled into a specifically designed form including studies and population characteristics, surgery techniques, complications, duration of catheterization, hospital stay, recurrence rate, methodological quality and other relevant information. We also managed to contact the authors to obtain unpublished data. When there was a disagreement between the two researchers, a third researcher (Haixiao Wu) will participate in a discussion about the divergence until a consensus was achieved.

Assessment of Quality and Risk of Bias
Two authors (Ting Huang and Qing Yang) assessed the quality of the included literatures according to the type of research. As to RCTs, the Cochrane Collaboration's risk of bias tool [6] was used to evaluate literatures according to the following items: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other biases. Each item was assigned a risk value (i.e., low risk, high risk, or uncertain). As to nRCTs and retrospective studies, the Newcastle-Ottawa Quality Assessment Scale [7] was used to evaluate literatures, which is consist of three parts: patient selection, comparability of the study groups, and assessment of outcomes. We get a final score of each study then evaluated the quality of the studies in accordance with the final score: 7-9 is considered as "good", 4-6 is considered as "fair", 0-4 is considered as "poor". Similarly, any divergence was resolved by discussion until consensus was achieved.

Statistical Analysis
Statistical analysis was conducted using Stata 14.0. The odds ratio (OR) was used for dichotomous variables, and mean difference (MD) was used for continuous data, both with 95% confidence intervals (CI). Methodological heterogeneity was assessed during selection, and statistical heterogeneity was measured using the χ2 test and I2 scores. If χ2 heterogeneity was reported as P > 0.1 and I2<50%, heterogeneity was considered low.
A fixed-effects model was used to assess the data of included studies with minimal or no heterogeneity while a random-effects model was applied. A P-value for significance was set at <0.05. In addition, RevMan5.3 was used for assessing the quality of RCTs.

Results
Search Results 854 publications were screened after a systematic search.404 publications were removed as duplicates, then 364 publications were removed after screening the titles and abstracts.50 full-text were screened out, including 34 were review articles. 16 literatures were finally screened out after removing 3 publications lacking of sufficient date. We 6 described the study procedure's details in Figure 1.

Study Characteristics
A total of 16 trials with 2262 participants were included, of which 1147 and 1115 underwent ERBT and TURBT respectively. The enrolled individuals and tumor characteristics are presented in Table 1 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] . The result of our research are based on the prospective studies and retrospective studies are only for reference as few date was available in RCTs, so subgroup analysis stratified by research categories is completed and our conclusions are made based on the prospective studies. Risk of bias are assessed by the Cochrane Collaboration's risk of bias tool [6] in RCTs( Figure 2).The Newcastle-Ottawa Quality Assessment Scale [7] was used to evaluate the quality of nRCTs and retrospective studys, most researches scored 7 except two researches scored 6 The data of outcome of interest We enumerated main outcomes of complications, periopretive and postopretive data extracted from included articles in Table 2 where bias had a great impact on the results,then we get a homogeneous result. After reading the excluded study carefully,we found some mixed surgical techniques were used in ERBT group,and it probably impact the result of the study in obturator nerve reflex.

Discussion
Bladder carcinoma is the most common malignancy of the urinary tract. The worldwide age standardized incidence rate (ASR) is 10.1 per 100,000 for men and 2.5 per 100,000 for women [24] . Although most patients present with non-muscle invasive bladder cancer (NMIBC) (70%), formerly known as superficial bladder cancer which is confined to either the mucosa (stage Ta, carcinoma in situ) or submucosa (stage T1), the high rate of recurrence and long-term monitoring cost much both physically and financially [25] . All mainstream guidelines including guidelines published by American Urological Association(AUA), European Association of Urology (EAU), National Comprehensive Cancer Network (NCCN) recommend TURBT as the gold standard for the initial diagnosis and 8 treatment of NMIBC [26] , and repeat TURBT 2 to 6 weeks after the initial procedure is recommended in patients with high grade T1 tumors, incomplete initial resection or when the specimen contained no muscle tissue [27] . Gontero [28] have shown in a recent study with more than 2000 patients that the most important parameter associated with recurrence-free survival was the detection of detrusor muscle (DM) within the tissue. The authors stated that second resection may be avoided in the presence of DM in high-risk NMIBC. As a matter of fact, a recent retrospective study demonstrated that 70% of included patients had an incomplete initial resection [29] . Complete resection including a sample of the underlying muscularis propria is recommended by the guidelines of the European Association of Urology (EAU) and American Urological Association (AUA) [30,31] .
In order to achieve this goal, appropriate resection techniques were developed and applied in recent decades, including bipolar TURB, photodynamic diagnosis, Narrow band imaging (NBI), Confocal laser endomicroscopy (CLE) and so on. ERBT technique is popularized and mastered by clinicians gradually since it was first reported by Ukai in 2000 [5] .
The feasibility and Safety of en bloc resection has been demonstrated by several researchers. Herrmann [32] confirm the hypothesized potential of ERBT as a concept to overcome limitations of cTURBT with regard to reproducibility of surgical result and limitations of pathological staging in cTURBT specimen. Rohit Upadhyay [33] reported that en-bloc TURBT was safe and gave well-controlled resection of the whole tumor due to better visualization. Yield of detrusor muscle present in the specimen is significantly better with en-bloc TURBT. However, there are some limitations of ERBT like the size and location of the lesion. Bach T deemed roughly 30% of patients are not eligible because of tumor size, formation, and localization [34] . Few surgeons favor ERBT in cases when tumors are located at the anterior and posterior bladder wall, at the bladder cervix, and when tumors exceed the size of 3 cm [35] . EAU outlined this resection techniques depending on the size of the lesion [27] . Many researchers consider that small tumors can be resected by en bloc and larger tumors should be resected separately in fractions [36] . Naselli A [37] concluded that irrespective of the equipment, it was possible to resect the tumor without fragmentation lesions of 4-5 cm whereas the biggest lesion ever treated successfully was 7 cm [38] . Surgeons may master the characteristics of lesions by different kinds of imaging checkups or cystoscopy and assess whether it's suitable for enucleation and make an operative planning before the surgery. In the 7 prospective studies included, no statistically significant differences were found in tumor size or tumor multiplicity [9] .
Our review of the published data of sixteen comparative studies(seven prospective studies and nine retrospective studies) suggested that ERBT was better than conventional TURBT group for NMIBC in following aspects: catheterization time, hospitalization time and the duration of postoperation bladder irritation are shorter in ERBT group than TURBT group.
In addition, the incidence rate of obturator nerve reflex, bladder irritation, bladder perforation is significantly lower in ERBT group. No statistical difference was noted for ureterostenosis rate and the 2-year recurrence-free survival. It is worth mentioning that the detrusor present rate is significantly higher in ERBT group which means specimens of higher quality can get by this technique. And the 1-year and 3-year recurrence-free survival improved in the ERBT group than in the TURBT group. In conclusion, ERBT may decrease the incidence rate of common complication and increase the quality of specimens and recurrence-free survival. The outcomes may related with the procedures of ERBT, surgeons commonly made a circular incision around the tumor at first, this procedure can cut off blood supply to local mucosa and provide a clearer view for the surgery, so that a specific histrionic layer can be recognized which is the major procedure

Conclusions
The latest studies confirm potential of ERBT as a concept to overcome limitations of cTURBT. Although data on longer follow-up are available now, no final conclusion on recurrence can be drawn, our study integrated the date and get a systematic conclusion that ERBT technique is a feasible, safe procedures that may provide an alternative treatment for NMIBC. With the technological progress and innovation, the limitations of the size and location to ERBT may be overcome and the technique translates in to daily clinical practice.

Conflict of interest
We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.   Tables   Due to technical limitations, Table 1 is only available as a download in the supplemental files section.  Figure 1 Diagram of studies identified, included and excluded. 18