NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022

Featured Updates to the NCCN Guidelines

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Thomas W. Flaig University of Colorado Cancer Center;

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Philippe E. Spiess Moffitt Cancer Center;

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Michael Abern Duke Cancer Institute;

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Neeraj Agarwal Huntsman Cancer Institute at the University of Utah;

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Rick Bangs Patient advocate;

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Stephen A. Boorjian Mayo Clinic Cancer Center;

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Mark K. Buyyounouski Stanford Cancer Institute;

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Kevin Chan City of Hope National Medical Center;

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Sam Chang Vanderbilt-Ingram Cancer Center;

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Terence Friedlander UCSF Helen Diller Family Comprehensive Cancer Center;

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Richard E. Greenberg Fox Chase Cancer Center;

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Khurshid A. Guru Roswell Park Comprehensive Cancer Center;

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Harry W. Herr Memorial Sloan Kettering Cancer Center;

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Jean Hoffman-Censits The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;

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Amar Kishan UCLA Jonsson Comprehensive Cancer Center;

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Shilajit Kundu Robert H. Lurie Comprehensive Cancer Center of Northwestern University;

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Subodh M. Lele Fred & Pamela Buffett Cancer Center;

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Ronac Mamtani Abramson Cancer Center at the University of Pennsylvania;

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Vitaly Margulis UT Southwestern Simmons Comprehensive Cancer Center;

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Omar Y. Mian Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;

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Jeff Michalski Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;

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Jeffrey S. Montgomery University of Michigan Rogel Cancer Center;

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Lakshminarayanan Nandagopal O’Neal Comprehensive Cancer Center at UAB;

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Lance C. Pagliaro Mayo Clinic Cancer Center;

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Mamta Parikh UC Davis Comprehensive Cancer Center;

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Anthony Patterson St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center;

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Elizabeth R. Plimack Fox Chase Cancer Center;

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Kamal S. Pohar The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;

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Mark A. Preston Dana-Farber/Brigham and Women’s Cancer Center;

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Kyle Richards University of Wisconsin Carbone Cancer Center;

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Wade J. Sexton Moffitt Cancer Center;

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Arlene O. Siefker-Radtke The University of Texas MD Anderson Cancer Center;

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Matthew Tollefson Mayo Clinic Cancer Center;

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Jonathan Tward Huntsman Cancer Institute at the University of Utah;

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Jonathan L. Wright Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; and

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Mary A. Dwyer National Comprehensive Cancer Network.

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Carly J. Cassara National Comprehensive Cancer Network.

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Lisa A. Gurski National Comprehensive Cancer Network.

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The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non–muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non–muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.

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  • 3.

    American Urological Association. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO joint guideline (2020). Accessed April 27, 2022. Available at: https://www.auanet.org/guidelines/bladder-cancer-non-muscle-invasive-guideline

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    Ritch CR, Velasquez MC, Kwon D, et al. Use and validation of the AUA/SUO risk grouping for nonmuscle invasive bladder cancer in a contemporary cohort. J Urol 2020;203:505511.

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    Eroglu A, Ekin RG, Koc G, et al. The prognostic value of routine second transurethral resection in patients with newly diagnosed stage pT1 non-muscle-invasive bladder cancer: results from randomized 10-year extension trial. Int J Clin Oncol 2020;25:698704.

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    Grimm MO, Steinhoff C, Simon X, et al. Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol 2003;170:433437.

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    Petrelli F, Giannatempo P, Maccagnano C, et al. Active surveillance for non-muscle invasive bladder cancer: a systematic review and pooled-analysis. Cancer Treat Res Commun 2021;27:100369.

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  • 11.

    Sylvester RJ, 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;69:231244.

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    Laukhtina E, Abufaraj M, Al-Ani A, et al. Intravesical therapy in patients with intermediate-risk non-muscle-invasive bladder cancer: a systematic review and network meta-analysis of disease recurrence. Eur Urol Focus 2022;8:447456.

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    Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin 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;63:462472.

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    Sylvester RJ, van der Meijden AP, 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;49:466465, discussion 475–477.

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    Huncharek M, McGarry R, Kupelnick B. Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis. Anticancer Res 2001;21:765769.

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    Böhle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003;169:9095.

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    Han RF, Pan JG. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006;67:12161223.

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    Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int 2001;88:209216.

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    Shelley MD, Wilt TJ, Court J, et al. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int 2004;93:485490.

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    Balar AV, Kamat AM, Kulkarni GS, 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;22:919930.

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    Herr HW, Sogani PC. Does early cystectomy improve the survival of patients with high risk superficial bladder tumors? J Urol 2001;166:12961299.

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    Mari A, Kimura S, Foerster B, et al. A systematic review and meta-analysis of the impact of lymphovascular invasion in bladder cancer transurethral resection specimens. BJU Int 2019;123:1121.

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    Catto JWF, Gordon K, Collinson M, et al. Radical cystectomy against intravesical BCG for High-risk high-grade nonmuscle invasive bladder cancer: results from the randomized controlled BRAVO-feasibility study. J Clin Oncol 2021;39:202214.

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    American Urological Association. BCG Shortage Notice. Accessed April 27, 2022. Available at: https://www.auanet.org/bcg-shortage-notice

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    Friedrich MG, Pichlmeier U, Schwaibold H, et al. Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with Bacillus Calmette-Guérin (BCG) in patients with non-muscle-invasive bladder carcinoma. Eur Urol 2007;52:11231129.

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    Sylvester RJ, van der Meijden AP, Witjes JA, et al. Bacillus Calmette-Guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 2005;174:8691, discussion 91–92.

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    van der Meijden AP, Brausi M, Zambon V, et al. Intravesical instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer genito-urinary group randomized phase III trial. J Urol 2001;166:476481.

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    Barlow LJ, McKiernan JM, Benson MC. The novel use of intravesical docetaxel for the treatment of non-muscle invasive bladder cancer refractory to BCG therapy: a single institution experience. World J Urol 2009;27:331335.

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    Breyer BN, Whitson JM, Carroll PR, et al. Sequential intravesical gemcitabine and mitomycin C chemotherapy regimen in patients with non-muscle invasive bladder cancer. Urol Oncol 2010;28:510514.

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    Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol 2020;203:902909.

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    Steinberg RL, Packiam VT, Thomas LJ, et al. Intravesical sequential gemcitabine and docetaxel versus bacillus Calmette-Guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG. Urol Oncol 2022;40:9.e19.e7.

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    Martínez-Piñeiro JA, Martínez-Piñeiro L, Solsona E, et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 2005;174:12421247.

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    Pfister C, Kerkeni W, Rigaud J, et al. Efficacy and tolerance of one-third full dose bacillus Calmette-Guérin maintenance therapy every 3 months or 6 months: two-year results of URO-BCG-4 multicenter study. Int J Urol 2015;22:5360.

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    Yokomizo A, Kanimoto Y, Okamura T, et al. Randomized controlled study of the efficacy, safety and quality of life with low dose bacillus Calmette-Guérin instillation therapy for nonmuscle invasive bladder cancer. J Urol 2016;195:4146.

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    Steinberg RL, Brooks NA, Thomas LJ, et al. Bacillus Calmette-Guerin strain may not affect recurrence-free survival when used intravesically with interferon-alpha2b for non-muscle-invasive bladder cancer. Urol Oncol 2017;35:201207.

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    Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 2017;3:e172411.

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    Broderick JM. Durvalumab FDA indication for bladder cancer voluntarily withdrawn. Urology Times. February 22, 2021. Accessed April 28, 2022. Available at: https://www.urologytimes.com/view/durvalumab-fda-indication-for-bladder-cancer-voluntarily-withdrawn

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    Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2020;21:15741588.

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    Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:19091920.

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    Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018;391:748757.

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    The ASCO Post Staff. Atezolizumab’s indication in previously treated metastatic bladder cancer is withdrawn. Accessed April 28, 2022. Available at: https://ascopost.com/news/march-2021/atezolizumab-s-indication-in-previously-treated-metastatic-bladder-cancer-is-withdrawn/

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    Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 2019;37:25922600.

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    Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021;384:11251135.

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    Yu EY, Petrylak DP, O’Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2021;22:872882.

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  • 63.

    Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: a phase i study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol 2020;38:10411049.

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  • 64.

    U.S. Food and Drug Administration. Enfortumab vedotin-ejfv for injection, for intravenous use [prescribing information]. Accessed April 27, 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s006s008lbl.pdf

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  • 65.

    Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol 2021;39:24742485.

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