Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
•This ESMO Clinical Practice Guideline provides key recommendations for diagnosis, staging and management of bladder cancer.•Recommendations for personalised medicine are also included.•All recommendations were compiled by a multinational and multidisciplinary group of experts.•Recommendations are based on the latest available scientific data and the authors’ expert opinions.•These recommendations are updated continuously in order to include results of the latest clinical trials. Urothelial carcinoma (UC), also described as bladder cancer, is the 10th most common cancer type worldwide, with an estimated 549 000 new cases and 200 000 deaths in 2018. The highest incidence rates in Europe are observed in Southern Europe, e.g. Greece (5800 new cases and 1537 deaths in 2018), Spain and Italy, and Western Europe, e.g. Belgium and the Netherlands.1Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (58377) Google Scholar The most important risk factor for developing bladder cancer is tobacco smoking, which accounts for ∼50% of cases,2van Osch F.H. Jochems S.H. van Schooten F.J. et al.Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies.Int J Epidemiol. 2016; 45: 857-870Crossref PubMed Scopus (126) Google Scholar followed by occupational exposure to aromatic amines and ionising radiation.3Burger M. Catto J.W. Dalbagni G. et al.Epidemiology and risk factors of urothelial bladder cancer.Eur Urol. 2013; 63: 234-241Abstract Full Text Full Text PDF PubMed Scopus (1475) Google Scholar Painless haematuria is the most common presenting symptom in bladder cancer and should be investigated in all cases. Other common symptoms include dysuria, increased frequency and/or urgency (Figure 1). Bladder ultrasonography or cross-sectional imaging can identify an intraluminal mass in the bladder, but the final diagnosis is based on cystoscopic examination of the bladder and histological evaluation of the tissue obtained either with cold-cup biopsy or transurethral resection of the bladder tumour (TURBT). Complete resection of all tumour tissue should be achieved when possible. The presence of lamina propria and detrusor muscle in the resected specimen is essential for accurate staging in most cases. Concurrent carcinoma in situ (CIS) is an adverse prognostic factor;4Griffiths T.R. Charlton M. Neal D.E. et al.Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance.J Urol. 2002; 167: 2408-2412Crossref PubMed Google Scholar hence, bladder biopsies from suspicious urothelium or mapping biopsies from normal-looking mucosa in patients with positive urine cytology, or a history of high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) should be taken.5Hara T. Takahashi M. Gondo T. et al.Risk of concomitant carcinoma in situ determining biopsy candidates among primary non-muscle-invasive bladder cancer patients: retrospective analysis of 173 Japanese cases.Int J Urol. 2009; 16: 293-298Crossref PubMed Scopus (0) Google Scholar In patients with high-risk NMIBC (described in Table 1), and in particular those with CIS, upper tract imaging should be carried out to screen for synchronous upper urinary tract urothelial carcinoma (UTUC). Computed tomography (CT) urography or magnetic resonance imaging (MRI) urography is used to detect papillary tumours in the urinary tract.6Trinh T.W. Glazer D.I. Sadow C.A. et al.Bladder cancer diagnosis with CT urography: test characteristics and reasons for false-positive and false-negative results.Abdom Radiol (NY). 2018; 43: 663-671Crossref PubMed Scopus (33) Google Scholar The management of bladder cancer is based on the pathological findings of the biopsy, with attention to histology, grade and depth of invasion (Table 1). Muscle-invasive bladder cancer (MIBC) should be staged according to the Union for International Cancer Control (UICC) TNM (tumour–node–metastasis) eighth edition and the American Joint Committee on Cancer (AJCC) TNM staging systems and should be grouped into categories (Supplementary Tables S1 and S2, available at https://doi.org/10.1016/j.annonc.2021.11.012).Table 1Risk group stratification of patients with NMIBC and treatment recommendationsRisk group stratificationCharacteristicsTreatment recommendationsLow-risk tumoursPrimary, solitary, Ta G1 (PUNLMP, LG), <3 cm, no CISOne immediate instillation of intravesical ChT after TURBT [I, A] followed by cystoscopic surveillanceIntermediate-risk tumoursAll tumours not defined in the two adjacent categories (between the category of low and high risk)In patients with previous low recurrence rate (less than or equal to one recurrence per year) and expected EORTC recurrence score <5, one immediate instillation of intravesical ChT after TURBT [IV, C]In all patients, either:•instillations of ChT for a maximum of 1 year [I, A]Or•one-year full-dose BCG treatment (induction plus 3-weekly instillations at 3, 6 and 12 months) [I, A]High-risk tumoursAny of the following:•T1 tumour•G3, HG tumour•CIS•Multiple, recurrent and large (>3 cm) Ta G1-G2/LG tumours (all features must be present)Full-dose BCG instillations for 1-3 years or radical cystectomy [I, A]Subgroup of highest-risk tumours•T1 G3/HG associated with concurrent bladder CIS•Multiple and/or large T1 G3/HG and/or recurrent T1 G3/HG, T1 G3/HG with CIS in the prostatic urethra•Some forms of variant histology of urothelial carcinoma, lymphovascular invasionRadical cystectomy or BCG induction and 3 years of maintenance if achievable [I, A]BCG, bacillus Calmette-Guerin; ChT, chemotherapy; CIS, carcinoma in situ; EORTC, European Organisation for Research and Treatment of Cancer; G, grade; HG, high grade; LG, low grade; NMIBC, non-muscle-invasive bladder cancer; PUNLMP, papillary urothelial neoplasm of low malignant potential; TURBT, transurethral resection of the bladder tumour. Open table in a new tab BCG, bacillus Calmette-Guerin; ChT, chemotherapy; CIS, carcinoma in situ; EORTC, European Organisation for Research and Treatment of Cancer; G, grade; HG, high grade; LG, low grade; NMIBC, non-muscle-invasive bladder cancer; PUNLMP, papillary urothelial neoplasm of low malignant potential; TURBT, transurethral resection of the bladder tumour. Pathological diagnosis should be made according to the World Health Organization (WHO) 2016 classification (Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2021.11.012).7Humphrey P.A. Moch H. Cubilla A.L. et al.The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours.Eur Urol. 2016; 70: 106-119Abstract Full Text Full Text PDF PubMed Scopus (998) Google Scholar Approximately 75% of patients with bladder cancer present with NMIBC pTa-pT1, pTis).3Burger M. Catto J.W. Dalbagni G. et al.Epidemiology and risk factors of urothelial bladder cancer.Eur Urol. 2013; 63: 234-241Abstract Full Text Full Text PDF PubMed Scopus (1475) Google Scholar The majority of patients with MIBC (pT2a-pT4b) are diagnosed with primary invasive bladder cancer and up to 15% of patients have a previous history of NMIBC, almost exclusively high-risk NMIBC.3Burger M. Catto J.W. Dalbagni G. et al.Epidemiology and risk factors of urothelial bladder cancer.Eur Urol. 2013; 63: 234-241Abstract Full Text Full Text PDF PubMed Scopus (1475) Google Scholar All MIBCs are considered as HG. TURBT or bladder biopsy only allow for staging up to T2. Clinical T3 or T4 disease is identified by bimanual exam under anaesthesia and/or cross-sectional imaging. NMIBC is graded as low grade (LG) or HG according to the latest WHO 2016 criteria. Ninety percent of carcinomas of the upper and lower urothelial tract are UCs, with or without other variants (Supplementary Table S3, available at https://doi.org/10.1016/j.annonc.2021.11.012). The percentage of the variant morphology should be given in the pathological report. If the squamous or adenocarcinoma part is >95%, the UC should be considered as a pure squamous/adenocarcinoma. The variant histology group comprises nested carcinoma, large nested, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid/signet ring cell/diffuse, sarcomatoid, giant cell, poorly differentiated, lipid rich and clear-cell UC, all of which are of urothelial origin.7Humphrey P.A. Moch H. Cubilla A.L. et al.The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours.Eur Urol. 2016; 70: 106-119Abstract Full Text Full Text PDF PubMed Scopus (998) Google Scholar Small-cell/neuroendocrine subtypes should be specified when they are present and the percentage should be noted. Urine cytology can facilitate the diagnosis of HG UC but should not be used as the primary method of histological diagnosis. It has a high sensitivity in HG tumours including CIS (84%), but low sensitivity in G1/LG tumours (16%).8Yafi F.A. Brimo F. Steinberg J. et al.Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer.Urol Oncol. 2015; 33: 66.e25-66.e31Crossref PubMed Google Scholar Further molecular diagnosis is being investigated in the advanced disease setting, but its role has yet to be clearly defined. Oncogenic alterations [e.g. fibroblast growth factor receptor (FGFR) DNA alterations] and other forms of immuno-oncology therapy biomarker testing, such as programmed death-ligand 1 (PD-L1) expression, are being used for patient selection. Multiple methodologies exist for biomarker measurement and clinicians should follow European Medicines Agency (EMA) guidance for PD-L1, linking specific biomarkers methods with specific agents. Molecular diagnostics such as molecular subtype classification, FGFR and PD-L1 status are not routinely required [IV, C]. Molecular subtype analysis does not currently have a role in treatment selection. Genomic testing (PCR- or next-generation sequencing-based) should be used for detection of FGFR2/3 mutations and fusions.9Loriot Y. Necchi A. Park S.H. et al.Erdafitinib in locally advanced or metastatic urothelial carcinoma.N Engl J Med. 2019; 381: 338-348Crossref PubMed Scopus (770) Google Scholar,10Sfakianos J.P. Cha E.K. Iyer G. et al.Genomic characterization of upper tract urothelial carcinoma.Eur Urol. 2015; 68: 970-977Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar A personalised medicine synopsis is shown in Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2021.11.012. •Painless haematuria is the most common presenting symptom in bladder cancer and should in all cases be investigated [IV, A].•The diagnosis of bladder cancer is based on cystoscopic examination of the bladder and histological evaluation of tissue obtained either with cold-cup biopsy or TURBT. Complete resection of all tumour tissue should be achieved when possible. Muscle tissue should be included in the biopsies, except when a Ta/LG is expected [IV, A].•Cross-sectional upper tract imaging (CT/MRI urography) is recommended to screen for synchronous UTUC, in cases of HG bladder cancer [IV, B].•Pathological diagnosis should be made according to latest WHO classification [IV, A].•In addition to stage and grade, presence and percentage of variant histology, lymphovascular invasion and presence of detrusor muscle should be reported [IV, A].•Urine cytology can facilitate the diagnosis of HG UC but cannot be used as the primary method of histological diagnosis [IV, B]. The Paris system should be used for reporting.•Molecular diagnostics such as The Cancer Genome Atlas (TCGA) classification and PD-L1 status are not required for all tumours [IV, C]. A scoring system and risk assessment table has been developed to predict 1- and 5-year disease recurrence and progression in patients with Ta-T1 disease, using the WHO 1973 grading system.11Sylvester R.J. van der Meijden A.P. 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 (discussion 475-467): 466-475Abstract Full Text Full Text PDF PubMed Scopus (2191) Google Scholar An updated model has been developed for patients with Ta-T1 bladder cancer, treated with 1-3 years of bacillus Calmette-Guerin (BCG) maintenance. Patients with CIS alone were not included. The scoring system takes into account the number and size of tumours resected, depth of invasion, prior recurrences, presence of CIS and grade of the tumours after TURBT. Based on the above, the European Association of Urology classified the patients into four risk categories: low-risk, intermediate-risk, high-risk and very-high-risk tumours (Table 1), which constitutes the basis for treatment and follow-up recommendations in NMIBC [IV, B]. Patients with NMIBC have a heterogeneous prognosis. While patients with high-risk NMIBC suffer from a high recurrence rate (up to 50% at 5 years), they also have a low progression rate (<5% at 5 years). Those with T1/HG (grade 3) do poorly, with 1- and 5-year disease progression rates with 11% and 20%, respectively. Cancer-specific 5-year survival for these patients is >90%.12Cambier S. Sylvester R.J. Collette L. et al.EORTC Nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance bacillus Calmette-Guerin.Eur Urol. 2016; 69: 60-69Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar,13Rieken M. Xylinas E. Kluth L. et al.Long-term cancer-specific outcomes of TaG1 urothelial carcinoma of the bladder.Eur Urol. 2014; 65: 201-209Abstract Full Text Full Text PDF PubMed Google Scholar If muscle invasion has been confirmed, regional and distant staging should be carried out with further imaging studies such as contrast-enhanced CT of the chest, abdomen and pelvis or MRI of the abdomen and pelvis (with CT of the chest). The risk of lymph node (LN) metastasis increases proportionally with advancing local tumour stage.14Shariat S.F. Karakiewicz P.I. Palapattu G.S. et al.Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium.J Urol. 2006; 176 (discussion 2422): 2414-2422Crossref PubMed Scopus (588) Google Scholar,15Shariat S.F. Rink M. Ehdaie B. et al.Pathologic nodal staging score for bladder cancer: a decision tool for adjuvant therapy after radical cystectomy.Eur Urol. 2013; 63: 371-378Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Both tests can be used to assess extravesical invasion but are often unable to reliably differentiate between T stages. Imaging is recommended before TURBT. Both tests are useful to detect enlarged LNs, but have low sensitivity (48%-87%) and specificity for the detection of LN metastasis.16Siegel C. Bladder cancer: analysis of multi-detector row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging.J Urol. 2005; 174: 1250-1251Crossref PubMed Google Scholar,17Yang W.T. Lam W.W. Yu M.Y. et al.Comparison of dynamic helical CT and dynamic MR imaging in the evaluation of pelvic lymph nodes in cervical carcinoma.AJR Am J Roentgenol. 2000; 175: 759-766Crossref PubMed Google Scholar Overall, pelvic nodes >8 mm and abdominal nodes >10 mm in maximum short-axis diameter, detected by CT or MRI, should be considered as suspicious for LN metastasis.18Barentsz J.O. Engelbrecht M.R. Witjes J.A. et al.MR imaging of the male pelvis.Eur Radiol. 1999; 9: 1722-1736Crossref PubMed Scopus (64) Google Scholar,19Dorfman R.E. Alpern M.B. Gross B.H. et al.Upper abdominal lymph nodes: criteria for normal size determined with CT.Radiology. 1991; 180: 319-322Crossref PubMed Google Scholar MRI generally is more accurate for determining depth of invasion and is recommended when imaging definition of stage of invasion is important. A scoring system for defining muscle invasion has been proposed (VI-Rads) with some accuracy, with a sensitivity and specificity of 0.83 [95% confidence interval (CI) 0.70-0.90] and 0.90 (95% CI 0.83-0.95), respectively.20Woo S. Panebianco V. Narumi Y. et al.Diagnostic performance of vesical imaging reporting and data system for the prediction of muscle-invasive bladder cancer: a systematic review and meta-analysis.Eur Urol Oncol. 2020; 3: 306-315Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,21Stimson C.J. Cookson M.S. Barocas D.A. et al.Preoperative hydronephrosis predicts extravesical and node positive disease in patients undergoing cystectomy for bladder cancer.J Urol. 2010; 183: 1732-1737Crossref PubMed Scopus (0) Google Scholar A chest-abdomen-pelvis CT should also be carried out for staging of potential distant metastatic disease [III, A]. The authors did not reach a consensus on the role of [18F]2-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET)-CT in MIBC. Despite inconsistencies in sensitivity (23%-89%), FDG-PET-CT seems to have a high specificity (81%-100%) for LN staging.22Swinnen G. Maes A. Pottel H. et al.FDG-PET/CT for the preoperative lymph node staging of invasive bladder cancer.Eur Urol. 2010; 57: 641-647Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar •Patients with NMIBC are classified into four risk categories based on tumour characteristics (low risk, intermediate risk, high risk and very-high-risk; Table 1), which constitutes the basis for treatment and follow-up recommendations [IV, B].•In patients with invasive disease (≥T1), regional and distant staging should be carried out with further imaging studies such as contrast-enhanced CT of chest-abdomen-pelvis or MRI of abdomen/pelvis combined with chest CT [IV, B]. FDG-PET-CT may aid in the detection of LN and distant metastases [IV, C], but no clear consensus was reached. Optimal treatment of NMIBC is the complete removal of all visible lesions in the bladder, followed by intravesical instillations or early radical cystectomy (RC), according to risk stratification described in the preceding text [I, A] (Figure 2, Table 1, Supplementary Table S5, available at https://doi.org/10.1016/j.annonc.2021.11.012). If available, improved tumour visualisation techniques (fluorescence cystoscopy, narrow-band imaging) during TURBT are recommended. In patients with low-risk NMIBC and those with small papillary recurrences, detected >1 year after the previous tumour, single, immediate, intravesical chemotherapy (ChT) instillation, such as mitomycin C (MMC), is recommended [I, A], in combination with continued cystoscopic surveillance. Immediate, intravesical ChT instillation significantly reduces the 5-year recurrence rate compared with TURBT alone (59% versus 45%).23Sylvester R.J. Oosterlinck W. Holmang S. et al.Systematic review and Individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa-pT1 urothelial carcinoma of the bladder: which patients benefit from the instillation?.Eur Urol. 2016; 69: 231-244Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar The rate of progression is negligible (<2% at 5 years).13Rieken M. Xylinas E. Kluth L. et al.Long-term cancer-specific outcomes of TaG1 urothelial carcinoma of the bladder.Eur Urol. 2014; 65: 201-209Abstract Full Text Full Text PDF PubMed Google Scholar In patients with intermediate-risk NMIBC, additional courses of intravesical therapy are recommended to reduce risk of recurrence [I, A]. This can consist of either:1.Instillations of ChT for a maximum of 1 year. Or2.12 months of BCG instillation therapy (induction therapy with six BCG instillations at weekly intervals, followed by maintenance therapy with three BCG instillations each at 3, 6 and 12 months after the start of the induction cycle) is recommended [I, A]. In trials with BCG therapy (induction and maintenance therapy) in intermediate- and high-risk NMIBC, there was a 32% reduction in the risk of recurrence (P < 0.0001) for BCG compared with MMC. However, no statistically significant difference was observed in progression rate between the two groups.24Malmstrom P.U. Sylvester R.J. Crawford D.E. et al.An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer.Eur Urol. 2009; 56: 247-256Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar In patients with high-risk NMIBC, full-dose intravesical BCG for 1-3 years (at least 1 year) is recommended [I, A]. Three-year maintenance is more effective than 1 year to prevent recurrences.25Oddens J. Brausi M. Sylvester R. et al.Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance.Eur Urol. 2013; 63: 462-472Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar Induction consists of weekly instillations for 6 weeks while maintenance consists of weekly instillations for 3 weeks. Instillations at 3, 6, 12, 18, 24, 30 and 36 months are recommended [I, A]. The 3-year maintenance BCG schedule significantly reduces the risk or recurrence compared with 1-year maintenance [hazard ratio (HR) for 1 versus 3 years: 1.61, 95% CI 1.13-2.30, P = 0.01] in patients with high-risk tumours. This benefit of 3-year therapy does not occur for patients with intermediate-risk tumours.25Oddens J. Brausi M. Sylvester R. et al.Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance.Eur Urol. 2013; 63: 462-472Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar In patients with high-risk NMIBC, there is a significant risk of residual disease after initial TURBT.26Cumberbatch M.G.K. Foerster B. Catto J.W.F. et al.Repeat transurethral resection in non-muscle-invasive bladder cancer: a systematic review.Eur Urol. 2018; 73: 925-933Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar Therefore, a second resection should be carried out 4-6 weeks after the first resection when:•The initial TURBT was incomplete.•If there is no detrusor muscle in the specimen on the initial resection, except for Ta LG and CIS.•In all pT1 tumours and all HG tumours, except for patients with primary CIS [I, A]. The second TURBT should include a resection of the previous tumour site. The definition of failure after BCG therapy is important to identify patients who are unlikely to respond to further BCG therapy. In patients with very-high-risk NMIBC, these recommendations apply, except in those in whom early RC is planned. Early RC should be considered and discussed with all very-high-risk NMIBC cases. The final choice is made based on a shared decision-making process between patient and physician. BCG failure is divided into the following four types:27Kamat A.M. Sylvester R.J. Bohle A. et al.Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the International Bladder Cancer Group.J Clin Oncol. 2016; 34: 1935-1944Crossref PubMed Scopus (262) Google Scholar1.BCG-refractory:•persistent HG disease at 6 months despite adequate BCG treatment; OR•stage progression at 3 months after adequate BCG induction (i.e. HG T1 at 3 months after initial CIS or HG Ta).2.BCG-relapsing: recurrence of HG disease after achieving a disease-free state at 6 months after adequate BCG.3.BCG-intolerant: disease persistence as a result of inability to receive adequate BCG because of toxicity.4.BCG-unresponsive: combination of BCG-refractory and BCG-relapsing within 6 months of last BCG. RC should be carried out in HG tumours (T1/HG, Ta/HG, CIS) that are unresponsive to BCG due to the high risk of progression [III, B]. Thermo-ChT can be offered as an alternative, only in patients unwilling or unable to have RC and can obtain 2-year disease-free survival (DFS) in 47% of patients.28Arends T.J. van der Heijden A.G. Witjes J.A. Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer.J Urol. 2014; 192: 708-713Crossref PubMed Google Scholar BCG re-induction achieved similar disease control to thermo-ChT in a randomised trial [II, B]29Tan W.S. Panchal A. Buckley L. et al.Radiofrequency-induced thermo-chemotherapy effect versus a second course of bacillus Calmette-Guerin or Institutional Standard in patients with recurrence of non-muscle-invasive bladder cancer following induction or maintenance bacillus Calmette-Guerin therapy (HYMN): a Phase III, open-label, randomised controlled trial.Eur Urol. 2019; 75: 63-71Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and can be considered as an alternative. The immune checkpoint inhibitor (ICI) pembrolizumab given intravenously was evaluated in a single-arm phase II trial (KEYNOTE-057), in patients with BCG-unresponsive NMIBC with CIS who were ineligible for or elected not to undergo RC (n = 102).30Balar A.V. Kamat A.M. Kulkarni G.S. et al.Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.Lancet Oncol. 2021; 22: 919-930Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar At 3 months, the study showed a complete response (CR) rate of 41% (95% CI 31%-51%) in 96 patients with high-risk NMIBC with CIS with or without papillary tumours, and a median duration of response of 16.2 months (range: 0.0-30.4). Intravenous pembrolizumab can be considered in patients with BCG-unresponsive disease who are not fit for or refuse RC [III, C]. More robust data are required before stronger recommendations can be made. Intravesical nadofaragene firadenovec therapy [not Food and Drug Administration (FDA) or EMA approved as of November 2021] has also been studied in BCG-refractory NMIBC with CIS (n = 103; 53% CR at 3 months; 24% CR at 12 months) [III, C].31Boorjian S.A. Alemozaffar M. Konety B.R. et al.Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.Lancet Oncol. 2021; 22: 107-117Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar These data have the same recommendations as pembrolizumab in this population. Multidisciplinary care via tumour board discussions and/or directed consultations with a medical oncologist, radiation oncologist and urologist is recommended for the optimal management of bladder cancer [IV, B]. RC with pelvic lymph node dissection (PLND) is the standard treatment of MIBC cT2-T4a, N0 M0 [I, A].32Gakis G. Black P.C. Bochner B.H. et al.Systematic review on the fate of the remnant urothelium after radical cystectomy.Eur Urol. 2017; 71: 545-557Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar RC with PLND is strongly recommended in very-high-risk and BCG-unresponsive NMIBC (Figure 2). A continent orthotopic (neobladder), continent cutaneous (catheterisable pouch) or incontinent cutaneous (conduit) reconstructions are chosen based on patient’s general health and wishes.33Lee R.K. Abol-Enein H. Artibani W. et al.Urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes.BJU Int. 2014; 113: 11-23Crossref PubMed Scopus (247) Google Scholar A neobladder can be offered to patients lacking any contraindications and who have no tumour in the urethra or at the level of urethral dissection [IV, C]. Standard PLND is defined as the removal of all lymphatic tissues around the common iliac, external iliac, internal iliac and obturator regions up to the crossing of the ureters over the common iliac vessels at a minimum.34Simone G. Papalia R. Ferriero M. et al.Stage-specific impact of extended versus standard pelvic lymph node dissection in radical cystectomy.Int J Urol. 2013; 20: 390-397Crossref PubMed Scopus (50) Google Scholar,35Bruins H.M. Veskimae E. Hernandez V. et al.The impact of the extent of lymphadenectomy on oncologic outcomes in patients undergoing radical cystectomy for bladder cancer: a systematic review.Eur Urol. 2014; 66: 1065-1077Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar Extended lymphadenectomy includes lymphatic tissues in the region of the aortic bifurcation and presacral and common iliac vessels above the crossing ureters, in addition to the standard PLND region. The optimal extent of PLND is not established to date. In a recent prospective phase III, randomised trial, extended PLND failed to show a significant advantage in absolute improvement of 5-year recurrence-free survival compared with standard PLND, though the study suffered from many limitations.36Gschwend J.E. Heck M.M. Lehmann J. et al.Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial.Eur Urol. 2019; 75: 604-611Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Patients with radiological suspicious node-positive disease (cN1) can be considered for surgery37Shariat S.F. Ehdaie B. Rink M. et al.Clinical nodal staging sc