Review
Quality Control Indicators for Transurethral
Resection of Non
eMuscle-Invasive Bladder
Cancer
Murat Akand,
1,2Tim Muilwijk,
1Yannic Raskin,
1Maxime De Vrieze,
1Steven Joniau,
1Frank Van Der Aa
1Abstract
Complete transurethral resection of bladder tumor (TURBT) is the initial procedure of choice for nonemuscle-invasive bladder cancer, but its quality is far from optimal in clinical practice. We evaluated the existing body of evidence substantiating current quality control indicators (QCIs) for TURBT. A literature search was performed using PubMed and Embase, and selected articles were reviewed according to their level of evidence. Disease recurrence and pro-gression were used as the primary end points. No hard evidence supports complete resection as a QCI, but rationally, it is the most important indicator for TURBT. A repeat resection is an important QCI in high-risk disease patients, but evidence suggests that it may not be necessary when detrusor muscle is present in the initial resection specimen. The presence of detrusor muscle in the resection specimen is a validated QCI for TURBT. Adjuvant intravesical instillation is a scientifically proven QCI. Bladder perforation is a controversial QCI in the existing literature. No evidence indicates the ideal time frame for the initial TURBT; thus, initial therapy in thefirst 6 weeks after diagnosis is not a good QCI. Three of the 6 proposed QCIs for TURBT are supported by evidence. Our literature analysis indicated the use of complete resection, repeat resection, the presence of detrusor muscle, and intravesical instillation are QCIs to minimize recurrence and progression, and increase beneficial outcomes.
Clinical Genitourinary Cancer, Vol. 17, No. 4, e784-92 ª 2019 Elsevier Inc. All rights reserved. Keywords: Progression, Quality indicator, Quality parameter, Recurrence, TURBT
Introduction
Bladder cancer (BC) represents the 11th most common ma-lignancy worldwide, and it is the most common involving the urinary system, accounting for approximately 390,000 cases and 150,000 deaths each year.1-4Localized urothelial carcinoma of the
bladder is broadly categorized into nonemuscle-invasive BC (NMIBC) and muscle-invasive disease. Approximately 70% of new urothelial carcinoma of the bladder cases present as nonemuscle invasive, including tumor stage Ta (mucosa, 70%), Tis (carcinoma-in-situ, 10%), and T1 (submucosal invasive,
20%).5,6 Both tumor stage and histologic tumor grade are important prognostic factors influencing the outcome of dis-ease.7,8Risk stratification for progression categorizes patients into
low-, intermediate-, and high-risk groups. High-risk disease comprises Tis, T1, or high-grade (HG) lesions or multiple, large, low-grade (LG) Ta lesions.9 Low-risk BC is defined as solitary,
small, LG Ta lesions.9 Complete transurethral resection of all visible bladder tumor (TURBT) is the standard procedure for the initial diagnosis, staging, and treatment of NMIBC, as stated by the European Association of Urology (EAU), the American Urological Association (AUA), and the Society of International Urology (SIU).9-11
There are 3 main goals of TURBT in the management of BCs that are macroscopically visible with cystoscopy12:first, to provide tissue for pathologic examination to determine the histologic subtype and tumor grade; second, to assess the presence, depth, and type of tumor invasion; and third, to remove all macro-scopically visible tumor. The quality of the initial TURBT therefore directly affects the correct diagnosis and staging, adju-vant therapy, and disease prognosis of NMIBC. Hence, the
M.A. and T.M. contributed equally to this article, and both should be consideredfirst author.
1Department or Urology, University Hospitals Leuven, Leuven, Belgium 2Department or Urology, Selçuk University, School of Medicine, Konya, Turkey
Submitted: Feb 27, 2019; Revised: Apr 8, 2019; Accepted: Apr 11, 2019; Epub: Apr 19, 2019
Address for correspondence: Murat Akand, MD, FEBU, Department of Urology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
Fax:þ32 16 34 69 31; e-mail contact:drmuratakand@yahoo.com
recurrence and progression, and at the same time to guarantee minimal complications. Although TURBT is one of the most commonly performed surgeries in urology, its quality is far from optimal in clinical practice.13It is often seen as a straightforward procedure, but it is not always performed properly. Thisfinding is affirmed by the high interinstitutional variability of tumor recurrence after TURBT, which is directly associated with the quality of the initial procedure.14
Multiple studies have shown a recurrence rate of NMIBC ranging from 50% to 70%.14 It is commonly believed that early
recurrences are in fact residual or overlooked tumors present at the initial TURBT, thus emphasizing the importance of TURBT quality. Therefore, incomplete resection is one of the major reasons for high recurrence after initial TURBT.14It is assumed that im-plantation offloating cancer cells into the bladder urothelium after resection is also accountable for most early recurrences.14,15Finally, an aggressive, fast-growing tumor can also lead to recurrence.14
Current quality control indicators (QCIs) for TURBT are set by institutional guidelines, expert opinions, and consensus articles, and include complete macroscopic resection of all visible tumor, repeat resection for T1 and HG tumors, adjuvant intravesical instillation of chemotherapy or immunotherapy, presence of detrusor muscle (DM) in the resection specimen, absence of bladder perforation (BP), and initial therapy in thefirst 6 weeks after diagnosis.16-18
We evaluated the existing body of evidence substantiating the current QCIs for TURBT for NMIBC. It is important to address whether there is enough evidence to support the abovementioned QCIs that are currently used, whether there is a need for more extensive research on the use of these QCIs, and whether these indicators need to be adjusted.
Methods
A literature search for all sorts of articles, including caseecontrol studies, cohort studies, randomized controlled trials (RCTs), sys-tematic reviews, and meta-analyses, was conducted using the PubMed/Medline and Embase databases up to March 2018. This search was conducted using the following associated search terms: “bladder neoplasms,” “bladder cancer,” “NMIBC,” “cystoscopy,” “transurethral resection,” “complete resection,” “extensive resection,” “restaging,” “repeat resection,” “second resection,” “(intra)vesical administration,” “intravesical chemotherapy,” “adjuvant intravesical instillation,” “detrusor muscle,” “muscularis propria,” “bladder perforation,” “local recurrence,” “recurrence,” “progression,” “quality parameter,” and “quality indicator.” Both medical subject heading terms and nonstandardized search terms were used. Search results werefirst screened by title and abstract, then read thoroughly to make afinal selection of articles to be included in the review. Also, reference articles of the selected articles were included if relevant. All selected and reviewed articles are listed inTable 1.19-38
Articles published in English were eligible for inclusion. Articles were graded according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence system (Table 2).39If different levels of evidence (LE) were available on a specific topic, then the articles with the highest LE were reviewed rather than articles with a lower LE. All studies included in thefinal review had a LE of > 3. We report on the QCIs described in these articles.
measures to judge the value of the proposed QCI. Because of the tendency of NMIBC to recur, progression-free survival (PFS) is a more valuable disease outcome parameter than recurrence-free survival (RFS). However, in many studies, primary end points focused on tumor recurrence. Perhaps this is because tumor recur-rence is a more practicable outcome parameter because it occurs faster and thus requires a shorter follow-up (FU) period.
Complete Resection
The TURBT procedure should be performed to macroscopi-cally clear the tumor from the bladder with separate resection of the tumor base, and separate biopsy samples should be taken from the borders of the resection area.40Therefore, complete resection is unanimously accepted as an important QCI. Resection may be incomplete if the procedure is difficult as a result of large tumor size or tumor multifocality; if the tumor site is difficult to reach with the resectoscope; if the tumor is present but not visible; or if the procedure needs to be stopped immediately as a result of bleeding or BP.14
The adequacy and completeness of TURBT depends on the surgeon and the procedure. Brausi et al14found significant inter-institutional variability for early recurrences, using the recurrence rate at thefirst FU cystoscopy after TURBT; this could only be explained by the variability in the quality of the TURBT performed by different surgeons. Several studies have shown that TURBT is more often incomplete than is assumed.41In many cases, although
there appears to be no microscopically visible tumor left after the initial TURBT, residual tumor can be detected at the restaging TURBT.42,43
In general, there is little evidence on the importance of a com-plete initial resection, although there are multiple studies quanti-fying this problem. However, it can be assumed that an incomplete resection results in more recurrences. In line with this reasoning, Jancke et al19concluded that the presence of residual tumor in an extra marginal resection (MR) after a TURBT (indicating an incomplete resection) was associated with local recurrence in Ta and T1 BCs. Of 94 patients, 24 had a tumor-positive MR; the recur-rence rate in this group (83%) was higher than that of patients with tumor-free MR (57%). It must be noted that this study did not provide long-term FU or disease progression data. In our extensive literature search, we could notfind evidence regarding whether an incomplete initial resection, with or without a second TURBT shortly after the initial resection, has a negative impact on the long-term outcome of the patient. Because there is no real evidence indicating the superiority of a complete resection over an incom-plete resection, it remains unclear if these recurrences affect the long-term prognosis of NMIBC.
The lack of literature on this topic is likely due to the limits of clinical trial design. It would be unethical to perform a controlled trial where tumors were intentionally incompletely resected. Also, retrospectively analyzing TURBT cohorts for incomplete resections is a challenge because the incompleteness of resection is often nonintentional and thus often not noticed or documented. Although there is a lack of scientific evidence clearly demonstrating the benefit of complete resection, it is rational to resect a bladder tumor as completely as possible. Complete resection should be the
-starting point for every TURBT, and therefore is the most impor-tant QCI. At present, in clinical practice, it is not common to verify the extent of use of this QCI by performing MR or perioperative biopsies of the tumor bed and surrounding bladder mucosa. The highest percentage of residual tumor is detected for T1 and HG tumors; therefore, complete resection is vital in patients with these
tumors. Also, the use of adjuvant elements, such as photodynamic diagnosis or narrow band imaging (NBI), should be considered to improve the quality of TURBT.
Repeat Resection
Many studies have shown the presence of residual tumor and the need for upstaging to higher tumor stages (T2 or higher disease) in a significant portion of NMIBC patients when a sec-ond TURBT was performed after a few weeks.41,44The ambiguity
of definitions has led to varying rates of residual tumor (1.7-28%) and understaging (49-83%) after the second TURBT.44,45In up to 50% of cystectomies performed for T1G3 tumors, muscle-invasive disease is found during the pathologic examination of the resection specimen, indicating the frequent understaging in this group.46 In this context, repeat resection has been strongly advocated in an attempt to overcome quality issues of the initial TURBT and to improve disease outcome. The aim of repeat resection is to address incomplete resections and incorrect staging. Current guidelines advise repeat resection within 2 to 6 weeks after the initial TURBT in a particular set of circumstances, but mostly focusing on T1 and HG tumors.9
Sfakianos et al20retrospectively analyzed the single-center data of
1021 patients with NMIBC who received induction intravesical bacillus Calmette-Guérin (BCG) therapy after TURBT. Most pa-tients underwent restaging TURBT before initiating intravesical
Table 2 Oxford Centre for Evidence-Based Medicine Levels of Evidence
Level of
Evidence Definition
1a Systematic reviews (with homogeneity) of randomized controlled trials
1b Individual randomized controlled trials (with narrow confidence interval)
1c All-or-none randomized controlled trials 2a Systematic reviews (with homogeneity) of cohort studies 2b Individual cohort study or low-quality randomized controlled trials 2c Outcomes research, ecological studies
3a Systematic review (with homogeneity) of caseecontrol studies 3b Individual caseecontrol study
4 Case series (and poor-quality cohort and caseecontrol studies) 5 Expert opinion without explicit critical appraisal, or based on
physiology, bench research, orfirst principles
Table 1 Selected and Reviewed Articles
Study Year Type Level of Evidence N
Complete Resection
Jancke19 2012 Prospective cohort comparison 2b 94
Repeat Resection
Sfakianos20 2014 Retrospective cohort comparison 2b 1021
Kim21 2012 Prospective cohort comparison 2b 126
Divrik22 2010 Prospective cohort comparison 2b 210
Vasdev23 2012 Retrospective cohort comparison 2b 486
Gontero24 2016 Retrospective cohort comparison 2b 2451
Detrusor Muscle in Resection Specimen
Shoshany25 2014 Retrospective cohort comparison 2b 332
Mariappan26 2010 Retrospective cohort comparison 2b 356
Rouprêt27 2012 Retrospective cohort comparison 2b 486
Adjuvant Intravesical Instillations
Perlis28 2013 Meta-analysis 1a 2548
Sylvester29 2004 Meta-analysis 1a 1476
Holmäng30 2009 Systematic review 1a 1990
Onishi31 2017 Randomized controlled trial 1b 250
Shelley32 2000 Systematic review 1a 585
Herr33 1995 Randomized controlled trial 1b 86
Zhu34 2013 Meta-analysis 2a 3073
Huang35 2017 Meta-analysis 1a 1951
Malmström36 2009 Meta-analysis 1a 2820
Jiang37 2016 Meta-analysis 1a 1289
Bladder Perforation
Comploj38 2014 Prospective cohort comparison 2b 565
Quality Parameters for NMIBC
-BCG therapy, except those who had already started intravesical therapy at the initial consultation or who refused a restaging TURBT. Of 1021 patients, 894 underwent a restaging TURBT and had significantly lower recurrence rates at 3, 6, and 12 months of FU (9.6%, 16.6%, and 28.2%, respectively) compared to pa-tients with a single TURBT (43.3%, 44.8%, and 58.3%, respec-tively). At 5-year FU, recurrence rates were 61.6% in the restaging TURBT group and 77.2% in the single TURBT group. If patients from the single TURBT group with early recurrences in thefirst 3 months were excluded, then the recurrence rates at 5 years were equal in both groups. The PFS in patients with restaging versus single TURBT was 81.7% and 67.2%, respectively.
Kim et al21prospectively randomized 126 patients with NMIBC to undergo or not undergo immediate second resection of the tumor bed during the initial TURBT until DM was identified in the resection specimen. The 1- and 2-year RFS rates in the immediate second resection group were 87.5% and 77%, respectively, compared to 62.0% and 45.8%, respectively, in the group with no second resection. Furthermore, Kim et al found that only in the high-risk group, namely patients with any T1 or TaG3 tumor, was the 2-year RFS significantly higher in the immediate resection group than in the no second resection group (72.5% vs. 42.0%, respec-tively). No significant difference was found in the low-risk group. Recurrence at thefirst FU cystoscopy occurred in 6 patients (12%), all in the no second resection group. PFS did not differ between groups.
Divrik et al22prospectively randomized 210 patients with newly
diagnosed pT1 stage BC to undergo or not undergo a second TURBT within 2 to 6 weeks after the initial resection. The rates of RFS were 82%, 65%, and 59% in the second resection group and 57%, 37%, and 32% in the no second resection group for thefirst, third, and fifth year, respectively; the PFS rates were 96%, 93%, and 93%, respectively in the second resection group and 94%, 83%, and 79%, respectively, in the no second resection group. There were statistically significant differences for both parameters between the 2 groups.
Vasdev et al23 retrospectively collected data from 486 patients diagnosed with pT1 HG NMIBC. The patients were divided into those who underwent an early repeat resection and those who did not. The recurrence rate in the early repeat resection group was lower than that for the group that did not undergo early repeat resection (34.8% vs. 42.1%, respectively); however, this difference was not significant. They also found no significant difference in RFS between the groups. Finally, they found a higher stage progression rate at recurrence for the single resection group compared to the repeat resection group (14.4% vs. 3.3%, respectively), but once again, there was no statistically significant difference.
Gontero et al24retrospectively analyzed the multicenter data of 2451 patients with a primary or secondary pT1 HG NMIBC initially treated with BCG. Of these patients, 35 had a repeat TURBT. Patients were more likely to have undergone a second TURBT when they had large multifocal tumors or when they did not receive maintenance BCG therapy. Recurrence and progression were significantly lower in the repeat TURBT group than in the single TURBT group (recurrence: 58.3% vs. 60%, progression: 13.8% vs. 21.5%, respectively) only in patients for whom the resection specimen did not contain DM at the initial TURBT.
All acquired evidence promoting a second resection had a low LE (2b). In these studies, a high tumor presence was found at the 3-month FU in patients with a single TURBT. This is most likely the result of disease persistence rather than recurrence. When re-currences at 3 months were excluded, an almost identical recurrence rate was found at the 5-year FU, indicating that a second TURBT is especially important to eradicate residual tumor.20Also validating this claim is thefinding that no recurrences could be found at the first FU cystoscopy after an immediate second resection, in contrast with the control single resection group.21 It is important to note
that the beneficial effect of a second resection was only evident in patients with pT1 or HG tumors. This positive effect in this particular subgroup seemed to be limited to those patients whose first resection specimens did not contain DM.
Repeat TURBT is necessary for optimal disease management and the best prognosis for NMIBC. It has a proven influence on disease outcome in a particular subgroup: patients with T1 and HG tumors. A repeat TURBT should be considered in all patients with such tumors; however, a few additional factors, such as the presence of DM in the resection specimen, should also be taken into account. A repeat TURBT might not be necessary for pa-tients who have T1 or HG disease along with the presence of DM in thefirst resection specimen. Of course, a repeat TURBT should be considered when the first resection is known to be macro-scopically incomplete. Thus, a repeat resection can be avoided if the resection is deemed complete and DM is present in the initial resection specimen. In this case, there would be a positive impact on the burden of disease as a result of fewer complications asso-ciated with the additional surgery, and on thefinancial costs of the disease management.47,48Repeat resection is a valid QCI in the abovementioned circumstances and should be carefully used in clinical practice.
Presence of DM in Resection Specimen
The presence of DM in the resection specimen seems to be crucial for accurate staging; therefore, it is thought to improve the quality of the TURBT and is seen as an important QCI. The absence of DM is an important risk factor for understaging, and it may result in suboptimal treatment.49 The disease of significantly
more patients (up to 64%) is understaged when DM is absent.50
Some authors consider the presence of DM a substitute for resec-tion quality. However, in clinical practice, the rate that DM is found in resection specimens varies greatly. Several studies have shown an absence of DM in 15% to 66% of BC resection speci-mens.51-53The absence of DM was most often seen inflat papillary neoplasms, whereas it was mostly present in large multifocal non-papillary tumors.25,26,54It is unclear if the experience of the surgeon has an impact.25-27
In a retrospective study, Shoshany et al25 found almost equal recurrence rates at thefirst FU cystoscopy for patients with DM-present (25% of 265) and DM-absent (20% of 67) resection specimens. However, when only patients with T1 tumors (n¼ 79) were reviewed, patients with DM-absent specimens had a signifi-cantly higher rate of early recurrence than patients with DM-present specimens (48% vs. 22%, respectively, P ¼ .02). There was no significant difference in the long-term outcome, as recurrence and progression rates did not differ between groups, even when only T1
-tumors were reviewed. It must be noted that all HG T1 -tumors underwent a repeat TURBT, and this could influence the results and mask a possible significant difference.
Mariappan et al26concluded that the recurrence rate at thefirst FU cystoscopy was affected by the absence or presence of DM in a retrospective cohort comparison (44.4% in 90 patients without DM vs. 21.5% in 144 patients with DM). The absence of DM was associated with a higher risk of early recurrence not only in small tumors but also in large tumors (> 3 cm) (odds ratio, 2.2 and 20.0, respectively), with recurrence rates of 85.7% versus 23.1% for the absence versus presence of DM in the large tumor group. Furthermore, this significant difference was also observed for G1 þ G2Ta, all HG (G3), and all T1 tumors. Roupreˇt et al27 also confirmed in a retrospective study that the recurrence rate at the first FU cystoscopy was significantly worse when the DM was absent (52.9% in 102 patients) versus present (30.7% in 238 patients) for T1 tumors.
Erbay et al55 retrospectively analyzed data from patients who underwent TURBT for NMIBC on the lateral bladder wall. The use of an obturator nerve block to supplement spinal anesthesia and prevent the obturator reflex proved to have a positive impact on the presence of DM in the resection specimen. Subsequently, this technique was associated with significantly better 1- and 5-year RFS rates compared to only spinal anesthesia (93.6% vs. 74.6% and 82.2% vs. 60.2%, respectively).
Once again, all evidence recommending a good-quality resection with the presence of DM in the specimen was based on a low LE (2b). In general, the presence of DM in the resection specimen of tumors of all stages indicated a good-quality resection, with lesser rates of re-sidual tumor and reduced chances of recurrence. The absence of DM in the resection specimen of T1 or HG tumors could possibly alter disease management, as a repeat TURBT should be considered in this patient group. Nevertheless, it also indirectly affects the disease management of both Ta and T1 tumors by risking understaging. Thus, although the presence of DM is not necessary for correct staging for the majority of patients who have LG Ta tumors, obtaining DM-positive resection specimens is still important in these low-risk BC cases. Resection including DM should be one of the fundamentals of TURBT in high-risk NMIBC patients, and repeat TURBT should always be considered until DM is found in the resection specimen. The obturator nerve block technique can be used to increase the chance of including DM in resection specimens.
Adjuvant Intravesical Instillations
Adjuvant intravesical instillations (AIVIs), either with chemo-therapy or immunochemo-therapy, are well implemented in clinical practice for the management of NMIBC. Intravesical therapy is generally used to prevent tumor recurrence by destroying viable tumor cells that dwell in the bladder after TURBT. Although a lot of scientific research has been conducted on AIVIs after TURBT, there is no unanimity among researchers regarding the use of these adjuvant treatments. This may be due to mounting inconclusive evidence questioning how effective it is for pre-vention of disease progression.9However, the most recent EAU
and AUA guidelines advise AIVIs for all NMIBC patients.9,10
Thus, administering a specific AIVI regimen is currently an important QCI for TURBT.
The decision to proceed with an AIVI and the choice of the regimen depend primarily on the risk of progression. Therefore, different instillation regimens are used in different patient sub-groups, based on their risk stratification. In general, an immediate single postoperative chemotherapy instillation is advised for low-risk patients, and induction and maintenance intravesical BCG immu-notherapies are advised for intermediate- and high-risk patients.16It must be noted that the EAU guidelines recommend that all intermediate-risk patients should be treated with induction and maintenance intravesical chemotherapy (IVC) or BCG, but this treatment pathway is not recommended by other panels.16Because
this topic is extensive, we will only discuss the abovementioned generally validated treatment arms.
Single Immediate IVC for Low-Risk Disease
Perlis et al28performed a meta-analysis of 13 studies including 2548 patients to evaluate the effect of immediate post-TURBT IVC on the recurrence rate for NMIBC patients. Only patients with pathologically confirmed LG Ta or T1 tumors were eligible for inclusion. Most studies compared IVC with no adjuvant intravesical therapy; only a few studies compared IVC to instillations of distilled water. They concluded that a single IVC instillation administered in the first 24 hours after TURBT significantly prolonged the recurrence-free interval by 38% (hazard ratio, 0.62). Subgroup analysis showed that this effect was seen in both low- and high-risk patient groups, and when different chemotherapeutic drugs were used with statistically insignificant differences in effect size between subgroups. However, it must be noted that only mitomycin C (MMC) and epirubicin were included in the subgroup analysis as a result of the insufficient use of other drugs in the included studies. The effect on tumor progression was only reported in 4 studies and showed a small, nonsignificant difference favoring IVC to no AIVI at all. The meta-analysis of Perlis et al28 is a continuation of a previously performed meta-analysis by Sylvester et al,29including 6 of the same articles. They describe a similar decrease in the odds of recurrence of 39% (hazard ratio, 0.61) for patients receiving a single IVC instillation immediately after TURBT.
In contrast to these meta-analyses stating the superiority of a single immediate IVC instillation, Holmäng30 rejected IVC as a
valid treatment option, alleging publication bias due to study sample sizes and net benefits. They found that the net benefit of IVC, defined as the difference in recurrence between IVC and placebo, diminished in larger-sized RCTs. The 3 largest RCTs showed a net benefit ranging from 12% to 15%, with a number needed to treat of about 8 to prevent a single recurrence. These findings suggest that IVC is not powerful enough when considering the costs and burden of treatment, and that it is driven by small-sized RCTs with large effects.
It is still controversial whether a one-time intravesical instillation, independent of the instillation drug type or the tumor characteris-tics, is actually responsible for the perceived improvement in prognosis regarding tumor recurrence. Theoretically, there could be a placebo effect associated with the intravesical instillation due to mechanical lavage of the bladder or tumor cell lysis if the drug used is hypotonic.56 In a prospective RCT, Onishi et al31detected an
equal recurrence pattern when low- to intermediate-risk patients were treated with a single immediate intravesical MMC instillation
Quality Parameters for NMIBC
-versus a continuous saline bladder irrigation therapy regimen. The RFS rates were 81%, 70.7%, and 70% for the MMC group (n¼ 113) and 78.6%, 70.2%, and 62.6% for the continuous saline bladder irrigation group (n¼ 114) at 1, 3, and 5 years, respectively. The RFS was not significantly different by Kaplan-Meier analysis, suggesting that continuous saline bladder irrigation might be a valid alternative to IVC in low- and intermediate-risk patients. This study failed to provide evidence supporting such treatment practices for high-risk patients.
Induction and Maintenance Intravesical BCG Therapy for Intermediate- and High-Risk Disease
Shelley et al32 performed a systematic review that included 6 randomized trials assessing a total of 585 patients and that analyzed the efficacy of intravesical BCG therapy using the RFS in NMIBC. In only 2 of these studies was BCG induction therapy followed by maintenance therapy with various durations. The study authors concluded that intravesical BCG after TURBT reduced the risk of tumor recurrence by 56% (hazard ratio, 0.44) compared to TURBT alone. The 1-year recurrence rates were 26% and 51%, respectively, for intravesical BCG therapy after TURBT versus TURBT alone. It must be noted that tumor progression was not analyzed, which makes it difficult to assess these results.
The long-term outcome for intravesical induction BCG therapy (6 weeks) was studied by Herr et al33in a RCT including 86
pa-tients. The 10-year PFS rate was 61.9% in patients receiving intravesical BCG therapy after TURBT and 37% in patients un-dergoing only TURBT. In addition, the 10-year disease-specific survival was significantly better when intravesical BCG therapy followed TURBT (75% vs. 55%). Zhu et al34performed a meta-analysis on the ideal intravesical BCG therapy schedule, comparing induction versus maintenance therapy and low versus high doses. Results showed that maintenance therapy could signif-icantly extend both RFS and PFS. Furthermore, a subanalysis of high-risk patients led to similar significant results, suggesting the superiority of maintenance therapy in high-risk disease in terms of recurrence and progression. Furthermore, providing standard doses of BCG, as opposed to low doses, had a significant advantageous effect on recurrence. However, a similar significant effect on pro-gression was not present. This meta-analysis included both RCTs and retrospective cohort studies, thus decreasing its overall quality; however, the same significant results were found when they exclu-sively pooled the results from the RCTs.
Similarly, in a meta-analysis comparing various intravesical BCG therapy schedules, including induction and maintenance schedules, Huang et al35concluded that BCG maintenance was superior to BCG induction-only for NMIBC cases. However, a longer main-tenance period (3 years) did not significantly differ from a shorter one (1 year) in terms of recurrence and progression, and the 3-year maintenance period did not lead to more adverse effects than induction-only therapy. These findings make it difficult to deter-mine the best duration for the BCG maintenance therapy.
Malmström et al36aimed to clarify the role of intravesical BCG therapy versus MMC; they performed a meta-analysis of 9 trials, including a total of 2820 patients, 96.5% of whom had interme-diate- or high-risk disease. Intravesical BCG therapy with a main-tenance phase appeared to be superior to MMC for reducing tumor
recurrence (32% reduction). However, intravesical BCG therapy without maintenance appeared to be inferior to MMC for reducing tumor recurrence, with a 28% increase in the risk of recurrence. An analysis of a subset of articles with long-term outcomes showed no significant difference in progression and survival between groups. In another meta-analysis, Jiang et al37also concluded that intravesical BCG therapy was superior to MMC for reducing progression in NMIBC patients. The included trials showed 5-year PFS rates ranging from 34% to 75% versus 47% to 81% for MMC versus BCG, respectively, with a significant difference (hazard ratio, 0.53) gravitating toward BCG therapy.
In our literature review, we found sufficient evidence that AIVI is a valid QCI. Furthermore, an aggregation of evidence supported the current proposed AIVI regimens based on risk stratification. Although there are some reservations about the evidence that war-rants AIVI, every TURBT should be followed by a specific AIVI regimen. Thus, all NMIBC patients, independent of their risk stratification, would benefit from a single immediate postoperative IVC instillation. For low-risk tumors, a single immediate IVC instillation could be of great value to assure disease control. Patients with low-risk tumors that are likely to recur, such as multiple or large tumors, should be strongly considered for adjuvant therapy. In addition, all intermediate- and high-risk tumors should be treated with intravesical BCG therapy, including induction and mainte-nance. Although this QCI has been recommended for a long time and substantiated scientifically, its application in clinical practice remains low. In the United States, a survey of 259 urologists treating 1010 NMIBC patients showed that only 58.3% of patients with primary low-risk tumors received the advised immediate single IVC administration.57This QCI has not really been implemented in clinical practice; thus, there is a need to improve the knowledge about its benefits. Furthermore, in an effort to evaluate the compliance to BCG therapy, Serretta et al58found that 92.5% of patients completed induction therapy, but only 52.3% of patients completed 1-year maintenance therapy. Of the patients who stopped BCG therapy, 55% refused BCG as a result of mild discomfort and deterioration in the quality of their social life. These findings may call into question the feasibility of using intravesical BCG therapy as a good QCI.
Absence of BP
BP is one of the most feared perioperative complications of TURBT. It is the fourth most common complication after pain, urinary retention, and urinary infections.59Recent evidence notes that BP complicates the perioperative period in 0.5% to 3.8% of resections.59,60 It still remains controversial whether BP has a negative impact on the prognosis of NMIBC.
Theoretically, extravesical metastasis after BP due to tumor seeding is possible; however, the literature suggests that this is a rare phenomenon. Nieder et al61 reported a BP rate of 3.5% during TURBT, but without any subsequent extravesical tumor implan-tation. Similarly, Collado et al62reported BP in 1.3% of TURBTs, but without any new subsequent extravesical tumor localization. Finally, Mack et al63did not observe extravesical metastasis after BP
during a FU of 15 years. There is a small number of cases described where patients presented with extravesical tumor growth after BP during TURBT.64-66
-Comploj et al38performed a cohort comparison study reviewing the effect of BP on tumor behavior and the prognosis for patients with NMIBC. From their institutional data, 6.5% of a total of 565 NMIBC patients experienced BP. It must be noted that a few pa-tients in the BP group did not receive a complete initial resection because the procedure was stopped because of intraoperative bleeding, but these patients did receive a second TURBT after 6 weeks. Both recurrence and progression rates were slightly higher in cases with BP, but these findings were not significantly different from results observed in the nonperforation group. It must be noted that in all BP cases with T-stage progression at recurrence, lesions were present at the perforation site. Furthermore, there was a significantly increased T-stage progression rate at recurrence in pa-tients with BP compared to papa-tients with no BP (18.9% vs. 8.1%, respectively).
Skolarikos et al67concluded that the management of BP had an important impact on disease progression. Four of 34 patients with BP were treated with open surgery; all had extravesical tumor recurrence. The other 30 patients who were treated conservatively did not present with extravesical disease. No significant difference was observed in terms of the number of BPs when patients were randomized to undergo monopolar or bipolar transurethral resec-tion.68An obturator nerve block might be one way to avoid BP, as there is a minor, nonsignificant difference in BP rates.56
The impact of BP on prognosis and extravesical progression re-mains controversial. No hard evidence was found to suggest a sig-nificant shift in the prognosis after BP. In addition, no evidence was found concerning the impact of BP during TURBT on quality of life. Thus, BP should not be seen as a main QCI, but rather a complication that the surgeon should attempt to avoid.
Initial Therapy Within First 6 Weeks After Diagnosis In our extensive literature review, no evidence could be found indicating an ideal time to perform the initial TURBT. It is not clear whether fast initial treatment after the cystoscopic diagnosis results in a better long-term prognosis. Ideally, one can assume that TURBT should be performed within a fairly short period after diagnosis. Also, because the TURBT provides important histologic information, such as involvement of the DM or presence of an aggressive, fast-growing subtype, it might be beneficial to swiftly perform the TURBT. More research on this topic is needed before we can make conclusions about its usefulness. Afirst step could be analyzing patient data retrospectively to verify a difference in outcome based on the period between cystoscopic diagnosis and initial TURBT.
Discussion
Our starting point was the assessment of evidence supporting the established QCIs for TURBT. After reviewing the literature on all these indicators, we can conclude that most of the currently used QCIs are validated for general use in clinical practice. Only BP and initial therapy in thefirst 6 weeks did not have sufficient evidence supporting them as good QCIs. A high-quality TURBT should comprise a complete resection, followed by appropriate adjuvant intravesical therapy. Furthermore, a repeat TURBT should be strongly considered in high-risk tumors but could potentially be avoided when DM is present in the initial resection specimen. In
high-risk tumors, repeat resection should be performed until DM is found in the resection specimen. Although BP is a severe compli-cation, it is not proven to alter the course of disease or quality of life. Initial therapy in thefirst 6 weeks after cystoscopic diagnosis is not a good QCI.
Several alterations to the surgical technique have been proposed to improve the quality and completeness of TURBT. The imperfect sensitivity of standard white light cystoscopy (WLC) potentially explains some of the early recurrences soon after apparently com-plete removal of all visible tumors. Both photodynamic diagnosis and NBI are alternatives to the standard WLC approach. The photodynamic diagnosis is based on thefluorescence principle and is performed using violet light after intravesical instillation of 5-aminolevulinic acid or hex5-aminolevulinic acid. Various studies have confirmed that fluorescence-guided tumor detection is more sensitive than conventional procedures, particularly for carcinoma-in-situ, making resections more complete.69-71A meta-analysis by Burger et al72showed a favorable diagnostic accuracy and recurrence rate for photodynamic diagnosis with hexaminolevulinate, also known as blue light cystoscopy, compared to WLC. Blue light cystoscopy detected significantly more Ta and Tis tumors than the standard WLC (40.8% vs. 14.7%, respectively), resulting in significantly lower recurrence rates up to 12 months (34.5% vs. 45.4%). The NBI improves the detection of NMIBC using light of a narrow bandwidth to increase the contrast between the mucosa and small vascular structures with high resolution.73,74Xiong et al75
published a meta-analysis confirming that the diagnostic accuracy and recurrence rate with NBI cystoscopy were significantly better than with standard WLC. The NBI had a diagnostic accuracy of 95.8%, while WLC had a sensitivity index of 81.6%, resulting in significantly fewer recurrences after 3 and 12 months of FU (4.6% vs. 16.7% and 26.0% vs. 38.6%, respectively).
Additionally, the use of more extensive resections, such as a MR of the tumor bed after a macroscopically complete resection, shows good initial results. Qie et al76confirmed in a retrospective cohort comparison study that an extensive TURBT, performed by taking additional tumor base and MRs, improves the histologic diagnosis andfine-tunes the post-TURBT therapy. Furthermore, it reduces the recurrence rate at first FU cystoscopy compared to normal resection (4.7% vs. 13.1%, respectively). En bloc resection of bladder tumor is a promising alternative to conventional TURBT. One of the major benefits of en bloc resection of bladder tumor is the high percentage of DM in the resection specimens, as this is considered a valid parameter for resection quality.25,26,77However, more qualitative research is needed to clarify whether this technique results in lesser residual tumor and therefore in a more complete resection.
In general, we found there is not an abundance of evidence regarding the impact of using QCIs for TURBT. High-quality studies are especially lacking for certain QCIs. Most reviewed evi-dence had a low LE, although there was plenty of evievi-dence available on the topic of AIVIs, including multiple level 1 studies. We acknowledge that there is relatively poor evidence for these QCIs, and we plan to conduct more high-quality research concerning the impact of the use of QCIs for TURBT, notably for repeat resection and the presence of DM in the resection specimen. Prospective cohort comparison studies on disease progression with large
Quality Parameters for NMIBC
-numbers of included patients and a long FU period exceeding 5 years could provide a clearer perspective on these two indicators. Ideally, patients would be randomized to enhance the value of these long-term studies; however, as mentioned above, such a study design may be difficult to justify on ethical grounds.
We reviewed each QCI separately, but in clinical practice, these indicators interact. As a result of the wide scope of the issue and the heterogeneity of studies in thisfield, it is impossible to evaluate the value of every single indicator on its own, or the value of quality control as a whole in the treatment of NMIBC. The great variety in resection quality and techniques, adjuvant treatments, and FU pe-riods does not allow definite conclusions to be drawn. Also, we did not evaluate data on prostatic urethral or random bladder biopsies, which are relevant parameters to the quality of NMIBC treatment. In practice, a well-documented approach for NMIBC manage-ment is desirable. Before TURBT, all tumor locations and macro-scopic tumor characteristics, according to the diagnostic cystoscopy, should be noted on a bladder diagram. Using this diagram, a detailed resection protocol should be planned before TURBT. All tumor resection locations, as well as the locations of residual tumor when the resection is perceived as incomplete, should be carefully noted on the resection protocol. Furthermore, the presence or absence of DM in the resection specimen from each tumor location should be clearly noted. An eventual repeat resection should be processed in the same way. All AIVIs should be comprehensively noted in the patient records, including the name of the drug, and the number and schedule of instillations. This approach will make patient data more accessible for clinical research.
Conclusion
Three of the 6 QCIs for TURBT—repeat resection, presence of DM in the resection specimen, and AIVIs—are well substantiated by evidence and appear to be good QCIs. In addition, we conclude that a complete resection is also a valid QCI. In total, our literature analysis supports the use of these 4 QCIs in clinical practice to reduce recur-rence and progression, and increase beneficial disease outcomes.
Disclosure
The authors have stated that they have no conflict of interest.
References
1.Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:E359-86.
2.Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol 2009; 27:289-93.
3.Antoni S, Ferlay J, Soerjomataram I, et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol 2017; 71:96-108.
4.Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 2013; 63:234-41.
5.Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66:4-34.
6.Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017.
7.Heney NM, Ahmed S, Flanagan MJ, et al. Superficial bladder cancer: progression and recurrence. J Urol 1983; 130:1083-6.
8.Lutzeyer W, Rübben H, Dahm H. Prognostic parameters in superficial bladder
cancer: an analysis of 315 cases. J Urol 1982; 127:250-2.
9.Babjuk M, Böhle A, Burger M, et al. EAU guidelines on nonemuscle-invasive
urothelial carcinoma of the bladder: update 2016. Eur Urol 2017; 71:447-61. 10.Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of
non-muscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007; 178:2314-30.
11.Burger M, Oosterlinck W, Konety B, et al. ICUD-EAU International Consulta-tion on Bladder Cancer 2012: nonemuscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013; 63:36-44.
12.Carmack AJ, Soloway MS. The diagnosis and staging of bladder cancer: from RBCs to TURs. Urology 2006; 67:3-8.
13.Lee F, Patel H, Emberton M. The‘top 10’ urological procedures: a study of hospital episodes statistics, 1998-99. BJU Int 2002; 90:1-6.
14.Brausi M, Collette L, Kurth K, et al. Variability in the recurrence rate atfirst follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol 2002; 41:523-31. 15.Weldon TE, Soloway MS. Susceptibility of urothelium to neoplastic cellular
im-plantation. Urology 1975; 5:824-7.
16.Power NE, Izawa J. Comparison of guidelines on non-muscle invasive bladder cancer (EAU, CUA, AUA, NCCN, NICE). Bladder Cancer 2016; 2:27-36. 17.Woldu SL, Bagrodia A, Lotan Y. Guideline of guidelines: non-muscle-invasive
bladder cancer. BJU Int 2017; 119:371-80.
18.Kassouf W, Aprikian A, Black P, et al. Recommendations for the improvement of bladder cancer quality of care in Canada: a consensus document reviewed and endorsed by Bladder Cancer Canada (BCC), Canadian Urologic Oncology Group (CUOG), and Canadian Urological Association (CUA), December 2015. Can Urol Assoc J 2016; 10:E46.
19.Jancke G, Rosell J, Jahnson S. Residual tumour in the marginal resection after a complete transurethral resection is associated with local recurrence in Ta/T1 uri-nary bladder cancer. Scand J Urol Nephrol 2012; 46:343-7.
20.Sfakianos JP, Kim PH, Hakimi AA, et al. The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. J Urol 2014; 191:341-5.
21.Kim W, Song C, Park S, et al. Value of immediate second resection of the tumor bed to improve the effectiveness of transurethral resection of bladder tumor. J Endourol 2012; 26:1059-64.
22.Divrik RT, S¸ahin AF, Yildirim Ü, et al. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 uro-thelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. Eur Urol 2010; 58:185-90. 23.Vasdev N, Dominguez-Escrig J, Paez E, et al. The impact of early re-resection in
patients with pT1 high-grade non-muscle invasive bladder cancer. Ecancermedi-calscience 2012; 6:269.
24.Gontero P, Sylvester R, Pisano F, et al. The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/ grade 3 bladder cancer treated with bacille Calmette-Guérin. BJU Int 2016; 118:44-52.
25.Shoshany O, Mano R, Margel D, et al. Presence of detrusor muscle in bladder tumor specimens—predictors and effect on outcome as a measure of resection quality. Urol Oncol 2014; 32:40, e17-e22.
26.Mariappan P, Zachou A, Grigor KM. Detrusor muscle in thefirst, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol 2010; 57:843-9.
27.Roupreˇt M, Yates DR, Varinot J, et al. The presence of detrusor muscle in the pathological specimen after transurethral resection of primary pT1 bladder tumors and its relationship to operator experience. Can J Urol 2012; 19:6459-64. 28.Perlis N, Zlotta AR, Beyene J, et al. Immediate post-transurethral resection of
bladder tumor intravesical chemotherapy prevents nonemuscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. Eur Urol 2013; 64:421-30.
29.Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate post-operative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of ran-domized clinical trials. J Urol 2004; 171:2186-90.
30.Holmäng S. Early single-instillation chemotherapy has no real benefit and should be abandoned in nonemuscle-invasive bladder cancer. Eur Urol Suppl 2009; 8:458-63. 31.Onishi T, Sugino Y, Shibahara T, et al. Randomized controlled study of the efficacy and safety of continuous saline bladder irrigation after transurethral resection for the treatment of non-muscle-invasive bladder cancer. BJU Int 2017; 119:276-82. 32.Shelley MD, Court JB, Kynaston H, et al. Intravesical bacillus Calmette-Guérin in
Ta and T1 bladder cancer. Cochrane Database Syst Rev 2000:CD001986. 33.Herr HW, Schwalb DM, Zhang ZF, et al. Intravesical bacillus Calmette-Guérin
therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 1995; 13:1404-8. 34.Zhu S, Tang Y, Li K, et al. Optimal schedule of bacillus calmette-guerin for
non-muscle-invasive bladder cancer: a meta-analysis of comparative studies. BMC Cancer 2013; 13:332.
35.Huang Z, Liu H, Wang Y, et al. Determining optimal maintenance schedules for adjuvant intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. Curr Med Res Opin 2017; 33:1379-87.
36.Malmström PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for nonemuscle-invasive bladder cancer. Eur Urol 2009; 56:247-56.
37.Jiang SJ, Ye LY, Meng FH. Comparison of intravesical bacillus Calmette-Guerin and mitomycin C administration for nonemuscle invasive bladder cancer: a meta-analysis and systematic review. Oncol Lett 2016; 11:2751-6.
-38.Comploj E, Dechet CB, Mian M, et al. Perforation during TUR of bladder tu-mours influences the natural history of superficial bladder cancer. World J Urol 2014; 32:1219-23.
39.Heneghan C. EBM resources on the new CEBM website. Evid Based Med 2009; 14:67.
40.Liu JJ, Schoenberg MP. Transurethral resection of bladder tumors. In: Bladder Cancer: Diagnosis and Clinical Management. New York, NJ: Wiley; 2015:51-63. 41.Jakse G, Algaba F, Malmström PU, et al. A second-look TUR in T1 transitional
cell carcinoma: why? Eur Urol 2004; 45:539-46.
42.Adiyat KT, Katkoori D, Soloway CT, et al.“Complete transurethral resection of bladder tumor”: are the guidelines being followed? Urology 2010; 75:365-7. 43.Klän R, Loy V, Huland H. Residual tumor discovered in routine second
tran-surethral resection in patients with stage T1 transitional cell carcinoma of the bladder. J Urol 1991; 146:316-8.
44.Vianello A, Costantini E, Del Zingaro M, et al. Repeated white light transurethral resection of the bladder in nonmuscle-invasive urothelial bladder cancers: sys-tematic review and meta-analysis. J Endourol 2011; 25:1703-12.
45.Miladi M, Peyromaure M, Zerbib M, et al. The value of a second transurethral resection in evaluating patients with bladder tumours. Eur Urol 2003; 43:241-5. 46.Fritsche HM, Burger M, Svatek RS, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol 2010; 57:300-9.
47.Svatek RS, Hollenbeck BK, Holmäng S, et al. The economics of bladder cancer: costs and considerations of caring for this disease. Eur Urol 2014; 66:253-62. 48.Angulo J, Palou J, García-Tello A, et al. Second transurethral resection and
prognosis of high-grade non-muscle invasive bladder cancer in patients not receiving bacillus Calmette-Guerin. Actas Urol Esp 2014; 38:164-71.
49.Kurth K, Bouffioux C, Sylvester R, et al. Treatment of superficial bladder tumors:
achievements and needs. Eur Urol 2000; 37:1-9.
50.Dutta SC, Smith JA Jr, Shappell SB, et al. Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol 2001; 166:490-3.
51.Wijkström H, Norming U, Lagerkvist M, et al. Evaluation of clinical staging before cystectomy in transitional cell bladder carcinoma: a long-term follow-up of 276 consecutive patients. Br J Urol 1998; 81:686-91.
52.Cheng L, Neumann RM, Weaver AL, et al. Grading and staging of bladder car-cinoma in transurethral resection specimens: correlation with 105 matched cys-tectomy specimens. Am J Clin Pathol 2000; 113:275-9.
53.Dalbagni G, Herr HW, Reuter VE. Impact of a second transurethral resection on the staging of T1 bladder cancer. Urology 2002; 60:822-4.
54.Maruniak NA, Takezawa K, Murphy WM. Accurate pathological staging of uro-thelial neoplasms requires better cystoscopic sampling. J Urol 2002; 167:2404-7. 55.Erbay G, Akyol F, Karabakan M, et al. Effect of obturator nerve block during
transurethral resection of lateral bladder wall tumors on the presence of detrusor muscle in tumor specimens and recurrence of the disease. Kaohsiung J Med Sci 2017; 33:86-90.
56.Bolkier M, Moskovitz B, Ginesin Y, et al. Effect of distilled water and bacillus Calmette-Guérin on exfoliated bladder tumor cells. Eur Urol 1991; 19:319-21. 57.Cookson MS, Chang SS, Oefelein MG, et al. National practice patterns for
im-mediate postoperative instillation of chemotherapy in nonmuscle invasive bladder cancer. J Urol 2012; 187:1571-6.
58.Serretta V, Gesolfo CS, Alonge V, et al. Does the compliance to intravesical BCG differ between common clinical practice and international multicentric trials? Urol Int 2016; 96:20-4.
59.Gregg JR, McCormick B, Wang L, et al. Short term complications from tran-surethral resection of bladder tumor. Can J Urol 2016; 23:8198-203. 60.Avallone MA, Sack BS, El-Arabi A, et al. Ten-year review of perioperative
com-plications after transurethral resection of bladder tumors: analysis of monopolar and plasmakinetic bipolar cases. J Endourol 2017; 31:767-73.
61.Nieder AM, Meinbach DS, Kim SS, et al. Transurethral bladder tumor resection: intraoperative and postoperative complications in a residency setting. J Urol 2005; 174:2307-9.
62.Collado A, Chechile G, Salvador J, et al. Early complications of endoscopic treatment for superficial bladder tumors. J Urol 2000; 164:1529-32.
63.Mack D, Rammal E, Jakse G. Iatrogenic tumor cell implantation in bladder cancer. Urologe A 1988; 27:99-104.
64.Ohguchi N, Sakaida N, Okamura A, et al. Extravesical tumor implantation caused by perforation during transurethral resection of a bladder tumor: a case report. Int J Urol 1997; 4:516-8.
65.Kim JH, Yang WJ. Delayed spontaneous perforation of urinary bladder with intraperitoneal seeding following radical transurethral resection of invasive uro-thelial cancer: a case report. BMC Res Notes 2014; 7:167.
66.Cusano A, Murphy G, Haddock P, et al. Tumour seeding as a result of intra-peritoneal perforation during transurethral resection of non-muscle invasive bladder cancer. BMJ Case Rep 2014; 2014, bcr2014206631.
67.Skolarikos A, Chrisofos M, Ferakis N, et al. Does the management of bladder perforation during transurethral resection of superficial bladder tumors predispose to extravesical tumor recurrence? J Urol 2005; 173:1908-11.
68.Venkatramani V, Panda A, Manojkumar R, et al. Monopolar versus bipolar transurethral resection of bladder tumors: a single center, parallel arm, randomized, controlled trial. J Urol 2014; 191:1703-7.
69.Jichlinski P, Guillou L, Karlsen SJ, et al. Hexyl aminolevulinatefluorescence cystoscopy: a new diagnostic tool for photodiagnosis of superficial bladder cancer -a multicenter study. J Urol 2003; 170:226-9.
70.Schmidbauer J, Witjes F, Schmeller N, et al. Improved detection of urothelial carcinoma in situ with hexaminolevulinatefluorescence cystoscopy. J Urol 2004; 171:135-8.
71.Hungerhuber E, Stepp H, Kriegmair M, et al. Seven years’ experience with
5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology 2007; 69:260-4.
72.Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol 2013; 64: 846-54.
73.Cauberg EC, Kloen S, Visser M, et al. Narrow band imaging cystoscopy improves the detection of non-muscle-invasive bladder cancer. Urology 2010; 76:658-63. 74.Herr HW, Donat SM. A comparison of white-light cystoscopy and narrow-band
imaging cystoscopy to detect bladder tumour recurrences. BJU Int 2008; 102: 1111-4.
75.Xiong Y, Li J, Ma S, et al. A meta-analysis of narrow band imaging for the diagnosis and therapeutic outcome of non-muscle invasive bladder cancer. PLoS One 2017; 12:e0170819.
76.Qie Y, Hu H, Tian D, et al. The value of extensive transurethral resection in the diagnosis and treatment of nonmuscle invasive bladder cancer with respect to recurrence at thefirst follow-up cystoscopy. Onco Targets Ther 2016; 9: 2019-25.
77.Kramer MW, Altieri V, Hurle R, et al. Current evidence of transurethral en-bloc resection of nonmuscle invasive bladder cancer. Eur Urol Focus 2017; 3:567-76.
