Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline Sam S. Chang, Stephen A. Boorjian, Roger Chou, Peter E. Clark, Siamak Daneshmand, Badrinath R. Konety, Raj Pruthi, Diane Z. Quale, Chad R. Ritch, John D. Seigne, Eila Curlee Skinner, Norm D. Smith and James M. McKiernan From the American Urological Association Education and Research, Inc., Linthicum, Maryland Purpose: Although associated with an overall favorable survival rate, the Abbreviations heterogeneity of non-muscle invasive bladder cancer (NMIBC) affects patients’ and Acronyms rates of recurrence and progression. Risk stratification should influence evalu- ¼ ation, treatment and surveillance. This guideline attempts to provide a clinical AUA American Urological Association framework for the management of NMIBC. BCG ¼ bacillus Calmette-Guerin Materials and Methods: A systematic review utilized research from the Agency for Healthcare Research and Quality (AHRQ) and additional supplementation CIS ¼ carcinoma in situ by the authors and consultant methodologists. Evidence-based statements EORTC ¼ European Organization were based on body of evidence strength Grade A, B, or C and were designated for Research and Treatment of as Strong, Moderate, and Conditional Recommendations with additional Cancer statements presented in the form of Clinical Principles or Expert Opinions.1 FDA ¼ Food and Drug Results: A risk-stratified approach categorizes patients into broad groups of low-, Administration intermediate-, and high-risk. Importantly, the evaluation and treatment LVI ¼ lymphovascular invasion algorithm takes into account tumor characteristics and uniquely considers a NMIBC ¼ non-muscle invasive patient’s response to therapy. The 38 statements vary in level of evidence, but bladder cancer none include Grade A evidence, and many were Grade C. SUO ¼ Society of Urologic Conclusion: The intensity and scope of care for NMIBC should focus on patient, Oncology disease, and treatment response characteristics. This guideline attempts to TURBT ¼ transurethral resection improve a clinician’s ability to evaluate and treat each patient, but higher of bladder tumor quality evidence in future trials will be essential to improve level of care for WLC ¼ white light cystoscopy these patients. Accepted for publication June 9, 2016. Key Words: urinary bladder neoplasms, cystectomy, drug therapy, The complete guideline is available at http:// www.auanet.org/common/pdf/education/clinical- immunotherapy guidance/Non-Muscle-Invasive-Bladder-Cancer.pdf. This document is being printed as submitted independent of editorial or peer review by the editors of The Journal of UrologyÒ. For another article on a related BACKGROUND Surveillance Epidemiology and End topic see page 1270. Results program demonstrates that Epidemiology the incidence of all stages of NMIBC NMIBC represents approximately has been relatively stable from 80% of the 74,000 estimated new 5 1988-2006. Multiple factors are bladder cancer cases diagnosed in associated with bladder carcinogen- the United States in 2015 and pri- esis; however, tobacco smoking is marily affects Caucasian Americans 2e5 the most significant and common and those older than 65 years. 6 risk factor. National registry data from the U.S. 0022-5347/16/1964-1021/0 http://dx.doi.org/10.1016/j.juro.2016.06.049 THE JOURNAL OF UROLOGY® Vol. 196, 1021-1029, October 2016 www.jurology.com j 1021 Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Printed in U.S.A. 1022 DIAGNOSIS AND TREATMENT OF NON-MUSCLE INVASIVE BLADDER CANCER Staging and Grading quality and consideration of study design, consistency of Staging for bladder cancer is separated into clinical findings across studies, adequacy of sample sizes, and and pathologic stage, as outlined by the American generalizability of samples, settings, and treatments Joint Committee on Cancer.7 Pathological staging for the purposes of the Guideline. is based on the extent of disease following surgical Evidence-based statements are provided as Strong, Moderate, and Conditional Recommendations with addi- resection of the bladder and adjacent pelvic lymph tional statements provided in the form of Clinical Prin- nodes. ciples or Expert Opinion (table 1). Tumor grade is an important prognostic factor for determining risk of recurrence and progression. The World Health Organization/International Society of Urological Pathology 2004 classification, which GUIDELINE STATEMENTS designates tumors as “low-” or “high-grade,” is 8,9 currently the most widely utilizedsystemin the U.S. Diagnosis. 1. At the time of resection of sus- Prognosis pected bladder cancer, a clinician should The cancer-specific survival in high-grade NMIBC perform a thorough cystoscopic examination is approximately 70-85% at 10 years.10,11 Long-term of a patient’s entire urethra and bladder that follow-up of low-grade Ta lesions demonstrates a evaluates and documents tumor size, location, progression rate of approximately 6%, whereas configuration, number, and mucosal abnor- high-grade T1 lesions have an increased chance of malities. (Clinical Principle) progression of approximately 17%.10,12 Therefore, 2. At initial diagnosis of a patient with the ability to predict recurrence and progression bladder cancer, a clinician should perform risk based on patient-specific disease characteristics complete visual resection of the bladder tu- holds prognostic significance. mor(s), when technically feasible. (Clinical Principle) 3. A clinician should perform upper urinary METHODOLOGY tract imaging as a component of the initial The AUA categorizes body of evidence strength as evaluation of a patient with bladder cancer. Grade A, B, or C based on both individual study (Clinical Principle) Table 1. AUA nomenclature linking statement type to level of certainty, magnitude of benefit or risk/burden, and body of evidence strength Evidence Strength A Evidence Strength B Evidence Strength C (High Certainty) (Moderate Certainty) (Low Certainty) Strong Benefits > Risks/Burdens (or vice versa) Benefits > Risks/Burdens (or vice versa) Benefits > Risks/Burdens (or vice versa) Recommendation Net benefit (or net harm) is substantial Net benefit (or net harm) is substantial Net benefit (or net harm) appears substantial (Net benefit or harm substantial) Applies to most patients in most Applies to most patients in most Applies to most patients in most circumstances and future research is circumstances but better evidence circumstances but better evidence is likely unlikely to change confidence could change confidence to change confidence (rarely used to support a Strong Recommendation) Moderate Benefits > Risks/Burdens (or vice versa) Benefits > Risks/Burdens (or vice versa) Benefits > Risks/Burdens (or vice versa) Recommendation Net benefit (or net harm) is moderate Net benefit (or net harm) is moderate Net benefit (or net harm) appears moderate (Net benefit or harm moderate) Applies to most patients in most Applies to most patients in most Applies to most patients in most circumstances and future research is circumstances but better evidence circumstances but better evidence is likely unlikely to change confidence could change confidence to change confidence Conditional Benefits ¼ Risks/Burdens Benefits ¼ Risks/Burdens Balance between Benefits & Risks/Burdens Recommendation unclear Best action depends on individual Best action appears to depend on (No apparent net patient circumstances individual patient circumstances Alternative strategies may be equally benefit or harm) reasonable Future research unlikely to change Better evidence could change confidence confidence Better evidence likely to change confidence Clinical Principle A statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature Expert Opinion A statement, achieved by consensus of the Panel, that is based on members’ clinical training, experience, knowledge, and judgment for which there is no evidence DIAGNOSIS AND TREATMENT OF NON-MUSCLE INVASIVE BLADDER CANCER 1023 4. In a patient with a history of NMIBC with presence of CIS, and grade. A second risk stratifi- normal cystoscopy and positive cytology, a cation tool is that developed by the Club Urologico clinician should consider prostatic urethral Espanol~ de Tratamiento Oncologico.14 Both tools biopsies and upper tract imaging, as well as are limited by lack of applicability to current enhanced cystoscopic techniques (blue light patient populations because few patients from the cystoscopy, when available), ureteroscopy, or development cohort received BCG maintenance, random bladder biopsies. (Expert Opinion) underwent re-staging transurethral resection, or The most common presenting symptom is pain- received single-dose post-operative mitomycin C. A less hematuria (gross or microscopic). Irritative recent update of the EORTC nomogram for risk voiding symptoms may also be associated with car- stratification attempted to address the lack of BCG cinoma in situ in patients with no sign of urinary maintenance, but the updated study cohort lacked tract infection. A bimanual exam may be performed patients with CIS and again was limited by absence under anesthesia at the time of transurethral of routine re-resection.15 resection of bladder tumor and should be performed Despite the lack of evidence confirming a positive if the tumor appears invasive. Although not indi- influence on clinical outcome, the Panel agrees that cated for routine