Review Article. Kyle A. Richards,* Norm D. Smith and Gary D. Steinberg

Review Article The Importance of Transurethral Resection of Bladder Tumor in the Management of Nonmuscle Invasive Bladder Cancer: A Systematic Review of Novel Technologies Kyle A. Richards,* Norm D. Smith and Gary D. Steinberg From the Department of Surgery, Section of Urology, The University of Chicago Medical Center, Chicago, Illinois Purpose: Transurethral bladder tumor resection is one of the most commonly performed procedures by practicing urologists for the diagnosis, staging and treatment of nonmuscle invasive bladder cancer. There is wide variation in the technique and quality of transurethral bladder tumor resection among urologists. This is the first and critically important diagnostic and staging tool in the management of bladder cancer, which is a potentially lethal malignancy and the most costly urological malignancy to manage. In this review we provide an evidence-based rationale for the incorporation of novel technologies for transurethral resection of bladder tumor in the setting of previously set standards. Materials and Methods: A systematic MEDLINEÒ/PubMedÒ, Cochrane Library and Ovid MEDLINEÒ search was performed using 2 separate search queries. The MEDLINE/PubMed search was performed using the key words transurethral resection bladder tumor, filtering the search to include studies published within the last 5 years, English language and human species. A second search without filters was performed with the same key words in the Cochrane Library and Ovid MEDLINE. Study eligibility was defined based on patients with nonmuscle invasive bladder cancer, treatment with transurethral bladder tumor resection and with variable comparators based on novel technology used. All study designs were accepted except case reports, animal studies, editorials and review articles with various outcome measures reported including tumor detection, residual tumor detection, disease recurrence/progression and adverse events. Results: The literature search ultimately yielded 971 manuscripts for review with 42 meeting inclusion criteria for systematic review. Refinements in technique and surgeon experience are critical for the performance of a thorough, complete, high quality transurethral bladder tumor resection. Recent technological advances including bipolar electrocautery and regional anesthetic techniques may help reduce the complications associated with transurethral bladder tumor resection. Photodynamic diagnosis may help increase the diagnostic accuracy, reduce the recurrence rate and decrease the cost of treating patients with nonmuscle invasive bladder cancer. Repeat transurethral bladder tumor resection and perioperative intravesical chemotherapy remain standard components in select patients with nonmuscle invasive bladder cancer. Appropriate clinical staging and treatment of patients with nonmuscle invasive bladder cancer remain a challenge. Conclusions: Recent advances in transurethral bladder tumor resection should aid its diagnostic accuracy, reduce recurrences, decrease complications and reduce the cost of management of nonmuscle invasive bladder cancer. Urologists Abbreviations and Acronyms AUA ¼ American Urological Association BCa ¼ bladder cancer BCG ¼ bacillus Calmette-Guerin BL ¼ blue light CIS ¼ carcinoma in situ EAU ¼ European Association of Urology FDA ¼ Food and Drug Administration HAL ¼ hexaminolevulinate IVC ¼ intravesical chemotherapy NBI ¼ narrow band imaging NCCN ¼ National Comprehensive Cancer Network NMIBC ¼ nonmuscle invasive bladder cancer PDD ¼ photodynamic diagnosis TURBT ¼ transurethral resection of bladder tumor WL ¼ white light Accepted for publication January 7, 2014. * Correspondence: 5841 S. Maryland Ave. MC 6038, Chicago, Illinois 60637 (e-mail: kyle. richards@uchospitals.edu). Financial interest and/or other relationship with Photocure, Endo Pharmaceuticals, Karl Storz, Taris Biomedical, Abbott Molecular, Cold Genesys and Heat Biologics. See Editorial on page 1646. 0022-5347/14/1916-1655/0 THE JOURNAL OF UROLOGY 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. http://dx.doi.org/10.1016/j.juro.2014.01.087 Vol. 191, 1655-1664, June 2014 Printed in U.S.A. www.jurology.com j 1655

1656 IMPORTANCE OF TRANSURETHRAL BLADDER TUMOR RESECTION should incorporate these evidence-based strategies into current guideline recommendations to improve patient outcomes following transurethral resection of bladder tumor in everyday practice. Key Words: urinary bladder neoplasms; surgical procedures, operative IN 2012 bladder cancer was the 4th most common malignancy in men and the 10th most common malignancy in women in the United States. 1 With an estimated 585,390 Americans living with BCa and approximately 73,510 new cases diagnosed in 2012, 1 the management of BCa including transurethral bladder tumor resection is commonplace in urological practice. A majority of patients (70% to 80%) present with nonmuscle invasive bladder cancer, and require periodic surveillance cystoscopy and TURBT due to frequent recurrences. However, significant heterogeneity exists among patients with NMIBC such that the mortality rate from low risk disease is nil vs 30% at 10 years for high risk disease. 2 A critical component of managing NMIBC remains thorough, high quality TURBT as under staging, misdiagnosis and incomplete resection with an overreliance on intravesical therapy may lead to less optimal treatment of these patients, worse cancer outcomes and increased cost. BCa is the most expensive urological malignancy with an estimated $65,158 average lifetime cost per patient, of which $39,293 is associated with surveillance and management of recurrence, underscoring the importance of high quality TURBT. 3 In this review we identify evidence-based strategies that improve the quality of TURBT, reduce the recurrence rate of NMIBC and decrease the financial burden of bladder cancer management. MATERIALS AND METHODS Search Strategy A systematic MEDLINE/PubMed, Cochrane Library and Ovid MEDLINE search was performed on September 6, 2013. The MEDLINE/PubMed search was performed using the key words transurethral resection bladder tumor, filtering the search to include studies published within the last 5 years to focus the review on the most novel technologies. A second search without a time filter was performed with the same key words in the Cochrane Library and Ovid MEDLINE. In addition, the references of relevant articles were reviewed and cross-checked to identify additional literature of interest. Inclusion Criteria The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) criteria were used to evaluate records identified during the literature search (fig. 1). 4 Each individual abstract was reviewed by 2 co-authors independently according to the CONSORT (Consolidated Standards for Reporting Trials) 5 and STARD (Standards for the Reporting of Diagnostic Accuracy) 6 criteria to assess the articles with the highest level of evidence. A third independent research team member settled any disagreements. Study Eligibility Study eligibility was defined using the PICOS (patient population, intervention, comparator, outcome and study design) approach (Appendix 1). 4 These criteria were limited to the English language, original studies and meta-analyses, while we excluded meeting abstracts, review articles and editorials. If multiple studies reported on similar or overlapping data sets, the latest study was selected, unless different end points were investigated. Evidence Synthesis The literature search ultimately yielded 971 manuscripts for review (fig. 1). We report the results of the 42 articles selected for inclusion in this systematic review. INDICATIONS AND RATIONALE FOR HIGH QUALITY TURBT TURBT is an important first step for patients with a bladder tumor for diagnosis, staging and therapeutic reasons. The AUA, EAU and NCCNÒ guidelines on nonmuscle invasive bladder cancer recommend complete resection of all visible tumors including sampling of the muscularis propria whenever possible. 7e9 Despite these recommendations, complete eradication of all visible tumors and sampling of the muscularis propria remain elusive. Adiyat et al retrospectively reviewed the records of 47 patients who underwent a second TURBT within 4 weeks of referral to their center, excluding those with muscle invasive disease and known incomplete resection. 10 At re-turbt 70% of patients had visible tumor (30% at prior resection site, 70% with tumor away from prior resection site), highlighting the potential for incomplete resection presumably from variable or poor technique. Furthermore, operator experience and tumor location seem to impact quality of resection. Huang et al analyzed their prospective TURBT database, and identified 216 patients with primary bladder tumors judged to be NMIBC and completely eradicated at the time of resection. 11 Logistic regression analysis was conducted, revealing that junior surgeons, tumor size and tumor location (anterior/dome/lateral) were independently associated with the absence of muscularis propria in the TURBT specimens. Junior surgeons were also independently associated with an increased rate

IMPORTANCE OF TRANSURETHRAL BLADDER TUMOR RESECTION 1657 Figure 1. Flow diagram of evidence acquisition for systematic review of novel technologies of residual tumor. Others have also noted lower recurrence rates when TURBT is performed by more senior surgeons. 12,13 There is a learning curve and an art to performing high quality TURBT, and perhaps extended TURBT may help improve local tumor control. 14 By taking additional deep and marginal specimens (extended TURBT), excellent local control was achieved with a 5.1% recurrence rate in the same area as a unifocal primary tumor. With careful attention to technique, complete eradication of tumor and sampling of muscularis propria can be accomplished quickly and efficiently. Teaching trainees the skills necessary for TURBT can be a daunting task, which is often seen as a trivial procedure by junior residents. A solution to this problem could be incorporation of virtual reality simulation into training programs. The commercially available Uro-Trainer (Karl Storz GmbH, Tuttlingen, Germany) provides visual perception and haptic force feedback for TURBT simulation, and has shown promise in training and skills acquisition in novice surgeons. 15 Additional studies on virtual reality simulation for TURBT are needed. TECHNIQUE Anesthesia Typically general anesthesia with neuromuscular paralysis should be used to decrease the likelihood of an obturator reflex during TURBT, especially for tumors located posterolaterally. In 51 consecutive patients undergoing monopolar TURBT ishuang et al noted obturator reflex in 16%, half of which resulted in bladder perforation. 16 Obturator reflex was not noted in cases with tumors that did not extend to the lateral bladder wall. Spinal anesthesia with or without obturator nerve block may be used before TURBT as an alternative to general anesthesia. Lee et al described a novel technique of ultrasound guided obturator nerve block in which 20 ml 1% lidocaine with epinephrine was injected in the fascial space between the adductor longus and adductor brevis muscles. 17 After the injection TURBT was performed in 25 patients under spinal anesthesia with 96% successful inhibition of obturator reflex. Urologists can also perform a transurethral obturator nerve block at TURBT as described by Khorrami et al. 18 In 47 patients at high risk with general anesthesia with lateral tumors, transurethral obturator nerve block was performed along with spinal anesthesia, with 6.3% of patients noted to have an obturator reflex during TURBT. Patient Preparation All patients should receive antimicrobial prophylaxis with a fluoroquinolone or sulfamethoxazoletrimethoprim according to the AUA Best Practice Policy Statement on Urologic Surgery Antimicrobial

1658 IMPORTANCE OF TRANSURETHRAL BLADDER TUMOR RESECTION Prophylaxis. 19 Alternative choices for prophylaxis include an aminoglycoside with or without ampicillin, a 1st/2nd generation cephalosporin or amoxicillin/clavulanate with a duration of therapy of 24 hours or less. Patients with a prosthetic joint replacement undergoing TURBT the first 2 years after joint replacement, poor immune function, or increasing comorbidity are at increased risk for hematogenous total joint infection. These patients should receive prophylaxis with a quinolone given orally 1 to 2 hours preoperatively, 2 gm intravenous ampicillin (or vancomycin in patients allergic to penicillin), plus 1.5 mg/kg intravenous gentamicin 30 to 60 minutes preoperatively. 19 The American Heart Association no longer recommends antimicrobial prophylaxis in association with urological procedures solely to prevent infectious endocarditis. 20 Equipment/Electrocautery/Irrigation Successful TURBT requires essential equipment (Appendix 2). The type of resectoscope, energy source and loop can vary based on the preference of the surgeon. Traditionally TURBT was performed using monopolar electrocautery with conductive irrigation fluid. The disadvantages of monopolar TURBT include the risk of transurethral resection syndrome from absorption of hypotonic irrigation fluids and the need for the electrical current to travel through the patient s body to the return electrode. Bipolar generators and resectoscope platforms were subsequently developed to help mitigate these risks. The early clinical results of bipolar TURBT appear promising. Puppo et al assessed the safety of bipolar TURBT in 480 consecutive patients, and noted a 2% rate of obturator nerve reflex, 0.8% blood transfusion rate and no cases of transurethral resection syndrome or thermal skin lesion. 21 In addition, reducing the power settings to 50 W cutting and 40 W coagulation reduces the risk of obturator reflex and bladder perforation close to zero while maintaining its efficacy. 22 While traditional TURBT is performed with a right-angle or angled loop, novel electrodes and/or laser techniques have been described to help decrease the risk of complications. Canter et al presented their early experience on 15 patients using the Olympus Button Electrode (Olympus, Southborough, Massachusetts), which is a bipolar vaporization electrode. 23 The proposed advantages of the Olympus Button Electrode include improved visibility due to less bleeding, the ability to access difficult tumors at the dome or anterior bladder wall, and the lack of superficial char which would slow vaporization of deeper portions. The disadvantage of this approach is the need to obtain tissue for accurate staging and grading of the tumor. Tao et al compared the safety and efficacy of 120 W potassium-titanyl-phosphate laser vaporization to standard TURBT in 158 patients, and noted an excellent safety profile compared to standard TURBT. 24 This may be a viable option for patients who must be maintained on anticoagulation. While these novel techniques appear to have acceptable morbidity, further study is needed to determine the oncologic safety. The irrigation fluid should be tailored based on the type of energy used for TURBT. Normal saline should be used for procedures with bipolar or laser energy; whereas conductive fluid such as glycine, water or sorbitol is required for monopolar TURBT. The fluid should also be warmed to body temperature to help reduce the risk of hypothermia. 25 White Light White light has traditionally been used for illumination during TURBT. As recurrences are common for NMIBC following TURBT (31% to 78% within 5 years), 26 one hypothesis for such a high recurrence rate is incomplete resection due to failure to visualize the entirety of the tumor(s) under WL illumination. In a phase III multicenter study Fradet et al compared the performance characteristics of hexaminolevulinate fluorescence cystoscopy and WL cystoscopy for the detection of carcinoma in situ in patients with NMIBC. 27 WL cystoscopy had a sensitivity of 68% at the lesion level, a specificity of 72% by patient and a false-positive detection rate at the biopsy level of 31%. These data support ongoing efforts to improve technologies to assist in the complete eradiation of bladder tumors at the time of TURBT. Photodynamic Diagnosis (Fluorescence Cystoscopy) Photodynamic diagnosis has emerged as a viable option to improve outcomes during TURBT. The goal of PDD is to facilitate the detection of lesions, reduce recurrence rates and improve on the completeness of resection. PDD exploits the photodynamic properties of several compounds including 5-aminolevulinic acid and HAL (HexvixÒ, CysviewÒ, PhotocureÒ, Oslo, Norway). Cysview (hexaminolevulinate hydrochloride) was approved by the FDA in 2010 for use with the Karl Storz D-Light C PDD system with the blue light setting as an adjunct to the white light setting in the detection of NMIBC among patients suspected or known to have lesion(s) on the basis of prior cystoscopy (www.fda.gov). 5-Aminolevulinic acid is not currently approved for use in the urinary tract in the United States or Europe as the results of randomized prospective multicenter clinical trials have shown no clear advantage over WL cystoscopy. 28

IMPORTANCE OF TRANSURETHRAL BLADDER TUMOR RESECTION 1659 HAL (50 ml reconstituted solution) is introduced into the patient s empty bladder approximately 1 hour before TURBT via an intravesical catheter. Protoporphyrin I accumulates preferentially in neoplastic tissue, which can be visualized as a clearly demarcated red fluorescence under BL illumination (380 to 440 nm) (fig. 2). Stenzl et al conducted a prospective, randomized, multicenter clinical trial to assess the impact of HAL BL cystoscopy on recurrence rates. 29 A total of 814 patients with BCa at increased risk of recurrence were randomized to WL cystoscopy alone vs WL cystoscopy plus HAL BL. The HAL BL cystoscopy performed better than WL alone, detecting an additional Ta/T1 tumor in 16% of patients (p ¼ 0.001) as well as an additional CIS lesion in 46% (p <0.0001). There was no difference in the false-positive biopsy rate between the HAL BL group (12%) and the WL group (10%). Furthermore, fewer recurrences were noted during the 9-month surveillance period in the HAL BL group (47%) vs the WL group (56%, p ¼ 0.026), which also held true for patients with a history of recurrent bladder cancer (p ¼ 0.04). With long-term followup median time to recurrence was 9.4 months in the WL group and 16.4 months in the HAL BL group (p ¼ 0.04), and there was a trend toward decreased progression to muscle invasive BCa in the HAL BL group (3.1%) vs the WL group (6.1%) (p ¼ 0.066). 30 In a recent meta-analysis Burger et al reviewed data for HAL BL cystoscopy from prospective studies on 1,345 patients with NMIBC. 31 HAL BL cystoscopy detected significantly more CIS lesions (40.8%; OR 12.372, 95% CI 6.343e24.133) and detected at least 1 additional tumor in nearly a quarter of patients compared to WL cystoscopy alone. In addition, recurrence rates at 12 months were significantly lower overall with BL (34.5%) vs WL (45.4%; RR 0.761, 0.627e0.924). Furthermore, if performed at initial transurethral bladder tumor resection, HAL BL cystoscopy is cost-effective with an estimated $5,000 savings per patient during a 5-year followup period. 32 The EAU 2013 guidelines for the management of NMIBC recommend the use of PDD in patients suspected of harboring high grade tumor for guidance during TURBT. 8 HAL BL guidance may be helpful in other clinical scenarios (Appendix 3). 29,31,33 It appears to reduce recurrences from missed tumors, which may obviate the need for repeat TURBT and/or perioperative intravesical chemotherapy, thus eliminating extra expense, time, anesthesia and morbidity associated with these practices. Further research is needed to address these important questions. Narrow Band Imaging Narrow band imaging is a novel application that functions as an optical image enhancement technique, allowing easier endoscopic identification of abnormal urothelium. By filtering WL output into blue (415 nm) and green (540 nm) light, narrow band light is strongly absorbed by hemoglobin, thus enhancing the visibility of surface capillaries more prominent in hypervascular neoplastic tissues. 34 NBI is approved by the U.S. FDA for the enhanced visualization of structures in the gastroenterology/ urology setting (www.fda.gov). In a meta-analysis evaluating the accuracy of NBI compared with WL cystoscopy for NMIBC in 1,040 patients, Li et al noted that an additional 17% of patients (95% CI 10e25) and an additional 24% of tumors (95% CI 17e31) were detected by NBI. 35 Furthermore, an additional 28% of CIS (95% CI 14e45) was detected Figure 2. A, unremarkable appearance of bladder under WL cystoscopy. B, appearance of bladder under BL cystoscopy with HAL fluorescence cystoscopy showing red fluorescence of CIS.

1660 IMPORTANCE OF TRANSURETHRAL BLADDER TUMOR RESECTION by NBI and there was no difference in false-positive detection rate between NBI and WL cystoscopy. Yet given these findings, NBI has not gained widespread acceptance due to its relative lack of specificity for neoplastic tissue. NBI may also decrease the rate of recurrence for patients with NMIBC. Geavlete et al randomized 220 patients with suspected NMIBC to standard WL monopolar TURBT vs WL and NBI assisted bipolar plasma vaporization of bladder tumors. 36 Patients with NMIBC underwent repeat TURBT at 4 weeks, with significantly lower residual tumor rates in the NBI vs WL groups and significantly reduced overall 1-year recurrence rates in the NBI group (7.9% vs 17.8%). NBI should be considered a useful adjunct to WL cystoscopy at centers where this technology is available. POSTOPERATIVE MANAGEMENT If a bladder perforation is suspected a Foley catheter should be maintained postoperatively and perioperative IVC should not be administered. Postoperative pain is usually not significant. However, catheter related bladder discomfort can be a significant source of morbidity for some patients. In a randomized, placebo controlled, clinical trial in 100 patients 1,200 mg gabapentin administered orally 1 hour before surgery decreased the incidence of catheter related bladder discomfort from 90% in the placebo group to 26% in the 1,200 mg gabapentin group. 37 Larger studies on gabapentin are needed before adopting this approach for all patients before TURBT. PERIOPERATIVE INTRAVESICAL CHEMOTHERAPY The AUA, NCCN and EAU guidelines on the management of NMIBC all recommend the consideration of a single dose of IVC (usually mitomycin C) within 24 hours of resection. 7e9 Evidence for this approach was strengthened by a meta-analysis that revealed a decreased likelihood of recurrence in patients who received IVC with a number needed to treat to prevent 1 recurrence of 8.5. 38 An updated meta-analysis included 13 randomized controlled trials with 2,548 patients. 39 Postoperative IVC prolonged the recurrence-free interval by 38% (HR 0.62, 95% CI 0.50e0.77) with an absolute risk reduction of 12% for early recurrence. However, the overall quality of evidence was low due to the risk of bias (high risk of bias in 12 of 13 publications) and methodological inconsistency. Furthermore, the benefit of postoperative IVC is largely restricted to patients with low risk NMIBC. Postoperative IVC relies on passive diffusion into the urothelium to prevent cancer cell implantation. Laboratory and small clinical studies revealed increased mitomycin bladder uptake with intravesical electromotive drug administration, prompting a multicenter randomized trial comparing TURBT alone (124), immediate post-turbt IVC (126) or immediate pre-turbt electromotive drug administration intravesical mitomycin (124). 40 After a median followup of 86 months the recurrence rate (38%) and disease-free interval (52 months) were significantly improved in the pre- TURBT electromotive drug administration group compared to the TURBT alone (64% and 12 months, respectively) and immediate post-turbt IVC groups (59% and 16 months, respectively). While this technology appears promising, further study is needed to externally validate these results. Despite relatively strong clinical evidence in support of perioperative IVC, this approach varies widely in clinical practice. The Urological Surgery Quality Collaborative performed a prospective evaluation from 2010 to 2012 to understand the use and barriers to the use of postoperative IVC at 5 centers in the United States. 41 Data were collected on 1,931 patients presenting for TURBT, of whom 37.2% were deemed ideal candidates for postoperative IVC based on predetermined criteria (1 to 2 clinical stage Ta/T1, completely resected papillary tumors). Of the ideal candidates 37.9% (range 26.6% to 50.3%, p <0.001) received treatment with immediate postoperative IVC. Treating physicians cited several common reasons for not administering IVC in ideal candidates, including lack of confirmation of malignancy, uncertainty regarding the benefits and lack of medication availability. Sound clinical judgment remains a critical factor in assessing who should receive IVC, even in the setting of an ideal tumor. For instance, the risk-to-benefit ratio may be marginal for postoperative IVC in cases that involve a deep resection, resection of the ureteral orifice or bladder neck, cases where more aggressive therapy is planned, or cases of prior intravesical therapy. In these cases the omission of postoperative IVC represents sound clinical judgment. Further clinical trials are warranted to compare the efficacy of IVC with emerging technologies such as PDD. PERIOPERATIVE COMPLICATIONS TURBT is a procedure with low morbidity but certain complications deserve specific attention. Extravasation of postoperative IVC can be serious, resulting in a much more challenging radical cystectomy should the patient require such treatment.

IMPORTANCE OF TRANSURETHRAL BLADDER TUMOR RESECTION 1661 Mertens et al reported the complicated course of 9 patients during a 10-year period who presented with symptomatic extravasation of IVC. 42 According to the Clavien classification system 8 of 9 patients experienced a Clavien III or greater complication requiring a procedural intervention or surgery for management. Postoperative IVC is contraindicated when bladder perforation is suspected. Hollenbeck et al used the National Surgical Quality Improvement Program database, which prospectively enrolled 21,515 TURBTs from 1991 to 2002, to evaluate risk factors for complications. 43 The overall complication rate was 4.3% with the most common being urinary tract infection (3%) and hematuria (2.1%). Logistic regression analyses identified disseminated disease, preoperative weight loss, preoperative acute renal failure, preoperative hypoalbuminemia, poor functional status and emergent case status as independent predictors of any complication. As a majority of patients with BCa are elderly with multiple comorbid conditions, thorough preoperative medical evaluations remain prudent before TURBT. SECOND TURBT A second TURBT, also known as re-staging TURBT, should be considered standard for any high grade tumor, multifocal tumors, the majority of T1 tumors, incompletely resected tumors and if no muscularis propria is identified in the specimens of patients with NMIBC. 44 There are several rationales for second TURBT in high risk patients with NMIBC. It is critical to resect all visible papillary tumors, especially T1 lesions, as intravesical BCG is used to treat CIS and does not treat residual papillary tumors. In addition, the risk of under staging NMIBC is significant, with up to 30% of cases being up staged to T2 at the second TURBT. 44 A second TURBT may help better select patients for immediate radical cystectomy vs intravesical therapy as a majority of patients with residual T1 disease at the second resection tend to experience progression. 44 Lastly, a second TURBT may improve the outcomes of patients with NMIBC. Divrik et al performed a randomized prospective clinical trial in 210 patients with newly diagnosed T1 BCa. 45 Half of the patients underwent a second TURBT, whereas the other half did not, with a mean followup of 66.1 months. The second TURBT group had significantly improved recurrence-free survival (52% vs 21%, p ¼ 0.0001) and progression-free survival (93% vs 76%, p ¼ 0.0001) compared to the no second TURBT group. Therefore, a second TURBT remains standard in patients with high risk NMIBC. While emerging technologies such as PDD and NBI might contribute to the completeness of initial TURBT, it is unclear if they can solve the problem of under staging. PATHOLOGY The pathologist has a critical role in examining the specimens following TURBT to provide an accurate diagnosis. The NCCN and EAU guidelines recommend the 2004 WHO (World Health Organization) grading system (high grade vs low grade), and the pathologist should comment on the presence and involvement of muscularis propria, the presence or absence of lymphovascular invasion and the presence or absence of CIS. 8,9 In addition, any aberrant histology should be noted. Despite these recommendations, a survey of uropathologists in Europe revealed that only 50.9% use the WHO 2004 grading system. 46 It is essential that accurate staging and grading be obtained from TURBT, and the urologist should have a close working relationship with the pathologist. WHAT DO THE GUIDELINES SAY? The evidence-based guidelines of the AUA, NCCN and EAU for the management of NMIBC have been referenced throughout this review as they apply to specific technical considerations for TURBT. Inherent in the guidelines is the need to use sound clinical judgment and patient specific individualized treatment plans as some of the recommendations are based on lower level evidence and expert panel consensus. Appendix 4 presents a summary and comparison of these recommendations. FUTURE DIRECTIONS While recent advances in optical imaging including PDD and NBI have improved the diagnosis and treatment of NMIBC, there still are concerns over false positivity from infection and/or inflammation. Novel noninvasive optical coherence tomography is in development that enables the imaging of biological tissues at a high spatial resolution of 1 to 10 mm for 2 mm depth. 47 This technology allows subcellular imaging of the urothelium to grade urothelial carcinoma, showing promise for future optical biopsy combined with cystoscopy and optical imaging in vivo. 47e49 Studies are needed in humans to determine if this technique can minimize the aforementioned issues with diagnostic specificity and false positives. While HAL is only approved for the initial detection of NMIBC, its role could expand to use in the post-bcg setting and in patients with recurrence. Further studies are needed in these settings as well as to assess the utility of postoperative IVC and second TURBT after a potentially more complete TURBT with HAL assistance.

1662 IMPORTANCE OF TRANSURETHRAL BLADDER TUMOR RESECTION CONCLUSIONS High quality, complete TURBT is an essential skill for urologists that can impact diagnostic accuracy, recurrence and disease progression when properly performed. Under staging, overreliance on TURBT and intravesical therapy (perioperative administration of chemotherapy and multiple courses of BCG), and missed diagnosis of CIS with white light cystoscopy are major challenges in the management of NMIBC. While the basic principles of TURBT remain constant, technological advances and solid clinical trial evidence have greatly impacted the field in the last decade. Nonetheless, the treatment of patients with NMIBC should be individualized and tailored to their needs, incorporating the evidence-based strategies outlined in this review with the recommendations of the major urological guidelines. More work is needed to improve the diagnostic staging of TURBT, reduce recurrences and progression from NMIBC, and contain the financial costs associated with the management of these complex cases. APPENDI 1 Study eligibility using the PICOS approach 4 (P) Patient Population (I) Intervention (C) Comparator (O) Outcome (S) Study Design Patient cohort treated for NMIBC A cohort treated with TURBT Varied based on novel technology used to assist with TURBT (ie monopolar as gold standard compared to bipolar) Tumor detection, residual tumor detection, disease recurrence/progression and adverse events All study designs were accepted except case reports, animal studies, editorials and review articles APPENDI 2 Essential equipment for successful TURBT Camera Light source and cord Continuous flow resectoscope (26-28Fr) Irrigation fluid and tubing Telescope lenses (0, 12, 30, 70-degree) Generator for cautery/laser Loops, electrodes, laser fibers Toomey syringe or Ellik evacuator Appropriately labeled containers for pathological specimens APPENDI 3 Potential indications and rationale for use of HAL BL cystoscopy Indication Newly diagnosed bladder tumor, suspect NMIBC Positive urine cytology, negative WL cystoscopy Recurrent NMIBC Post-intravesical BCG, possible recurrence Rationale Recommended in this setting by the EAU Approved by the U.S. FDA in 2010 with this indication 25% increased detection rate compared to WL alone 31 This scenario is usually due to difficult to detect disease in the bladder (ie CIS) 41% increased detection of CIS compared to WL alone 31 Recurrence is common in patients with NMIBC 10% absolute reduction in recurrence rates with HAL BL 31 Lower recurrence rates noted in patients with recurrent NMIBC 29 High false-positive rates common due to inflammation and post-bcg changes Can detect additional pathology in 19% of cases 33 Lower false-positives than WL alone and when preoperative voided urine cytology is positive 33 APPENDI 4 Principles of surgical management of NMIBC: a comparison of AUA, EAU and NCCN guidelines NCCN AUA EAU Complete resection with muscle in the specimen Repeat TURBT within 6 weeks if incomplete initial resection, no muscle in original specimen for high grade disease, large or multifocal lesions, any T1 Multiple selective and/or random biopsies for suspected CIS Additional biopsy adjacent to papillary tumor for suspected CIS Consider prostatic urethral biopsy for suspected CIS Perform examination with patient under anesthesia for aggressive appearing tumors Repeat TURBT if initial resection incomplete and considering bladder preservation therapy If postoperative intravesical chemotherapy is planned, administration should be within 24 hours Upper tract axial imaging should be obtained prior to TURBT for aggressive appearing tumors In patients with palpable lesions before TURBT, bimanual palpation should be repeated after resection Office based fulguration is acceptable for patients with small papillary recurrences and history of low grade Ta tumors Bipolar electrocautery system may reduce the risk of complications HAL is recommended in patients who are suspected of harboring a high grade tumor

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