Repeated White Light Transurethral Resection of the Bladder in Nonmuscle-Invasive Urothelial Bladder Cancers: Systematic Review and Meta-Analysis

Introduction

W ith approximately 357,000 new cases worldwide in 2002, bladder cancer globally ranked ninth in worldwide cancer incidence. It was the fourth most common malignancy in men, coming after prostate, lung, and colon cancers ^1,2 and the 17th most common cancer in women. ³ Transitional-cell carcinoma, the most common primary subtype, accounts for >90% of bladder cancer tumors, ⁴ with squamous-cell carcinoma and adenocarcinoma occurring in 5% and 1% of cases, respectively. At diagnosis, 70% of bladder cancers are present as nonmuscle-invasive lesions (70% T_a lesions, 20% T₁, and 10% transitional-cell carcinoma in situ [T_is]) while the others invade the muscle. ^{2,5 –7} Even though follow-up may suffice for low-grade multiple T_a tumors, adjuvant endovesical chemotherapy/immunotherapy is needed for T1 tumors that show higher progression rates necessitating aggressive treatment.

In cases of bladder cancer, TURB in general has become crucial for correct staging, diagnosis, and treatment. ^8,9 It serves to identify patients for conservative treatment, organ-sparing strategy, or radical cystectomy despite its limitations, which are mostly biologic or operator dependent. Not all lesions are visible at first resection; judging the depth of resection is difficult if muscularis propria sampling is not performed; thus, the expertise of the operator is a crucial factor. Other difficulties include multiple cancer growths, location within a diverticulum, dome or bladder anterior wall, trabeculated or thin bladder wall, and risk of incidental perforation. ¹⁰ Another limit, despite being still controversial, is the potential development of a new lesion secondary to implantation of tumoral cells.

All these factors could compromise outcomes in terms of recurrence rate at the first follow-up cystoscopy. ⁸ In fact, guidelines generally recommend repeated TURB within a short time if the initial resection was incomplete, if multiple or large tumors were present, if there was a lack of muscularis propria in the specimen, and if a high-grade nonmuscle-invasive tumor or a T₁ tumor was detected. ^2,8,11

Because no randomized clinical trials or systematic reviews have been published on the role of repeated TURB in providing additional diagnostic and potential prognostic information and there are no data to support repeated TURB in T_a lesions, ¹² we reviewed all data and performed a meta-analysis on the role of a repeated transurethral resection in nonmuscle-invasive urothelial bladder cancers. This analysis of available reports aimed at assessing persistence and upstaging of nonmuscle-invasive bladder cancer at second look.

Methods

Results

There were 2327 original clinical articles and 562 reviews screened for retrieval; 101 potentially eligible studies were selected, 54 of which were duplicates; 47 articles were retrieved, and 18 articles matched inclusion and exclusion criteria. ^{19 –36} (Fig. 1) Three conference proceedings were excluded because they were also published later as articles and thus considered duplicates. ^{34 –36} Finally, data were pooled and analyzed from 15 studies reporting histologic assessments of bladder cancer at repeated TURB. ^{19 –33} All focused on the role of the repeated TURB in T₁ diseases at TURB; eight also dealt with the repeated TURB in T_a. ^{22,23,25 –27,29,31,33}

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FIG. 1.

Flowchart.

Meta-analysis

We included eight studies in the meta-analysis of the T_a prevalence rate at II look and 15 in meta-analysis of the T₁. As the heterogeneity test was highly significant (I2>80%, P<0.0001) in both analyses, the random-effects models were preferred to fixed-effects models. Beggs and Egger tests did not show significant publication bias. Sensitivity analysis did not result in loss of significance when one study was excluded at a time in both meta-analyses. The pooled prevalence rate of T_a at II look was 0.39 (95% CI=0.26 to 0.54) as shown in the forest plot (Fig. 2). The pooled prevalence rate of T₁ at second look was 0.47 (95% CI=0.41 to 0.53) (Fig. 3). The pooled prevalence rate in studies in which multiplicity was assessed was not significantly different compared with the global prevalence rate (0.33, CI=0.26 to 0.4 for T_a; 0.46, CI=0.39 to 0.53 for T₁). The pooled prevalence rate in studies that did not exclude patients in whom a muscle-invasive disease developed was not significantly different compared with the global prevalence rate (0.35, CI=0.26 to 0.44 for T_a; 0.45, CI=0.38 to 0.52 for T₁).

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FIG. 2.

Prevalence rates of T_a bladder cancer at II look.

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FIG. 3.

Prevalence rates of T₁ bladder cancer at II look.

Discussion

The results of this first meta-analysis on the role of white light repeated TURB in the management of nonmuscle-invasive urothelial bladder cancers underlined the necessity of a continuous improvement of the endoscopic approach in accordance with a prevalence in T_a diseases of 39% and in T₁ diseases of 47%, respectively. The high percentages of persistence and upstaging seemed linked to procedure-related technicalities, that are only partially overcome with separate resections of exophytic tumor, margins and base. ^37,38

Margins were sampled in 5 of 15 studies, but the authors did not describe the technique. For instance, they did not indicate where margins were sampled and how many specimens were collected. ^{21,25,26,28,31} Despite margin sampling, T_a persisted in 25.4% to 56% and was upstaged in 6.3% to 8% of patients ^25,26,31 ; T₁ persisted in 25% to 55% and was upstaged in 0% to 23.3% at the II look, respectively. ^{21,25,26,28,31} Because the repeated TURB was positive in the same site where the TURB had been performed in up to 46% both in T_a and T₁ diseases, ^21,25 these resections could have been microscopically incomplete along the borders of the diseases. On the other hand, the need to sample tumor bed muscular layer has long been known.

Herr and associates ³⁹ reported that when muscularis propria was present in specimens collected at the TURB, only 14% of T₁ were upstaged compared with 49% of nonsampled cases. The present review underlines that when muscle is not clearly stated to be present in the TURB specimens, upstaging was 14.3% for T_a disease ²⁹ and 23.3% for T₁, respectively. ²⁶ If the tumor base was sampled during the TURB, upstaging dropped to 6.4% for T_a disease ³¹ and to 9.5% for T₁, ³² respectively. The unexpectedly 23.3% upstaging rate of T₁ diseases assessed by Han and colleagues ²⁶ seems secondary to the fact that the authors had operated on patients who were referred to their institution from other hospitals and no information was available on the first TURB techniques that had been performed elsewhere. ²⁶

To improve high persistence and upstaging, different approaches such as using a bladder diagram, sampling suspicious areas and normal mucosa, or new technologies seem useful.

Using a bladder diagram would be useful to indicate tumor size, its location, as well as any tumor-suspicious areas. Photos or video pictures should also be taken. ^37,38 Writing down disease position on a map would not only record sites resected at the TURB but would also help make the repeated TURB more accurate. In five articles that used a bladder map, persistence was assessed as up to 86% at the primary site and up to 56% elsewhere. ^{19,21,23,25,32} Furthermore, quality control of surgical procedures during follow-up cystoscopy could also be performed by analyzing exact locations of tumor recurrences, distinguishing whether lesions had been missed or were really early recurrences. To our knowledge, relationships between tumor sites, recurrence, and progression during follow-up cystoscopies have never been investigated.

Several authors suggested suspicious areas and normal mucosa should undergo biopsy, because high-grade, multiple T_a and T₁ diseases showed significantly higher incidence of positive biopsies. ^9,40 On the other hand, the role of random bladder mucosa biopsies during TURB is still controversial; in fact, patients who did or did not undergo biopsy showed similar recurrence and progression rates, even though they are reported to detect abnormalities in up to 24% of patients and determine a treatment switch in up to 7% of patients ⁹ We can argue that random biopsies are useful. At the II look, T₁ diseases were discovered in areas other than those where the TURB had been performed in 16% to 56% ^19,21,25,32 ; however, Herr and Donat ²⁷ assessed that the 78% of patients in whom a stage progression developed complained of recurrence in remote sites within the bladder, with T_a diseases recurring in 83% to 86%. A possible explanation is that lesions might have been overlooked, because apparently normal mucosa was not routinely sampled at TURB and the repeated TURB was performed shortly afterward.

Using different methods, such as PPD photodynamic diagnosis (PPD) or narrow band imaging (NBI), could lower the persistence rate. The additional detection rate for PPD was higher than for white light cystoscopy (5%–49%) for nonmuscle-invasive tumors, with positive II look in 4.5% to 32.7%, lower than in cases of white light (25.2%–53.1%). ⁴¹ In addition, NBI seems an alternative and promising optical technology that enhances images of capillaries in the bladder mucosa; moreover, it has little cost and can be used an unlimited number of times in each patient without the necessity to instill a fluorescent agent. ⁴² NBI detected additional carcinoma in 41% of patients, ⁴³ with sensitivity of 69% to 92% and specificity of 58% to 79%, ⁴⁴ comparable to white light, and without the necessity of a long learning curve. ⁴⁴

Despite their limitations, both PPD and NBI seem helpful in detecting bladder cancers and for a complete resection of all lesions. PPD allows better resection and coagulation of T_is, and NBI could increase the detection of small tumors or areas of cancer growth enhancing the contrast between the neoplastic and normal mucosa and facilitating a better identification of tumor margins.

According to the results of Zurkirchen and coworkers, ³³ the importance of surgical skill seems unclear. The authors found 34.8% persistence and 1.7% upstaging rates, independent of whether the TURB was performed by a senior urologist or a trainee. Justification for this apparently contradictory discrepancy was that senior surgeons had to handle more difficult cases and, because they had to help whenever a resident was faced with a difficult resection, operations were considered to have been performed by experts. ³³ Authors stated operations were performed by “senior urologist or trainee with help of the senior” without further descriptions of procedures. Even though TURB is considered a relatively simple procedure, a learning curve is needed to have enough experience to deal with “difficult” bladder cancers.

Guidelines from the European Association of Urology, the American Urological Association, and the First International Consultation on Bladder Tumors suggested performing repeated TURB when there was a lack of muscle in the sample specimen, when TURB was incomplete, when a high-grade nonmuscle-invasive tumor was present, and when a T₁ lesion was detected. ^2,11,45 In fact, according to current literature, 10% of T_a and 35% of T₁ invade the muscle wall, and 5% of patients with the former and 20% with the latter undergo cystectomy. ⁴⁶

According to these guidelines, repeated TURB was indicated in 1851 (81.8%) patients in this meta-analysis ^{19 –33} ; on the other hand, 431 of 816 (52.8%) patients with T_a disease did not clearly fulfill criteria for a repeated TURB. ^{22,23,25 –27,29,31,33} Information for a correct risk stratification depending on the number and dimensions of lesions, previous recurrence rate, stage at the resection (T_a or T₁), presence of T_is, and grade of differentiation ⁴⁷ are provided for none of those 431 patients. They did not have high-grade disease, T_is was associated with a noninvasive lesion in only two cases, tumor dimensions were not assessed, and lesions varied widely in number. The repeated TURB, however, led to a switch in treatment for up to 18% of patients in studies including 63 patients with T_a and 317 with T₁ disease at TURB. ^{19,21,25,31,32} According to current reports, the 3-year recurrence rate is up to 48% in patients who undergo TURB without a II look, ⁴⁸ compared with 33% in a series of 63 patients with T_a and 20 with T₁ disease who underwent the repeated TURB. ²⁵

II look appeared to impact favorably on the outcomes of superficial bladder cancers with higher probability to achieve a complete response than a single transurethral resection (TUR) (71% vs 43%); in fact, as Herr ⁴⁹ has prospectively assessed, both T_a and T₁ diseases progressed less frequently in the case of re-TUR when compared with a single resection (7% vs 31% for T_a and 8 vs 43% for T₁). Furthermore, in a randomized clinical trial, Divrik and colleagues ⁵⁰ assessed a recurrence-free survival rate of 69% vs 37% at 3 years (median 27 vs 12 mos), with 81% of recurrences occurring during the first year after the single resection.

Despite this significant influence on outcome because of better local therapy and significant changes in management, from the present review, II look does not clearly seem justified in all patients who are affected by superficial bladder cancer. In addition to the above, further aspects difficult to measure would modify the behavior of the disease, and thus the approach: Previous history of tumors, size, location, and configuration of the neoplasms; if lamina propria, muscle, and fat were seen; and endoscopically free of tumor. The II look, however, seems drive the outcome regardless of the stage of the disease, because recurrence and progression rates were similar in patients who were affected by T_a or T₁ tumors after one or two TURBs. ⁴⁹

We acknowledge that our meta-analysis is beset by some flaws. T_is was associated in 27.9% of patients, persisting in up to 25%. ^{20,26 –28,30,32} The most important variable, however, was the completeness of the first resection, because unresected tumors are unlikely to be controlled by endovesical adjuvant therapy; in fact, T_is was not independently associated with higher risk of developing muscle-invasive forms of bladder cancer. ⁴⁹ Despite the fact that, in two studies, patients in whom a muscle-invasive disease developed at repeated TURB were not taken into consideration, ^27,28 excluding those studies, the pooled prevalence rate did not change significantly if compared with the global rates assessed by the meta-analysis. Thirteen studies did not state whether patients showed recurrent tumors at the first resection. Such recurrences are more aggressive. Only two studies reported minor complications in 5/216 (2.3%) patients ^21,32 ; on the other hand, this percentage is in line with current literature.

Ideally, studies included in systematic reviews and meta-analysis should be comparable with rigorous study design and with unbiased experimental methods and should evaluate the same outcome. Unfortunately, the prevalence of persistence was a secondary and comparable outcome only in a few observational studies included here, because no randomized clinical trials matched the inclusions and exclusion criteria. Moreover, populations were generally small; thus, heterogeneity was an unavoidable problem not completely resolved by adopting a random-effects model.

Conclusion

This first meta-analysis on the role of repeated TURB in the management of nonmuscle-invasive bladder cancers showed 39% of T_a and 47% of T₁ tumors persisted at the II look. The heterogeneity revealed by the present review underlines that the effectiveness of the II look in some situations is still controversial, especially in low- and middle-risk diseases. The re-TUR reduces and solves many but not all the uncertainties, but is clearly an overtreatment in some situations. We are confident that our effort in performing this systematic review can stimulate the development of prospective studies to optimize the surgical management of urothelial bladder cancer in accordance with proper risk stratification.