Safety and efficacy of en bloc transurethral resection versus conventional transurethral resection for primary nonmuscle-invasive bladder cancer: a meta-analysis

Background The purpose of this meta-analysis is to compare the safety and efficacy of en bloc transurethral resection of bladder tumor (EBRT) versus conventional transurethral resection of bladder tumor (CTURBT). Methods We performed a meta-analysis of relevant articles through November 2019 using PubMed, Embase, and Cochrane Central Register to compare the safety and efficacy of EBRT versus CTURBT. The main endpoint included the operation time (OT), hospitalization time (HT), catheterization time (AT), perioperative period complications, bladder detrusor muscle found in the specimen, the residual tumor on the base, the ratio of the same site recurrence, and 12/24/36-month recurrence rate. Cochrane Collaboration’s Revman software, version 5.3, was used for statistical analysis. Results A total of 19 studies with 2651 patients were included, 1369 underwent EBRT and 1282 underwent CTURBT. Patients treated with EBRT had a significantly lower AT, HT, obturator nerve reflex, bladder perforation, bladder irritation, postoperative complications, and 24-month recurrence rate than those who underwent CTURBT. While no significant difference was found in terms of OT, the ratio of bladder detrusor muscle found in the specimen, the residual tumor on the base, 12-month recurrence rate, 36-month recurrence rate, and the ratio of the same site recurrence. In mitomycin subgroup, EBRT was superior to CTURBT in terms of 12/24-month recurrence rate. Similarly, in the prospective subgroup and retrospective subgroup, EBRT had a lower 24-month recurrence rate than CTURBT. However, no significant difference was found in the low, intermediate, and high-risk group in the light of 12–36-month recurrence rate. Conclusions Based on the included 19 articles, EBRT had a significantly lower AT, HT, intraoperative and postoperative complications, and 24-month recurrence rate than those treated with CTURBT. Well-designed randomized controlled trials were needed to reevaluate these outcomes. Trial registration This meta-analysis was reported in agreement with the PRISMA statement and was registered on PROSPERO 2019 CRD42019121673.


Background
Bladder cancer is one of the most common diseases in the genitourinary system. Approximately 54,9393 new bladder cancer patients have been diagnosed all over the world in 2018, with 19,9922 cases estimated cancer deaths. In other words, bladder tumor accounts for 7% of new cancer diagnoses and 4% of new estimated deaths in men [1,2]. For nonmuscle-invasive bladder cancer (NMIBC), conventional transurethral resection of bladder tumor (CTURBT) combined with intravesical chemotherapy or Bacille Calmette-Guerin (BCG) is the standard treatment [3]. The identification of detrusor muscle in the specimen is an important factor for future treatment and prognosis. However, staging is often inaccurate because of charring of the resected tissues and absence of detrusor by TURBT. Complications such as obturator nerve reflex and bladder perforation may happen during the resection of lateral wall tumors, which is associated with urinary extravasation and neoplasm seeding [4]. Furthermore, the bladder tumor resected into fragments is contrary to the principle of tumor-free technique. Engilbertsson et al. had demonstrated that CTURBT induced the bladder tumor cell into the blood circulation [5]. However, it is now unknown whether CTURBT will increase the rate of metastatic disease. After the TURBT, the probability of recurrence rate reaches 15-61% in 1 year for TaT1, depending on the EORTC score and incomplete resection [3]. Thus, in order to achieve the complete resection, en bloc transurethral resection of bladder tumor (EBRT) has been gradually applied in the treatment of bladder tumor during the past years [3]. It has the ability to resect neoplasm with a 1 cm margin from the tumor base and precisely separate detrusor muscle as well as connective tissue and comply with oncological principles. In addition, the capacity to remove the neoplasm may yield the merit of shorter intervention time, because it avoids piece-bypiece removal by CTURBT, additionally prolonged by necessity to perform repeated hemostasis so as to improve visibility [6,7].

Inclusion and exclusion criteria
The inclusion criteria were as follows: retrospective/prospective/RCT trails; English language; full-text articles; and studies that compared EBRT with CTURBT in the treatment of primary NMIBC (Ta,T1,Tis). The diagnosis of NMIBC was demonstrated by cystoscopy or histological evaluation of tumor tissue. Case-reports, reviews, abstracts, animal experiments, and letters were excluded.

Literature search and data sources
We performed subject terms (MeSH) including "urinary bladder neoplasms" with their single words to search for relevant articles through November 2019 in PubMed, Embase, and Cochrane Central Register. The complete search used for PubMed was (urinary bladder neoplasms [MeSH terms] OR urinary bladder neoplasms [Text word]) AND (en bloc resection OR laser OR needle electrode OR endoscopic submucosal dissection OR Hybrid knife) AND (conventional transurethral resection of bladder tumor OR TURBT). The reference lists of relevant studies were also checked to identify potential records. Literature search and screening articles were achieved by two authors independently. The consensus was reached by discussion if there was any disagreement.

Data extraction
One reviewer noted the study authors, date of publication, level of evidence, surgical method, tumor size, number of patients treated with EBRT or ETURBT, tumor grade, tumor T-stage, the method of intravesical instillation, operation time (OT), catheterization time (AT), hospitalization time (HT), obturator nerve reflex, bladder perforation, bladder irritation, bladder detrusor muscle, postoperative complications, residual tumor on base, 12/24/36-month recurrence rate, and same site recurrence rate. Dates were then verified by another reviewer.

Quality assessment and statistical analysis
The Evidence-Based Medicine in Oxford was used to assess the level of evidence of all included articles [26]. Cochrane risk of bias tool was used to assess the methodological quality of included RCTs [27]. Furthermore, according to the Newcastle-Ottawa scale (including patient selection, comparability of the study groups, and assessment of outcome) [28], we could assess the methodological quality of non-randomized controlled trials.
Dichotomous or continuous data on OT, AT, HT, obturator nerve reflex, bladder perforation, bladder irritation, bladder detrusor muscle, postoperative complications, the residual tumor on base, 12/24/36-month recurrence rate, and same site recurrence were analyzed through Review Manager software, version 5.3 (Cochrane Collaboration, Oxford, United Kingdom). Subgroup analyses were performed based on study type and different therapy of intravesical instillations. Mantel-Haenszel chi-square test and I 2 statistic were performed to assess the impact of study heterogeneity on the result of the meta-analysis. If the P value was > 0.1 and I 2 < 50%, the fixed-effect model was performed. Otherwise, the random effect model was applied for meta-analysis. We used the mean difference (MD) and odds ratio (OR) to compare continuous and dichotomous variables, respectively. Funnel plots were used to evaluate the publication bias. The confidence interval (CI) was set at 95% and the P value < 0.05 was identified as statistically significant.

Quality assessment of included studies
We described the level of evidence of the 19 articles in Table 1. According to the risk of bias graph, four RCTs were all considered high-quality studies, with > 3 kinds of bias were at low risk (Fig. 2). Furthermore, 11 nonrandomized studies [6, 8, 9, 11, 15-17, 20-22, 24] were considered of high quality due to the score ≥ 7 stars (Table 1).

Operative time, hospitalization time, catheterization time
Twelve articles reported the HT, 15 articles reported the AT, and 17 articles reported the OT. Based on 12 included articles [6-9, 12, 13, 15, 16, 18, 21, 22, 24], the patients treated with EBRT had significantly decreased HT compared with CTURBT (P < 0.00001). The MD was − 1. 30 Table 2). While there was a high heterogeneity in all comparisons, which may come from the patient demographics, difference in types of surgery, and tumor characteristics.

The residual tumor on the base
The repeated biopsy on the base was performed by Zhang et al. [14,18] after the tumor was resected. Two pooled articles [14,18] showed that CTURBT had similar residual tumor rate compared with EBRT [OR, 0.47; 95% [Cl], 0.07 to 3.27; P = 0.44] ( Table 2).

Same site recurrence
Five included articles [11,13,18,19,23] evaluated the same site recurrence rate with the follow-up time between 12 and 38 months. Compared with the CTURBT, EBRT had a lower same site recurrence rate, while no significant difference was found between two groups [OR, 0.49; 95% [Cl], 0.21 to 1.14; P = 0.10] (Table 3).

Publication bias
According to the funnel plots, although a publication bias exists in obturator nerve reflex. No significant publication bias was detected for our other results.

Discussion
This meta-analysis showed that compared with CTURBT, EBRT for NMIBC had a significantly lower AT, HT, obturator nerve reflex, bladder perforation, bladder irritation, postoperative complications, and 24-month recurrence. While no significant difference was found in terms of OT, the ratio of bladder detrusor muscle found in the specimen, the residual tumor on the base, 12-month recurrence rate, 36-month recurrence rate, and the ratio of the same site recurrence. In the mitomycin subgroup, EBRT was significantly superior to CTURBT in terms of 12/ 24-month recurrence rate. Similarly, in the prospective subgroup and retrospective subgroup, EBRT had a lower 24-month recurrence rate than CTURBT. However, no significant difference was found in the low, intermediate, and high-risk group in the light of 12-36-month recurrence rate. Therefore, the pooled data lead support to EBRT as a superior method for NMIBC. As technology progresses, CTURBT is widely used in the treatment of NMIBC. However, there remain some limitations needing to be overcome. Firstly, it is inevitable for a tumor with a diameter of over 3 cm to be resected piece-by-piece and then the fragments would be washed out through the cystoscope sheath naturally, which is contradictory to the tumor-free principle. Secondly, detrusor muscle is one of the criteria to assess the completeness of resection. The eschar in the specimen caused by electric coagulation would affect the accuracy of tumor infiltration for its depth, grading, and staging. Thirdly, there is a real possibility for such complications as obturator nerve reflex and bladder perforation to occur during the resection of lateral wall tumors [29,30]. EBRT is a modified method for NMIBC. According to EAU guidelines, it is capable of providing high-quality specimen including muscle layer in 96-100% of the existing cases [31][32][33]. Meanwhile, EBRT could help reduce various complications, for example, obturator nerve reflex, bladder perforation, bladder irritation, and urethral stricture. Despite no significant difference of bladder detrusor muscle present in the specimen observed in our meta-analysis, the residual tumor on the base and same site recurrence rate between groups, detrusor muscle positive rate in EBRT were found superior to CTURBT group (94% vs. 86.9%). Similarly, EBRT revealed a lower residual tumor on the base (0.53% vs. 1.55%) and same site recurrence rate (3.74% vs. 8.69%). EBRT showed a shorter HT, AT, fewer complications, and lower 24-month recurrence rate than CTURBT in the treatment of NMIBC, which is a similar conclusion to that drawn in another meta-analysis published in 2016 [25]. In our meta-analysis, moreover, attempt was made to explore the differences between the two groups with regard to the ratio of bladder detrusor muscle found in the specimen, the residual tumor on the base, 12-month recurrence rate, 36-month recurrence rate, and the ratio of the same site recurrence. Furthermore, subgroups were set up based on the types of study and the characteristics of tumor. Despite the expansion of sample size and research area, the validity of our results was limited by the 12 retrospective studies.
Intravesical chemotherapy or Bacille Calmette-Guerin(BCG)was performed for postoperative patients. The duration and dosage of postoperative therapy varied. Therefore, based on the different therapies of intravesical instillations, a subgroup analysis was conducted to determine the 12/24-month recurrence rate. As revealed by the pooled studies, with regard to 12/24-month recurrence rate, EBRT was clearly superior to CTURBT for the patients receiving mitomycin. In other subgroups, EBRT showed a lower recurrence rate, despite no statistical significance, which suggested that postoperative adjuvant therapy is a crucial influencing factor for the prognosis.
Based on the study type, a subgroup analysis was carried out to evaluate the 12/24-month recurrence rate. Despite no significant difference found in respect of 12-month recurrence rate, EBRT exhibited a lower 24-month recurrence rate than CTURBT in the prospective subgroup (P = 0.02) and retrospective subgroup (P = 0.006), which is statistically significant. Furthermore, in the RCTs subgroup, two pooled studies revealed that 19% and 25% 24-month recurrence rate were observed in EBRT and CTURBT group, which indicates the advantages of EBRT.
The heterogeneity of each study on the pooled results was evaluated by excluding single study sequentially, which led to the results suggesting that the heterogeneity remained at a high level in respect of OT, AT, HT, and bladder detrusor muscle, which is speculated to result from the differences in the characteristics of tumor, demographics, and surgical technology. However, as for 36-month recurrence, the heterogeneity declined from 58 to 0 when the study performed by Cheng et al. was excluded, which indicates that this study should be responsible for the heterogeneity of our included studies. Reading the articles, the EBRT group with the application of HybridKnife had a significantly lower 36-recurrence rate than CTURBT (P = 0.008), while no difference was found in other studies when laser was applied. This might account for this situation. Therefore, the research conducted by Cheng  However, it is worth mentioning some limitations on this meta-analysis. Firstly, this meta-analysis involves a combination of prospective and retrospective studies, which has a potential to result in a significant bias across the studies. Secondly, the characteristics of tumor in our included articles show difference. Some articles included Ta and T1, while other articles involved Ta, T1, and Tis. Moreover, some patients had multiple tumors (including all patients in the study by Liu et al.) and there was a lack of information on how many of them were resected en bloc. Thirdly, the mean follow-up time was as little as 12-36 months. As demonstrated by the pooled studies, EBRT showed a lower 24-month recurrence rate compared with those treated with CTURBT. However, there was no significant difference observed in respect of 12-or 36-month recurrence rate. A sufficiently long follow-up time should be allowed to better compare the recurrencefree survival among different groups. Fourthly, the articles included in this study were restricted to those published in Embase, PubMed, and Cochrane Central Register, as a result of which case-reports, reviews, abstracts, animal experiments and letters were excluded, which is possible to cause potential selection bias and language bias. Fifthly, not all pathology departments put in place a routine to report whether there is muscle present or not and only four out of the 19 studies reported it. Furthermore, more studies should be performed to compare the safety and efficacy of EBRT against CTURBT based on the classification into low-risk, intermediate-risk, and high-risk. Finally, it is speculated that tumor recurrence rate could be affected by other influencing factors such as surgeon, available equipment, surgical team, smoking, and gene. All the limitations as mentioned above could compromise the value of our meta-analysis.

Conclusion
Our pooled studies showed that EBRT had a significantly lower AT, HT, intraoperative and postoperative complications, and 24-month recurrence rate than those treated with CTURBT, but due to the lack of randomization and selection bias, randomized studies will need to be performed to confirm our findings. Although, EBRT trended toward having a higher ratio of bladder detrusor muscle in the specimen, a lower ratio of residual tumor on the base and the same site recurrence, a lower ratio of 12-month and 36-month recurrence than CTURBT, but the differences did not reach statistical significance.