ICUD-EAU International Consultation on Bladder Cancer 2012: Non Muscle-Invasive Urothelial Carcinoma of the Bladder

Transcription

1 EUROPEN UROLOGY 63 (2013) available at journal homepage: Review Bladder Cancer ICUD-EU International Consultation on Bladder Cancer 2012: Non Muscle-Invasive Urothelial Carcinoma of the Bladder Maximilian Burger a,y, Willem Oosterlinck b,y, Badrinath Konety c, Sam Chang d, Sigurdur Gudjonsson e, Raj Pruthi f, Mark Soloway g, Eduardo Solsona h, Paul Sved i, Marko Babjuk j, Maurizio. Brausi k, Christopher Cheng l, Eva Comperat m, Colin Dinney n, Wolfgang Otto o, Jay Shah n, Joachim Thürof p, J. lfred Witjes q, * a Department of Urology and Pediatric Urology, Julius-Maximilians-University Medical Center, Würzburg, Germany; b Ghent University Hospital, Ghent, Belgium; c Department of Urology, University of Minnesota, Minneapolis, Minnesota, US; d Department of Urological Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, US; e Department of Clinical Sciences Urology, Skåne University Hospital, Malmö, Sweden; f Division of Urologic Surgery, Department of Surgery, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, US; g Department of Urology, University of Miami Miller School of Medicine, Miami, Florida, US; h Service of Urology, Instituto Valenciano de Oncología, Valencia, Spain; i University of Sydney, Sydney, ustralia; j Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Praha, Czech Republic; k Department of Urology, USL Modena, Modena, Italy; l Department of Urology, Singapore General Hospital, Singapore, Singapore; m Department of Pathology, La Pitié-Salpétrière, ssistance-publique Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France; n Department of Urology, The University of Texas MD nderson Cancer Center, Houston, Texas; o St Josef Medical Centre, Department of Urology of Regensburg University, Regensburg, Germany; p Department of Urology, University Medical Center, Johannes Gutenberg University, Mainz, Germany; q Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands rticle info rticle history: ccepted ugust 28, 2012 Published online ahead of print on September 5, 2012 Keywords: Bacillus Calmette-Guérin (BCG) Bladder cancer Cystoscopy Diagnosis Guidelines Intravesical chemotherapy Prognosis Transurethral resection (TUR) bstract Context: Our aim was to present a summary of the Second International Consultation on Bladder Cancer s on the diagnosis and treatment options for non muscle-invasive urothelial cancer of the bladder (NMIBC) using an -based approach. Objective: To critically review the recent data on the management of NMIBC to arrive at a general consensus. Evidence acquisition: detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. Evidence synthesis: The major findings are presented in an -based fashion. We analyzed large retrospective and prospective studies. Conclusions: Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta highgrade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy. # 2012 European ssociation of Urology. Published by Elsevier B.V. ll rights reserved. y These authors contributed equally. * Corresponding author. Department of Urology, Radboud University Nijmegen Medical Centre, Geert Grooteplein South 10 (659), PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel ; Fax: address: F.Witjes@uro.umcn.nl (J.. Witjes) /$ see back matter # 2012 European ssociation of Urology. Published by Elsevier B.V. ll rights reserved.

2 EUROPEN UROLOGY 63 (2013) Introduction Most new cases of urothelial cancer of the bladder (UCB) are Ta, T1, or carcinoma in situ (CIS) often grouped as non muscle-invasive bladder cancer (NMIBC), formerly known as superficial bladder cancer (BCa) [1]. Initial management is a complete endoscopic resection, which allows for the initial staging that is critical for management decisions. fter the initial surgery, the urologist should consider a reresection or perioperative and/or adjuvant intravesical therapy, depending on tumor grade, stage, and multiplicity. The Second International Consultation on Bladder Cancer has provided s on the diagnosis and treatment options for non muscle-invasive urothelial cancer of the bladder (NMIBC) using an -based approach. We present a summary of these s. 2. Evidence acquisition detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and followup. Proceedings from the last 5 yr of major conferences were also searched. The was analyzed using the Oxford method of assigning the levels of, and summary s based on these levels of were graded as advised by the Oxford Centre for Evidence-based Medicine, which are similar to the Grading of s ssessment, Development and Evaluation working group s [2]. t the end of each section we provide a summary of the s and a ready reference table with the s and the levels of as well as the grades of the s. 3. Evidence synthesis 3.1. Initial diagnosis of urothelial carcinoma of the bladder UCB presents with microhematuria, painless macrohematuria, and/or irritative voiding symptoms that require investigation. CIS of the bladder causes irritative lower urinary tract symptoms more often than does papillary UCB. t presentation of bladder tumors, neither stage nor grade can be assessed with sufficient certainty prior to histopathologic evaluation [3] Transurethral resection The goal of transurethral resection (TUR) in UCB staged Ta, T1, and CIS is complete removal of all visible papillary lesions [4]. Larger tumors should be resected in fractions that include the exophytic part of the tumor, the lamina propria, the muscularis propria, and the edges of the resection area [3]. These fractions may be submitted separately. The absence of detrusor muscle in the specimen is associated with a significantly higher risk of residual disease and early recurrence. Photodynamic diagnosis and narrow-band imaging have been shown to detect roughly 20% additional papillary lesions and have an improved recurrence-free survival of stage Ta UCB patients compared with white light cystoscopy [7]. The growth pattern of UCB staged CIS is flat and thus may evade detection by white light cystoscopy; photodynamic diagnosis has been shown to improve the diagnostic accuracy of CIS [5 7]. n improvement of detection also has been demonstrated for narrow-band imaging [8] Role of urinary markers in initial diagnosis While the initial diagnosis of UCB relies on histopathologic assessment of tumor, high-grade UCBs usually shed cells into the urine and will have positive urinary cytology. CIS lacks cellular cohesion, so the sensitivity and specificity of urinary cytology have been reported as >90% [9]. Positive urinary cytology in the absence of visible lesions in the bladder necessitates investigation for a high-grade urothelial carcinoma (UC) in the upper or lower urinary tract, including the prostatic urethra [9]. While some urinary markers have been tested and approved in the early detection of BCa, they have not been widely adopted [10,11] Early instillation of chemotherapy The rationale for perioperative instillation of chemotherapy is the destruction of residual microscopic tumor at the site of the TUR and the destruction of floating cells, preventing implantation immediately following the TUR [12,13]. large meta-analysis confirmed the effectiveness of single perioperative chemotherapy in treated patients compared with TUR alone, reporting a 39% decrease in the odds of recurrence [14]. This effect seems most pronounced in primary and/or Ta low-grade UCB; the effect is uncertain in recurrent and multiple UCB staged Ta and questionable in UCB staged CIS and T1 [15,16]. To be effective, the instillation should be performed on the same day as the transurethral resection of bladder tumor (TURBT). Delayed instillations do not appear to yield similar benefits. Since the urologist does not know the stage of the tumor with certainty at the time of the TUR, a single initial dose of chemotherapy is indicated unless UCBs staged T1 and CIS are likely present because of previous UCB staged T1 and UCB or obvious macroscopic appearance. Perioperative mitomycin C should not be administered to patients with bladder perforation following TUR, as extravasation of this drug is caustic and may lead to serious complications. In a recent randomized trial, the efficacy of a postoperative instillation of gemcitabine and saline bladder irrigation in primary or recurrent Ta/T1 UCB was not superior to irrigation alone [17]. The recurrence rate was very low in both arms, suggesting a role for bladder irrigation in the prevention of recurrence. This observation needs further exploration (Table 1) Ta low-grade urothelial carcinoma of the bladder Specific aspects of diagnosis Biopsy and cystoscopy. Cold-cup biopsies can be used to remove tumor in patients with recurrent Ta low-grade UCB.

3 38 EUROPEN UROLOGY 63 (2013) Table 1 Initial diagnosis s Malignant tumor cells on urinary cytology and papillary tumors on cystoscopy suggest Ta high-grade urothelial carcinoma. In patients with positive cytology but normal white light cystoscopy, photodynamic diagnosis with hexaminolevulinic acid should be considered to detect pcis. The goal is a complete resection of all tumors. If there is any question regarding the completeness of the initial TURBT, repeat TURBT is advised. In apparent low-risk UCB (Ta low-grade), immediate post-tur intravesical chemotherapy by instillation of mitomycin C or epirubicin is recommended, as it can prevent recurrences. If high-risk UCB (Ta high-grade, Tis, T1) is suspected, the use of one immediate postoperative instillation of chemotherapy is not supported by consistent data and therefore is only an option. 3 B 1a 2b 1a 1a TURBT = transurethral resection of bladder tumor; UCB = urothelial carcinoma of the bladder; TUR = transurethral resection; pcis = pathologic carcinoma in situ. Obtaining muscle is not necessary for suspected recurrence of Ta low-grade tumors Urinary cytology and urinary markers. Urinary cytology and urinary markers are of limited value in patients with Ta low-grade UCB. Urinary markers should detect recurrent tumors before they are large and numerous. While several urinary markers have a higher sensitivity than cytology, many low-grade tumors visible in cystoscopy are not detected by urinary markers (ie, a high false-negative rate). One potential role for urinary markers is reducing the frequency of cystoscopy. While most protein-based urinary markers, such as NMP22, are affected by tumor volume, recurrent low-grade UCs often are small. Hence, urinary markers may only have a role in low-intensity surveillance programs to monitor for larger, recurrent Ta low-grade UCB during the cystoscopy intervals. Large prospective randomized studies of alternative surveillance regimens incorporating urinary markers are required to establish the utility of such markers in the surveillance of Ta low-grade tumors. Numerous recent reviews on urinary markers support these statements [10] Upper tract studies. UCs have the propensity for multifocal growth. Despite this characteristic, imaging to detect synchronous renal or ureteral tumors at diagnosis of Ta low-grade UCB is controversial. Data regarding the incidence of synchronous upper tract UC with Ta low-grade UCB are difficult to interpret because most reports include patients with high-risk UCB. It has been suggested that multifocal disease is associated with a higher risk of concomitant upper tract UC [18]. In the largest review investigating metachronous upper tract UC in UCB, Wright et al. studied almost patients in the Surveillance Epidemiology and End Results registry [19]. Of patients with a Ta UCB at diagnosis, 472 patients (0.3%) were subsequently diagnosed with an upper tract UC. Patients with Ta UCB were more likely to be diagnosed with upper tract UC than patients with muscle-invasive BCa. The mean time to upper tract recurrence in the entire cohort was 33 mo. There is no that the prognosis of patients with upper tract UC after Ta BCa is improved by early detection compared with patients presenting with symptoms. s synchronous or metachronous upper tract UC is rare and computed tomography, magnetic resonance imaging, and intravenous pyelography have risks, routine upper tract imaging is not recommended Therapy Expectant management and office fulguration of Ta low-grade urothelial carcinoma of the bladder. lthough a significant percentage of patients with Ta low-grade UCB will experience recurrence, few will have stage progression [20]. TUR is not without risks, especially in the elderly or patients with medical comorbidities, and any hospital procedure is expensive. Consequently, some practitioners have questioned whether an aggressive follow-up and treatment regimen is warranted for low-risk patients. Herr has shown that recurrent low-risk papillary tumors are accurately diagnosed by cystoscopy and urine cytology in substantially >90% of tumors [21]. Several small observational studies demonstrated observation in low-risk disease to be acceptable [22]. Office fulguration may serve as an appropriate alternative to TURBT in selected patients. Observation or fulguration should not replace formal TURBT as primary treatment of initial tumor or for recurrence that is suspected to represent a change in tumor stage or grade. These approaches are appropriate for recurrent Ta lowgrade tumors only (Table 2) Intravesical chemotherapy. Intravesical chemotherapy plays an important role in decreasing the recurrence rate [23]. Various agents have been used. Mitomycin C has a molecular weight of 329 kda, and absorption resulting in myelosuppression is most unlikely. strict strategy consisting of a period of dehydration (limited fluids for 8 h prior to treatment), urinary alkalinization, complete bladder drainage prior to instillation, and a higher mitomycin C concentration (40 mg in 20 ml of sterile water) has been shown in one study to be advantageous [24]. Becauseof doxorubicin s high molecular weight of 580 kda, absorption and systemic toxicity from its use are also rare. Epirubicin is chemically related to doxorubicin and appears to have a favorable toxicity profile and good efficacy. Intravesical gemcitabine has been shown to decrease the recurrence rate in intermediate- and high- risk patients [25]. There is no

4 EUROPEN UROLOGY 63 (2013) Table 2 Ta low-grade s Routine upper tract studies are not recommended for patients with Ta low-grade UCB tumors at diagnosis. 2b B Upper tract evaluation in patients with Ta low-grade UCB is recommended in the presence of gross hematuria and 2b B unexplained positive urine cytology. Routine upper tract studies are not recommended for Ta low-grade UCB during follow-up. 2b B Expectant management should be pursued only in patients with an established history of Ta low-grade UCB. 3 B Optimal characteristics for observation include low tumor burden, advanced age, or comorbidity. 4 C Surveillance includes periodic cystoscopy. 3 C Patients who have a change in the appearance of papillary tumors or who develop positive urine cytology should 3 B undergo formal TUR. Office fulguration is a good option for patients with small Ta low-grade UCB. Fulguration can be followed by immediate intravesical chemotherapy. 3 B UCB = urothelial carcinoma of the bladder; TUR = transurethral resection. that multiple adjuvant instillations of chemotherapy after one immediate instillation have additional benefit in patients at initial diagnosis of Ta low-grade UCB. More therapy should be individualized based on the prognostic factors of the patient s tumors. testing other immunomodulating agents. However, so far no alternative immunologic treatment has been shown to have comparable efficacy to BCG (Table 3) Ta high-grade urothelial carcinoma of the bladder Immunotherapy (bacillus Calmette-Guérin). lthough there is some that bacillus Calmette-Guérin (BCG) is superior to intravesical chemotherapy following a TUR of Ta low-grade UCB, BCG is overtreatment because of its higher toxicity and the low risk of pta low-grade UCB to progress. Despite the significant decrease in recurrence rate by immediate post-tur instillation of chemotherapeutic agents and/or a complete course of chemotherapy in patients with multiple tumors, only 30 50% of patients will remain free of recurrence. The role of intravesical BCG has been analyzed in a meta-analysis by Shelley et al. [26]. In 1901 patients, no significant difference in efficacy between intravesical BCG and repeat mitomycin C was found, while BCG was significantly superior to mitomycin C in a subgroup of patients at high risk of recurrence ( p = ). These and other data support the superiority of BCG as rescue therapy in patients with recurrent tumor who are receiving intravesical chemotherapy [27]. Despite the fact that many of these studies included patients with different stages and grades and were not restricted to Ta low-grade UCB, it appears that BCG is effective in salvaging some patients who have low-risk recurrences despite intravesical chemotherapy. s BCG is generally considered to be the most effective intravesical agent for UCB, there has been interest in developing and pproximately 20% of pta UCB is high-grade (grade III). Treatment and follow- up strategies generally resemble the strategies for CIS [28] Specific aspects of diagnosis Urinary cytology and urinary markers. In contrast to lowgrade disease, the diagnosis of high-grade UCB is facilitated by urinary cytology, with sensitivity and specificity rates of >90% in experienced centers [9] Restaging transurethral resection. Studies on the quality of TURBT showed that the residual tumor rate for Ta UC was 70% at 4 wk after first resection in a high-volume department. Thorough TUR and a restaging transurethral resection of the bladder (TURB) in Ta high-grade UCB are important, as subsequent instillation therapy is more effective and as proper histopathologic staging is crucial for therapy planning [29,30] Installation therapy The recurrence rate of patients with Ta high-grade UCB can be lowered with maintenance BCG therapy. The impact of maintenance BCG on progression of pta high-grade UCB remains unclear, however [27,31,32] (Table 4). Table 3 Intravesical therapy s Induction chemotherapy with or without maintenance has unclear but potential benefit after one immediate 2b B instillation. The risks of repeated courses of intravesical chemotherapy have to be weighed against the benefits. 4 C Intravesical BCG is not appropriate as initial intravesical therapy for patients with low-grade UCB. 3 B Intravesical BCG could potentially be used in patients with recurrent Ta low-grade UCB who have not responded to 3 B intravesical chemotherapy. Secondary immunomodulating therapies do not have a role in management of Ta low-grade UCB at this time. 3 C BCG = bacillus Calmette-Guérin; UCB = urothelial carcinoma of the bladder.

5 40 EUROPEN UROLOGY 63 (2013) Table 4 Ta high-grade s complete resection has to be pursued. If there is any question regarding the completeness of the initial TURBT, 2a repeat TURBT is advised. BCG instillation therapy should be initiated in patients with pta high-grade urothelial carcinoma. 1b TURBT = transurethral resection of bladder tumor; BCG = bacillus Calmette-Guérin Carcinoma in situ Primary CIS is found in approximately 3% of all patients with BCa, concomitantly with early invasive (T1) bladder cancer in 50% and with muscle-invasive disease (T2 T4) in 60% [28]. CIS is flat, does not invade the lamina propria, and by definition is high grade. ccordingly, CIS has been suggested to be a precursor lesion of invasive disease and concomitant CIS to be a significant risk factor for poor outcome. The European Organization for Research and Treatment of Cancer (EORTC) risk score attaches significant weight to the presence of CIS [14] Specific aspects of diagnosis Three characteristics determine the diagnostic work-up: CIS lacks profound cellular cohesion, its growth pattern is flat, and it may be found throughout the urinary tract. Because of the first trait, CIS can often be detected and monitored by urinary cytology. There is some to suggest that white light cystoscopy misses up to 50% of cases. Like all UC, CIS may be multifocal, and monitoring of the entire urinary tract is warranted Therapy Few data are available on CIS without any association with Ta or T1 tumors. For CIS with and without concomitant non muscle-invasive UC, there is no consensus on radical cystectomy compared with bladder conservation. While disease-specific survival ranges from 85% to 90% following radical cystectomy for CIS only, early radical cystectomy is overtreatment in approximately 50% of patients [33]. If bladder preservation is chosen, TUR of all concomitant papillary tumors is mandatory for correct staging and grade determination. Intravesical BCG has been widely used in the treatment of CIS. The arbitrary standard induction schedule of six weekly instillations yields a complete response rate of approximately 70%. pproximately 40 60% of patients who do not respond will respond to a second series of three to six weekly instillations. In complete responders, 1 3 yr of maintenance BCG therapy is recommended [31]. No definite conclusions can be drawn from studies comparing BCG with intravesical chemotherapy [34]. pproximately 40 50% of patients with CIS eventually fail intravesical BCG. Follow-up thus needs to be close and intense. While no specific data exist on the best schedule, a monitoring schedule of every 3 mo is widely used. Recurring patients have a poor prognosis, with a high risk of progression to muscle-invasive disease and death as a result of BCa. In one study, the 3-yr BCa-specific survival was 67% in patients initially presenting with muscleinvasive disease but was only 37% in patients whose disease progressed after intravesical treatment [35]. In general, the results for conservative treatment after BCG failure are disappointing, and radical cystectomy is the recommended treatment (Table 5) T1 urothelial carcinoma of the bladder Specific aspects of diagnosis restaging TURBT is warranted in patients with T1 UCB, as the rate of residual tumor is high, and 30% of tumors are Table 5 Tis s If CIS is clinically suspected, urinary cytology should be obtained, and white light cystoscopy and (when available) 2a blue light or narrow-band imaging should be performed. Imaging of the upper urinary tract should be obtained. Diagnosis of CIS is based on histopathologic assessment of biopsy or resection specimen. N Radical cystectomy at the time of CIS diagnosis provides for excellent disease-free survival but is overtreatment in 2a up to 50% of patients. Intravesical BCG is recommended, as it provides the highest complete response rate and the highest long-term 1a disease-free rate among intravesical treatments. Maintenance BCG is required, but the optimal maintenance schedule is unknown. In the absence of treatment 2a failure, 1 yr of maintenance BCG is recommended. The response to intravesical BCG should be assessed 3 mo after starting treatment. If no response is seen, the options are 2b B cystectomy, another 6-wk course of BCG, or three weekly boosters. The optimal time to abandon conservative treatment and proceed to cystectomy is unknown. Cystoscopy and urinary cytology should be performed every 3 mo for 2 yr, every 4 mo in the third year, every 6 mo in the fourth and fifth years, and once per year thereafter. If there is no recurrence, imaging of the upper urinary tract by ultrasonography, conventional IVU, or CT should be performed periodically. N C CIS = carcinoma in situ; BCG = bacillus Calmette-Guérin; IVU = intravenous urography; CT = computed tomography; N = not available.

6 EUROPEN UROLOGY 63 (2013) upstaged when muscle was absent in the first obtained specimen [36]. Traditional factors used to predict the clinical outcome of T1 UCB include tumor grade, multiplicity, tumor size, concomitant CIS, depth of lamina propria invasion, and response to intravesical therapy. Nevertheless, these prognostic factors are not accurate enough to predict the individual clinical behavior in a patient with T1 urothelial BCa. No molecular markers have been established in clinical use [37].T1tumorswithamicropapillary or nested variant have a more ominous prognosis, and a radical cystectomy at initial diagnosis should be considered Therapy Instillation therapy. The two treatment options are immediate radical cystectomy or intravesical therapy with a delayed radical cystectomy for recurrence. Because of the lack of from randomized trials, there is no definite Bacillus Calmette-Guérin. Intravesical BCG has been shown to be superior to chemotherapy or TUR alone in preventing recurrences and progression of non muscleinvasive UCB. meta-analysis, carried out by the EORTC, of 4863 patients enrolled in 24 randomized trials demonstrated a 27% reduction in the odds of progression with BCG treatment ( p = ). In the 20 trials in which BCG maintenance was provided, a reduction of 37% in the odds of progression ( p = ) was observed [38]. The longterm risk of tumor progression remains significant despite BCG. fter long- term follow-up, roughly 30% of patients underwent radical cystectomy, 30% died of BCa, and 30% were living with an intact bladder [39]. While bladder preservation is an attractive option for many patients with high-grade NMIBC, there is a subgroup of patients with the highest risk of progression who benefit from early radical cystectomy. They include patients with multifocal T1 highgrade UCB, size >3 cm, and associated CIS. Patients with at least two of these factors and CIS could benefit from immediate radical cystectomy [40]. The most important prognostic factor is the absence of high-grade UCB in the first surveillance cystoscopy [41] Early radical cystectomy. Disease-specific survival after radical cystectomy for patients with non muscle-invasive UC from one series was actually higher than for patients with muscle-invasive disease. However, the benefits must be balanced against the morbidity and mortality rates of surgery. In a multicenter series of 1136 cystectomies for T1 UCB without neoadjuvant chemotherapy, rates of upstaging to muscle-invasive disease and cancer-specific mortality were 49.7% and 35.5%, respectively. The rate of restaging TURB was not assessed in this study, however [42]. Current proposed indications for immediate surgery include younger patients with T1 tumors with at least one additional bad prognostic factor, including multifocality, associated CIS, prostatic involvement, tumor at sites difficult to resect, and noncompliance. s mentioned, radical cystectomy should be offered to patients with recurrent or persistent T1 after BCG immunotherapy (Table 6) Treatment options for bacillus Calmette-Guérin failure Following BCG, the median time to progression is generally >12 mo, with an estimated progression rate of 5% by 6 mo. For patients with BCG failure that is, refractory UCB with disease at 6 mo following BCG induction therapy and maintenance at 3 mo radical cystectomy continues to be the gold standard. However, patients may be reluctant to undergo major surgery for a condition that does not pose an immediate threat to their lives. Radical cystectomy is not a suitable treatment option for a subset of patients with severe comorbidities. number of alternatives have thus been developed Repeat bacillus Calmette-Guérin This treatment may be appropriate for both BCG-resistant disease (ie, persistence at 3 mo after the induction cycle) and BCG-relapsing disease (ie, recurrence after a diseasefree interval of 6 mo). However, only a few published studies have addressed this issue, and data are insufficient to assess the effectiveness of repeated BCG in refractory or recurrent T1 disease [43] Intravesical salvage chemotherapy There have been limited data on the use of intravesical chemotherapy in patients failing BCG. Valrubicin, a semisynthetic analog of doxorubicin, was approved by the US Food and Drug dministration for the treatment of BCG-refractory CIS in patients who are medically unfit or who refuse radical cystectomy. The success rate is low, and the number of patients treated is small. Gemcitabine seems to have some effect in patients who have failed BCG [44]. Given the present data, current intravesical salvage Table 6 T1 s The prognosis of T1 urothelial carcinoma should be based on tumor grade, early recurrence, multiplicity, tumor size, 1a concomitant CIS, urothelial carcinoma involving the prostate, and depth of lamina propria invasion. High-risk patients and patients with recurrent or persisting disease after BCG should be offered a cystectomy. 2a If a bladder-sparing approach is desired, a secondary TURBT should be performed and followed by intravesical BCG therapy. 3 B CIS = carcinoma in situ; BCG = bacillus Calmette-Guérin; TURBT = transurethral resection of bladder tumor.

7 42 EUROPEN UROLOGY 63 (2013) Table 7 Bacillus Calmette-Guérin failure s The threat of progression remains real but comfortably low enough within the first 6 mo of initiating BCG to consider 2b B alternatives to cystectomy for those patients unfit or unwilling to undergo this standard management option. Failure to achieve a complete response to BCG is an indication for cystectomy. 2a The current best option for BCG-resistant disease (persistence 3 mo after induction cycle) and BCG-relapsing 1b disease (recurrence after disease-free interval of 6 mo) is repeat TURBT and BCG. Gemcitabine and thermochemotherapy have shown efficacy, but more studies are needed. There is no reported of significant efficacy using current intravesical chemotherapy, interferon-a monotherapy, photodynamic therapy, or radiation therapy. 4 C BCG = bacillus Calmette-Guérin; TURBT = transurethral resection of bladder tumor. chemotherapy has little to offer to patients who have failed BCG, especially patients with stage T1 disease Interferon-a immunotherapy While several single-institutional studies have assessed a combination of low-dose BCG and interferon-a as a salvage regimen for BCG failures, disease-free rates of 50 60% suggest that interferon-a provides limited benefit [45] Thermo-chemotherapy There is a recent report of thermo-chemotherapy in patients with recurrent UCB following BCG [46]. fter six weekly induction treatments and four to six sessions with a 6-wk interval, disease-free survival estimates were 85% and 56% after 1 and 2 yr, respectively. Only three patients progressed. Hyperthermia treatment appears to be a possibility for patients failing BCG, although more studies are needed (Table 7). 4. Conclusions UCB staged Ta, T1, and CIS poses greatly varying, but uniformly demanding, challenges to urologic care. On the one hand, the high recurrence rates, contrasted by low progression rates, of Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy providing oncologic safety. Urologists need to be aware of these challenges [47 50]. uthor contributions: J. lfred Witjes had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Burger, Konety, Oosterlinck, Witjes. cquisition of data: Burger, Konety, Oosterlinck, Witjes, Chang, Gudjonsson, Pruthi, Soloway, Solsona, Sved, Babjuk, Brausi, Cheng, Comperat, Dinney, Otto, Shah, Thürof. nalysis and interpretation of data: Burger, Konety, Oosterlinck, Witjes, Chang, Gudjonsson, Pruthi, Soloway, Solsona, Sved, Babjuk, Brausi, Cheng, Comperat, Dinney, Otto, Shah, Thürof. Drafting of the manuscript: Burger, Konety, Oosterlinck, Witjes, Chang, Gudjonsson, Pruthi, Soloway, Solsona, Sved, Babjuk, Brausi, Cheng, Comperat, Dinney, Otto, Shah, Thürof. Critical revision of the manuscript for important intellectual content: Burger, Konety, Oosterlinck, Witjes, Chang, Gudjonsson, Pruthi, Soloway, Solsona, Sved, Babjuk, Brausi, Cheng, Comperat, Dinney, Otto, Shah, Thürof. Statistical analysis: None. Obtaining funding: None. dministrative, technical, or material support: None. Supervision: Burger, Konety, Oosterlinck, Witjes. Other (specify): None. Financial disclosures: J. lfred Witjes certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Soloway MS. It is time to abandon the superficial in bladder cancer. Eur Urol 2007;52: [2] Phillips B, Ball C, Sackett D, et al. Oxford Centre for Evidence-based Medicine levels of. March Centre for Evidence-based Medicine Web site. [3] min MB, McKenney JK, Paner GP, et al. ICUD-EU International Consultation on Bladder Cancer 2012: pathology. Eur Urol 2013;63: [4] Pan D, Soloway MS. The importance of transurethral resection in managing patients with urothelial cancer in the bladder: proposal for a transurethral resection of bladder tumor checklist. Eur Urol 2012;61: [5] Kausch I, Sommerauer M, Montorsi F, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur Urol 2010;57: [6] Grossman HB, Stenzl, Fradet Y, et al. Long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. J Urol 2012;188: [7] Witjes J, Redorta JP, Jacqmin D, et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the and s. Eur Urol 2010;57: [8] Herr HW, Donat SM. Reduced bladder tumour recurrence rate associated with narrow-band imaging surveillance cystoscopy. BJU Int 2011;107: [9] Sylvester RJ, van der Meijden, Witjes J, et al. High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 2005;66(Suppl 1): [10] Tilki D, Burger M, Dalbagni G, et al. Urine markers for detection and surveillance of non-muscle-invasive bladder cancer. Eur Urol 2011;60:

8 EUROPEN UROLOGY 63 (2013) [11] Kamat M, Hegarty PK, Gee JR, et al. ICUD-EU International Consultation on Bladder Cancer 2012: screening, diagnosis, and molecular markers. Eur Urol 2013;63:4 15. [12] Soloway MS, rianayagam M. Point: routine use of postoperative intravesical chemotherapy after TURBT should it be done? Urology 2010;76: [13] Soloway MS. Rationale for intensive intravesical chemotherapy for superficial bladder cancer. J Urol 1980;123: [14] Sylvester RJ, Oosterlinck W, van der Meijden P. single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a metaanalysis of published results of randomized clinical trials. J Urol 2004;171: , quiz [15] De Nunzio C, Carbone, lbisinni S, et al. Long-term experience with early single mitomycin C instillations in patients with low-risk non-muscle-invasive bladder cancer: prospective, single-centre randomised trial. World J Urol 2011;29: [16] Gudjonsson S, dell L, Merdasa F, et al. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? the results of a prospective randomised multicentre study. Eur Urol 2009;55: [17] Bohle, Leyh H, Frei C, et al. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. Eur Urol 2009; 56: [18] Palou J, Rodriguez-Rubio F, Huguet J, et al. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumor. J Urol 2005;174:859 61, discussion 861. [19] Wright JL, Hotaling J, Porter MP. Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. J Urol 2009;181:1035 9, discussion [20] Sylvester RJ, van der Meijden PM, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49: [21] Herr HW. Does cystoscopy correlate with the histology of recurrent papillary tumours of the bladder? BJU Int 2001;88: [22] Soloway MS. Expectant treatment of small, recurrent, low-grade, noninvasive tumors of the urinary bladder. Urol Oncol 2006;24: [23] Bouffioux C, Kurth KH, Bono, et al. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group. J Urol 1995;153: [24] u JL, Badalament R, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001;93: [25] Shelley MD, Jones G, Cleves, Wilt TJ, Mason MD, Kynaston HG. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJU Int 2012;109: [26] Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int 2004;93: [27] Malmstrom PU, Sylvester RJ, Crawford DE, et al. n individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesicalmitomycin C versusbacilluscalmette-guerin for non-muscle-invasive bladder cancer. Eur Urol 2009;56: [28] Sauter G, lgaba F, min MB, et al. Non-invasive urothelial neoplasias: WHO classification of non invasive papillary urothelial tumors. In: Eble JN, Sauter G, Epstein JI, Sesterhenn I, editors. World Health Organization classification of tumors pathology and genetics: tumors of the urinary system and male genital organs. Lyon, France: IRC Press; [29] Herr HW. Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette- Guerin therapy. J Urol 2005;174: [30] diyat KT, Katkoori D, Soloway CT, De los Santos R, Manoharan M, Soloway MS. Complete transurethral resection of bladder tumor : are the guidelines being followed? Urology 2010;75: [31] Sylvester RJ, Brausi M, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010;57: [32] Jarvinen R, Kaasinen E, Sankila, Rintala E, FinnBladder Group. Long-term efficacy of maintenance bacillus Calmette-Guerin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol 2009;56: [33] Tilki D, Reich O, Svatek RS, et al. Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients. J Urol 2010;183: [34] Sylvester RJ, van der Meijden P, Witjes J, Kurth K. Bacillus Calmette-Guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a metaanalysis of the published results of randomized clinical trials. J Urol 2005;174:86 91, discussion [35] Schrier BP, Hollander MP, van Rhijn BW, Kiemeney L, Witjes J. Prognosis of muscle-invasive bladder cancer: difference between primary and progressive tumours and implications for therapy. Eur Urol 2004;45: [36] Dalbagni G, Vora K, Kaag M, et al. Clinical outcome in a contemporary series of restaged patients with clinical T1 bladder cancer. Eur Urol 2009;56: [37] van Rhijn BW, Burger M, Lotan Y, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009;56: [38] Sylvester RJ, van der Meijden P, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168: [39] Shahin O, Thalmann GN, Rentsch C, Mazzucchelli L, Studer UE. retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival. J Urol 2003; 169: [40] Denzinger S, Fritsche H-M, Otto W, Blana, Wieland W-F, Burger M. Early versus deferred cystectomy for initial high-risk pt1g3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53: [41] Herr HW, Dalbagni G. Defining bacillus Calmette-Guerin refractory superficial bladder tumors. J Urol 2003;169: [42] Fritsche HM, Burger M, Svatek RS, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma

9 44 EUROPEN UROLOGY 63 (2013) treated with radical cystectomy: results from an international cohort. Eur Urol 2010;57: [43] Gallagher BL, Joudi FN, Maymi JL, O Donnell M. Impact of previous bacille Calmette-Guerin failure pattern on subsequent response to bacille Calmette-Guerin plus interferon intravesical therapy. Urology 2008;71: [44] Di Lorenzo G, Perdona S, Damiano R, et al. Gemcitabine versus bacille Calmette-Guerin after initial bacille Calmette-Guerin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. Cancer 2010;116: [45] Duchek M, Johansson R, Jahnson S, et al. Bacillus Calmette-Guerin is superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer: a prospective, randomized, Nordic study. Eur Urol 2010; 57: [46] Nativ O, Witjes J, Hendricksen K, et al. Combined thermochemotherapy for recurrent bladder cancer after bacillus Calmette- Guerin. J Urol 2009;182: [47] Babjuk M, Oosterlinck W, Sylvester R, et al. EU guidelines on nonmuscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 2011;59: [48] Stenzl, Cowan NC, De Santis M, et al. Treatment of muscleinvasive and metastatic bladder cancer: update of the EU guidelines. Eur Urol 2011;59: [49] van den Bosch S, lfred Witjes J. Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol2011;60: [50] Meijer RP, van Rhijn BW. plea for long-term surveillance in bacillus Calmette-Guerin-treated non-muscle-invasive bladder cancer. Eur Urol 2012;61:508 9.