Evaluating repeat transurethral resection after en bloc resection for non-muscle invasive bladder cancer

Abstract

Objective:

Many studies have stressed the necessity of repeat transurethral resection (reTURB) following the initial conventional transurethral resection of the bladder for non-muscle invasive bladder cancer (NMIBC) patients. However, there have been few studies focusing on the role of reTURB after en bloc resection of bladder tumor (ERBT) for NMIBC by far. This study aimed to evaluate whether reTURB can be avoided after ERBT.

Materials and methods:

We conducted research in PubMed, Web of Science, EMBASE, and the Cochrane Library up to November 14, 2024, to identify studies on the reTURB after initial ERBT. For data conversion and the combined calculation of the incidence rate, we utilized R software (R Foundation for Statistical Computing, Vienna, Austria) and Cochrane Review Manager 5.4 (The Cochrane Collaboration, London, UK) along with the double arcsine method. This systematic review protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) under number 1082989.

Results:

A total of 17 studies involving 1051 participants were included. The rates of residual tumor and tumor upstaging detected by reTURB or cystoscopy after ERBT were 9% (95% confidence interval (CI) = 4%–16%) and 0% (95% CI = 0%–1%). No statistically significant positive effect of reTURB after initial ERBT was exhibited in recurrence-free survival (RFS), tumor recurrence, and progression. The pooled hazard ratios of 1-year and 5-year RFS were 0.77 (95% CI = 0.41–1.44, p = 0.41) and 0.83 (95% CI = 0.58–1.20, p = 0.33). The pooled odds ratio of progression and recurrence were 1.13 (95% CI = 0.53–2.41, p = 0.75) and 0.78 (95% CI = 0.53–1.16, p = 0.23).

Conclusion:

ERBT can successfully regulate the rate of tumor upstaging and residual tumor to an acceptable level. For patients with NMIBC, subsequent reTURB may not be required following the initial ERBT.

Plain language summary

Systematic review of reTURB after ERBT

This article aimed to evaluate whether repeat transurethral resection (reTURB) can be avoided after En bloc resection of bladder tumor (ERBT) and found that reTURB may not be required following the initial ERBT in non-muscle invasive bladder cancer.

Introduction

Bladder cancer (BC) ranks among the 10 most prevalent cancer types globally, with an annual incidence of approximately 550,000 new cases.^1,2 In the European Union, the age-standardized incidence rate per 100,000 individuals is 20 for men and 4.6 for women. ³ Epidemiological projections ⁴ suggest a rising trend in BC incidence over the coming decades. Smoking ranks as the most important risk factor for BC.^5,6 Non-muscle-invasive bladder cancer (NMIBC) is the most frequent BC, accounting for approximately 75% of all BC cases. ⁷

Numerous factors^8–15 influence the development and prognosis of BC, among which the selection of surgical approaches plays a pivotal role. The gold standard for treating NMIBC is a combination of conventional transurethral resection of the bladder (cTURB) and subsequent postoperative intravesical instillation therapy. ¹⁶ However, numerous disadvantages are inherent to cTURB, including the dissemination of tumor cells via fragmentation, the peril of tumor cell seeding and reimplantation, the induction of thermal injury to delicate tissues within the resected specimens, and the potential for incomplete tumor resection.^17,18

To address the limitations associated with cTURB, clinical practice has adopted the techniques of en bloc resection of bladder tumor (ERBT). Currently, many studies have compared the prognosis of ERBT with cTURB. For patients with BC(s) of ⩽3 cm, ERBT is an evolving alternative to cTURB, with a number of essential advantages such as a higher muscle detection rate, better quality of pathology specimen, a lower complication rate, and a higher recurrence-free survival (RFS). ¹⁹ In terms of muscle layer detection rates and recurrence risks, some research reported that cTURB demonstrates non-inferiority compared to ERBT, ²⁰ while others reported ERBT’s significant advantage over cTURB. ²¹

Repeated transurethral resection of bladder (reTURB) can further eliminate residual tumorous tissues, detect understaging BC, and augment the responsiveness to Bacillus Calmette–Guérin vaccine instillation.^22–24 To reduce recurrence or progression to MIBC, NCCN guidelines recommend reTURB for cases with the following characteristics: high-grade Ta BC, T1 BC, visually incomplete resection, or high-volume tumor at initial cTURB. ²⁵ However, reTURB significantly increases the complication risk and financial stress, ²⁶ which underscores the necessity for a rigorous and thorough evaluation prior to the implementation of reTURB. At present, many studies have focused on the necessity of reTURB after initial cTURB. Although given the ERBT’s advantages over cTURB, it is still unclear whether reTURB should be performed after initial ERBT. It is under debate whether reTURB can improve the prognosis after initial ERBT and whether it is feasible to diminish the necessity for a reTURB in NMIBC patients after initial ERBT.

To answer these questions, we conducted this meta-analysis to both demonstrate the potent curative potential of ERBT and evaluate the role of reTURB after initial ERBT. Based on this study, we intended to provide research support for the selection of surgical options for patients with NMIBC.

Methods

Literature search and study selection

This study was conducted in accordance with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. ²⁷

A comprehensive search was conducted in PubMed, Web of Science, EMBASE, and the Cochrane Library up to November 14, 2024. The search terms included the following: “ERBT,” “En bloc,” “enbloc,” “enucleate,” “one piece,” “reTURBT,” “re-transurethral,” “second,” “repeat,” “restage,” “reTURB,” “re-look,” “re-resect,” “bladder cancer,” “bladder tumor,” “bladder carcinoma,” and “urothelial carcinoma.” In addition, the references of the selected manuscripts were reviewed to identify any further relevant studies.

Initial screening of titles and abstracts was performed independently by two investigators to identify eligible studies. Disagreements between the investigators were resolved through consensus with the involvement of a third-party coauthor.

Inclusion and exclusion criteria

Inclusion criteria are as follows: (1) patients diagnosed with NMIBC who have undergone initial ERBT; (2) patients having received reTURB after ERBT; (3) outcome indicators, including at least one of the following: tumor residual rate, tumor upstaging rate, tumor recurrence rate, tumor progression rate, and RFS.

Exclusion criteria are as follows: (1) patent records, reviews, conference abstracts, editorials, animal studies, case reports, and letters; (2) data incomplete or invalid.

Regardless of the pathological classification of the tumor, we included all patient records that met the aforementioned criteria for meta-analysis.

Data extraction

Two researchers independently extracted and verified study characteristics and clinical outcomes. Data were extracted regarding the first author, year, country, number of patients, study period, ERBT method, re-resection time, tumor stage, tumor residual rate, tumor upstaging rate, RFS, tumor recurrence rate, and tumor progression rate.

Quality and risk of bias assessment

We assessed the quality of literature using a Methodological Index for Nonrandomized Studies (MINORS). ²⁸ The first eight items of MINORS were specially used for quality assessment of noncomparative studies, with 16 points. The remaining four items applied to comparative studies, contributing an additional 8 points. A score greater than or equal to 12 points was considered moderate to high literature quality.

For outcome indicators from more than 10 studies, publication bias was evaluated using both the Egger linear regression approach and funnel plots. ²⁹

Sample size calculation and trial sequential analysis

The trial sequential analysis (TSA) was conducted utilizing TSA software (version 0.9.5.10) developed by the Copenhagen Clinical Trials Centre, Copenhagen, Capital Region of Denmark, Denmark. The analysis parameters included an anticipated 20% odds ratio (OR) reduction, with α (Type I error) = 0.05 and β (Type II error) = 0.20 to determine the required information size (RIS). ³⁰ Statistical significance was established when cumulative Z-curves crossed predefined RIS thresholds, simultaneously confirming adequate sample size attainment for conclusive evidence interpretation.

Data processing and statistical analysis

Dichotomous variables were presented as counts and percentages. The impact of reTURB on survival was assessed using the hazard ratio (HR) with its corresponding 95% confidence interval (CI) as the effect size. They were extracted directly from each study if reported by the authors. Otherwise, these data were estimated indirectly using the method described by Tierney et al. ³¹ We conducted a single-arm meta-analysis for non-comparative studies and a double-arm meta-analysis for comparative studies. All statistical analyses in this study were performed using R software (version 4.1) and Cochrane Review Manager 5.4, with a significance level set at p < 0.05. In a meta-analysis of prevalence, if the event incidence was greater than 0.8 or less than 0.2, the double arcsine method was employed. ³² Inconsistencies (I²) statistics were used to assess heterogeneity. Depending on the degree of heterogeneity, we selected either a random effects model (when I² > 50%) or a fixed effects model (when I² ⩽ 50%).

Valid subgroup analyses require fulfillment of two prerequisite conditions: (1) availability of comparable outcome metrics for each subgroup stratum; (2) utilization of standardized subgroup classification criteria across at least two independent studies. These pre-specified conditions were unmet in the current evidence base, which limited the feasibility of subgroup analyses.

Results

Basic characteristics and quality assessment

Figure 1 shows the process of literature search and study selection. A total of 235 records were identified through database and register searches. We removed 108 duplicates and got 127 studies for screening. After carefully screening 127 articles, 17 studies^33–49 were included, of which 8 were prospective and 9 were retrospective.

Figure 1.

Literature search and selection.

Table 1 summarizes the characteristics of the 17 eligible studies, totaling 1051 cases (ERBT + reTURB: 757; ERBT: 294), published from 2011 to 2024. These studies were conducted across various countries, including Austria (1), China (6), Egypt (1), France (1), Germany (1), Italy (4), Japan (2), and Poland (1). Despite including a control group in five studies,^{43–45,48,49} only four of them are available for double-arm meta-analysis due to the lack of available data from one ⁴³ of the control groups, while the remaining single-arm studies can only be utilized for single-arm meta-analysis. In the studies included, thulium laser and electrotomy emerged as the most prevalent methods utilized for ERBT, with the majority of reTURB procedures being conducted within a 6-week timeframe.

Table 1.

Literature basic information.

First author	Year	Country	Study type	Study period	No. patients	No. patients	Stage (Ta/T1/Tis)		ERBT method	Re-resection time
					(ERBT + reTURB)	(ERBT)	(ERBT + reTURB)	(ERBT)
Andrea 33	2023	Austria	Prospective study	January 2019–January 2022	24	0	NA	NA	Electrotomy	NA
Fan 34	2022	China	Retrospective study	2013–2019	27	0	NA	NA	KTP laser	Within 6 weeks
Hashem 35	2021	Egypt	Prospective study	September 2015–September 2018	44	0	2/42/0	NA	Holmium laser	4 weeks
Hu 36	2021	China	Retrospective study	January 2019–October 2019	10	0	NA	NA	Holmium laser	4–6 weeks
Hurle 37	2020	Italy	Retrospective study	September 2011–April 2017	78	0	17/57/4	NA	Thulium laser/Electrotomy	40 days
Levy 38	2024	France	Retrospective study	January 2014–June 2022	75	0	NA	NA	NA	NA
Migliari 39	2015	Italy	Prospective study	February 2012–September 2013	53	0	30/23/0	NA	Thulium Laser	90 days
Muto 40	2014	Italy	Prospective study	April 2011–September 2012	49	0	31/18/0	NA	Thulium laser	30–90 days
Poletajew 41	2021	Poland	Prospective study	NA	37	0	NA	NA	Electrotomy	2–6 weeks
Soria 42	2020	Italy	Prospective study	2012–2017	42	0	NA	NA	Electrotomy	36–61 days
Wolters 43	2011	Germany	Prospective study	June 2010–October 2010	5	1	2/3/0	1/0/0	Thulium laser	6 weeks
Xu 44	2021	China	Retrospective study	June 2015–June 2019	51	64	16/35/0	15/49/0	RevoLix 2-μm laser	Within 6 weeks
Yanagisawa 45	2022	Japan	Retrospective study	April 2013–February 2021	50	56	0/50/0	0/56/0	Electrotomy	Within 2–6 weeks
Yanagisawa 46	2023	Japan	Retrospective study	January 2012–February 2022	46	0	NA	NA	Electrotomy	4–6 weeks
Yang 47	2020	China	Prospective study	October 2015–June 2017	28	0	NA	NA	Electrotomy	2–6 weeks
Zhou 48	2020	China	Retrospective study	June 2012–June 2018	108	143	60/48/0	87/56/0	Thulium laser	2–6 weeks
Zhou 49	2023	China	Retrospective study	June 2018–July 2022	30	30	14/15/1	12/17/1	Thulium laser/Electrotomy	4–6 weeks

ERBT, en bloc resection of bladder tumor; reTURB, repeated transurethral resection of bladder.

Supplemental Table 1 presents the outcome of a quality assessment conducted using the MINORS. All of the studies included in the analysis scored 12 points or higher, reflecting the satisfactory quality of these studies.

Single-arm meta-analysis results

Residual tumors and upstage at reTURB/cystoscopy after ERBT

All 17 studies reported the status of residual tumor after ERBT. Given that the residual tumor rates reported in the included studies were consistently below 20%, we employed the double arcsine method for data conversion. Due to pronounced heterogeneity observed (I² = 83.2%), the meta-analysis results utilizing the random effects model showed that the residual tumor rate after ERBT was 9% (95% CI = 4%–16%; Figure 2(a)).

Figure 2.

Forest plots of tumor residual rate (a) and upstaging rate (b) detected by reTURB or cystoscopy after initial ERBT.

ERBT, en bloc resection of bladder tumor; reTURB, repeated transurethral resection of bladder.

Thirteen studies disclosed the upstaging rate at reTURB or cystoscopy after ERBT, which ranged from 0% to 4%. Following normalization and adjustment of the data using the double arcsine transformation, the meta-analysis results using the fixed effects model showed that the tumor upstaging rate was 0% (95% CI = 0%–1%; Figure 2(b)).

Double-arm meta-analysis results

Recurrence-free survival

Four studies recorded RFS of NMIBC patients. The pooled HRs of 1-year and 5-year RFS were 0.77 (95% CI = 0.41–1.44, p = 0.41; Figure 3(a)) and 0.83 (95% CI = 0.58–1.20, p = 0.33; Figure 3(b)), indicating no statistically significant benefit for reTURB after ERBT in improving RFS.

Figure 3.

Forest plots of 1-year RFS (a) and 5-year RFS (b) between the ERBT + reTURB group and the ERBT group.

ERBT, en bloc resection of bladder tumor; reTURB, repeated transurethral resection of bladder; RFS, recurrence-free survival.

Progression and recurrence

The prognostic data concerning progression and recurrence rates during the follow-up period were reported in four studies. The pooled OR of progression and recurrence were 1.13 (95% CI = 0.53–2.41, p = 0.75; Figure 4(a)) and 0.78 (95% CI = 0.53–1.16, p = 0.23; Figure 4(b)), which suggested no statistically significant benefit for reTURB after ERBT in reducing progression and recurrence rate.

Figure 4.

Forest plots of progression rate (a) and recurrence rate (b) between the ERBT + reTURB group and the ERBT group.

ERBT, en bloc resection of bladder tumor; reTURB, repeated transurethral resection of bladder; RFS, recurrence-free survival.

Risk of bias assessment

Given the availability of data from over 10 studies on tumor residual rate and upstaging rate, Egger linear regression approach and funnel plots were employed for publication bias evaluation. As shown in Figure 5, the results indicated an absence of statistically significant publication bias in both the meta-analysis examining the tumor residual rate (p = 0.3596; Figure 5(a)) and the analysis assessing the upstaging rate (p = 0.4716; Figure 5(b)), which implied these pooling results were stable and reliable.

Figure 5.

Funnel plots and Egger’s test of tumor residual rate (a) and upstaging rate (b).

TSA results

We carried out a TSA to reduce the risk of type I error and to assess the RIS. Final results indicated that the sample size did not reach the RIS for the assessment of progression (Supplemental Figure 1). Therefore, more studies are required to perform the meta-analysis. But for recurrence, the sample size was adequate (Supplemental Figure 2).

Discussion

Since the Stern-McCarthy resectoscope became the foundation of cTURB, cTURB has remained as the cornerstone treatment of BC until now. ¹⁶ However, cTURB’s oncological outcomes have been doubted. Piecemeal resection during cTURB may lead to seeding of normal urothelium by tumor cells, ⁵⁰ which might lead to a higher recurrence rate and worse prognosis. Thus, ensuring complete resection of BC, ERBT can minimize the risk of tumor seeding by extracting the bladder tumor in one piece. According to the study conducted by Migliari et al., ⁵⁰ ERBT demonstrates a lower recurrence rate at the site of resection compared to cTURB. A meta-analysis ⁵¹ also reported that ERBT had better or comparable perioperative outcomes.

However, there are still limitations in ERBT. The removal of large bladder tumors has always been a challenge in ERBT. Teoh and Mostafid et al. ⁵² published their experiences on routine implementation of ERBT and reported that when stratified based on tumor size, the technical success rates of ERBT were 84.3% for BC of 3 cm or less and 29.6% for tumors exceeding 3 cm. However, according to Petov et al. ⁵³ and Babaevskaya et al., ⁵⁴ ERBT may be feasible for tumors >3 cm, with operator experience possibly moderating technical challenges and explaining outcome variations. While expertise may overcome size limitations, further validation in larger lesions remains warranted.

According to the single-arm meta-analysis results of our research, the tumor upstaging rate and tumor residual rate at reTURB/cystoscopy after ERBT were low, especially the tumor upstaging rate, which was consistent with the studies conducted by Yanagisawa et al. ⁴⁶ and Cumberbatch et al. ⁵⁵ In a single-center retrospective study conducted by Zhou et al., ⁴⁸ the tumor residual rate was merely 5.6% (6/108) following the reTURB of 108 high-risk NMIBC patients who had undergone ERBT. On the contrary, a recent meta-analysis ⁵⁶ reported the tumor residual rate of 31.4% in patients who have undergone reTURB following cTURB, compared with a markedly lower rate of 9% in patients who have undergone reTURB following ERBT in our study. While our single-arm meta-analysis precludes direct ERBT-cTURB comparisons, it demonstrates that ERBT achieves satisfactory control of tumor upstaging and residual tumors.

Double-arm meta-analysis results of our study further exhibited the superiority of ERBT. Our research has revealed that there was no statistically significant benefit observed for reTURB following ERBT in improving RFS, reducing progression and recurrence rate, which means it might be unnecessary for NMIBC patients to undergo reTURB after initial ERBT. In a prospective study, patients initially diagnosed with T1 NMIBC were randomly assigned to either a reTURB group or a non-reTURB group. The first-year RFS rate was 82% and the third-year rate was 65% in the reTURB group, compared to 57% and 37%, respectively, in the non-reTURB group. These findings suggest that re-resection can significantly enhance the RFS rates of patients. ⁵⁷ However, the patients of this study had undergone cTURB instead of ERBT. According to the study of Calo et al., ⁵⁸ when the initial resection was thorough, subsequent re-resection did not result in any significant improvement in RFS or progression-free survival, which was consistent with our study. Although reTURB was reported to be significantly positive for NIMBC patients with T1, Tx, or high-grade BC found in the primary cTURB, ⁵⁹ reTURB might not be necessary for patients having undergone ERBT. Given the trauma and economic burden associated with reTURB, for patients with poor physical conditions who find it challenging to tolerate further surgery, it may be prudent to consider avoiding reTURB when appropriate. As reTURB may be unnecessary following initial ERBT, subsequent ERBT could also be omitted within this treatment paradigm. According to European Association of Urology guidelines, ¹⁶ reTURB can increase RFS, improve outcomes after primary cTURB. However, the guideline did not address the differential impact of surgical techniques on reTURB. Our data indicated that NMIBC patients undergoing ERBT derived limited measurable benefit from reTURB. These observations highlighted the need for prospective trials to clarify the clinical value of routine reTURB after ERBT. In the future, the integration of reTURB for NMIBC with novel immunotherapeutic strategies holds promise for precisely controlling tumor progression. ⁶⁰ This approach may address the limitations of current surgical interventions by combining local tumor resection with systemic immune modulation, thereby optimizing personalized therapeutic regimens for NMIBC patients.

There are still limitations in our study. First, given that few studies comparing the prognosis of patients with ERBT + reTURB and ERBT, we only found four comparative studies for double-arm meta-analysis results, which might limit the universality of our findings. Second, single-arm studies inherently carry a risk of bias. To mitigate this effect, we employed the random model and assessed the risk of bias. Third, insufficient studies reported stratified outcomes for relevant patient subgroups, such as Ta or T1 stages. Consequently, we were unable to perform additional subgroup analyses to adjust for these effects. Lacking subgroup-specific data creates uncertainty in applying pooled results to individual patients. Finally, despite conducting a meta-analysis, the overall sample size remains inadequate. Therefore, future research necessitates more large-scale randomized controlled studies to further validate our findings.

Conclusion

ERBT can successfully regulate the rate of tumor upstaging and residual tumor to an acceptable level. For patients with NMIBC, particularly those facing poor physical health and financial constraints, subsequent reTURB may not be required following the initial ERBT. However, considering the inadequate sample size, further high-quality comparative trials are necessary to confirm these findings.