American Urological Association Inc., Report on The Management of Non-Muscle-Invasive Bladder Cancer (Stages Ta, T1 and Tis) Archived Document— For Reference Only Bladder Cancer Guidelines Panel Members: Joseph A Smith, Jr., MD, Chair Richard F Labasky, MD, Facilitator James E Montie, MD Randall G Rowland, MD Abraham T.K Cockett, MD John A Fracchia, MD Consultants: Hanan S Bell, PhD Patrick M Florer Curtis Colby Bladder Cancer Clinical Guidelines Panel Members and Consultants Members Joseph A Smith, Jr., M.D (Panel Chair) Department Head Department of Urology Vanderbilt University Medical Center Nashville, Tennessee Richard F Labasky, M.D (Panel Facilitator) Assistant Professor Division of Urology University of Utah Salt Lake City, Utah James E Montie, M.D Professor and Head Section of Urology University of Michigan Ann Arbor, Michigan Consultants Abraham T.K Cockett, M.D (Physician Consultant) Department of Urology University of Rochester Rochester, New York John A Fracchia, M.D (Physician Consultant) Chief Section of Urology Department of Surgery Lenox Hill Hospital New York, New York Hanan S Bell, Ph.D (Consultant in Methodology) Seattle, Washington Patrick M Florer (Database Design and Coordination) Dallas, Texas Curtis Colby (Editor) Washington, D.C Residents (Data Extraction) Jack Baniel Elie Benaim Clay Gould Blake Hamilton Jeff Holzbeierlien Fred Leach John Mansfield Mitchell S Steiner Brad Stoneking Joseph Trapasso Margaret Wolf Archived Document— For Reference Only Randall G Rowland, M.D Professor and Director Division of Urology University of Kentucky Chandler Medical Center Lexington, Kentucky The Bladder Cancer Clinical Guidelines Panel consists of board-certified urologists who are experts in the treatment of bladder cancer This Report on the Management of Non-Muscle-Invasive Bladder Cancer (stages Ta, T1 and Tis) was extensively reviewed by over 50 physicians throughout the country in February 1999 The Panel finalized its recommendations for the American Urological Association (AUA) Practice Parameters, Guidelines and Standards Committee, chaired by Joseph W Segura, MD, in July 1999 The AUA Board of Directors approved these practice guidelines in August 1999 The Summary Report also underwent independent scrutiny by the Editorial Board of the Journal of Urology, was accepted for publication in August 1999, and appeared in its November 1999 issue A Doctor’s Guide for Patients and Evidence Working Papers have also been developed; both are available from the AUA The AUA expresses its gratitude for the dedication and leadership demonstrated by the members of the Bladder Cancer Clinical Guidelines Panel in producing this guideline ISBN 0-9649702-5-2 Introduction More than 50,000 new bladder cancer cases are diagnosed each year in the United States, and the incidence rate (number of new cases per 100,000 persons per year) has been slowly rising, concurrent with an aging population (Landis, Murray, Bolden, et al., 1999; Parker, Tong, Bolden, et al., 1996, 1997; Wingo, Tong, Bolden, et al., 1995) Bladder cancer is largely a disease afflicting the late middle age and old age populations Although the disease does occur in young persons—even in children—more than 70 percent of new cases are diagnosed in persons aged 65 and older (Lynch and Cohen, 1995; Yancik and Ries, 1994) As the baby boom generation ages over the next two decades, the incidence of bladder cancer will likely accelerate At any age, most bladder cancers, when initially diagnosed, have not invaded the detrusor muscle (Fischer, Waechter, Kraus, et al., 1998; Fleshner, Herr, Stewart, et al 1996) These noninvasive cancers are the subject of this Report on the Management of Non-Muscle-Invasive Bladder Cancer (Stages Ta, T1 and Tis) The report was produced by the American Urological Association's Bladder Cancer Clinical Guidelines Panel The AUA charged the panel with the task of analyzing published outcomes data to assess potential benefits and possible adverse effects of treatment interventions and to produce practice policy recommendations accordingly The three types of outcomes the panel determined to be most important for analysis are: 1) probability of tumor recurrence; 2) risk for tumor progression; and 3) complications of treatment The panel developed practice policy recommendations for three types of patients: 1) a patient who presents with an abnormal growth on the urothelium, but who has not yet been diagnosed with bladder cancer; 2) a patient with established bladder cancer of any grade, stage Ta or T1, with or without carcinoma in situ (CIS), who has not had prior intravesical therapy; and 3) a patient with CIS or high-grade T1 cancer who has had at least one course of intravesical therapy The panel avoided use of the term "superficial" in this report to categorize the three non-muscle-invasive stages of bladder cancer: Ta, T1 and Tis The panel agrees with the International Society of Urological Pathology's recommendation that such use of the term should be discouraged (Epstein, Amin, Reuter, et al., 1998) Ta, T1 and Tis tumors have often been grouped together as "superficial" cancers because they are all superficial to the detrusor muscle, but in most other respects they behave differently from one another and to group them in a single category is misleading (See the discussion on page 16.) A summary of this report has been published in the Journal of Urology (November 1999) A Doctor's Guide for Patients and Evidence Working Papers are available for purchase through the AUA Archived Document— For Reference Only Copyright © 1999 American Urological Association, Inc Page i Archived Document— For Reference Only Contents Introduction i Executive Summary Methodology Background Treatment alternatives Treatment recommendations Chapter 1: Methodology Literature search, article selection and data extraction 10 Evidence combination 10 Limitations 11 Chapter 2: Non-muscle-invasive bladder cancer and its management 13 Etiology 13 Major types of bladder cancer 13 Histology 14 Diagnosis 14 Staging 15 Grade classification 17 Prognostic indicators 17 Treatment alternatives 18 Follow-up 20 Chapter 3: Outcomes analysis for treatments of non-muscle-invasive bladder cancer 21 The outcome tables 21 Variability of outcomes data 25 Outcomes summary:recurrence and progression 25 Outcomes summary: treatment complications 26 Chapter 4: Recommendations for management of non-muscle-invasive bladder cancer 28 Treatment policies: levels of flexibility 28 Index patients 28 Treatment recommendations 29 Areas for future research 31 References 33 Appendix A – Data Presentation 38 Appendix B – Data extraction form 54 Appendix C – Data analysis 56 Index 58 Archived Document— For Reference Only Copyright © 1999 American Urological Association, Inc Page iii Archived Document— For Reference Only Managing Editor Lisa Emmons Graphic Desgner Gary Weems Copy Editor Lisa Goetz Copyright © 1999 American Urological Association, Inc Executive Summary: Report on the management of non-muscle-invasive bladder cancer (stages Ta, T1 and Tis) Methodology To develop recommendations for treatment of non-muscle-invasive bladder cancer, the AUA Bladder Cancer Clinical Guidelines Panel reviewed the literature on bladder cancer from January 1964 to January 1998 and extracted and meta-analyzed all relevant data to estimate as accurately as possible both desirable and undesirable outcomes of alternative treatment modalities The panel followed an explicit approach to the development of practice policy recommendations (Eddy, 1992) This approach emphasizes the use of scientific evidence in estimating outcomes If the evidence has limitations, the limitations are clearly stated When panel opinion is necessary, the explicit approach calls for an explanation of why it is necessary and/or for discussion of the factors considered For a full description of the methodology, see Chapter hematuria This set of symptoms is associated with diffuse CIS or muscle-invasive disease Routine diagnostic methods for bladder cancer include: a thorough history, especially regarding exposure to known carcinogens; a physical examination; urine analysis; and a cystoscopic examination of the bladder and urethra Diagnostic cystoscopies today are usually outpatient procedures done with a flexible or rigid cystoscope under local anesthesia Diagnostic tools available in addition to cystoscopy include cytologic assessment and several new urinary tests approved by the FDA for detection or monitoring of recurrences of bladder cancer A transurethral resection of a bladder tumor (TURBT) is usually performed both to excise all visible tumors and to provide specimens for pathologic evaluation to determine tumor stage and grade (Shelfo, Brady and Soloway, 1997) Additional loop or cold-cup biopsies may be taken to evaluate other areas of the urothelium, and a bimanual palpation before and after resection may provide further information on tumor size and depth of penetration A repeat TURBT may be performed in cases of incompletely resected Ta tumors and T1 tumors Archived Document— For Reference Only Background More than 90 percent of all bladder cancers in the United States and Europe, both muscleinvasive and noninvasive, are transitional cell carcinomas originating in the urothelium that forms the bladder lining (Fleshner, Herr, Stewart, et al., 1996) Transitional cell carcinomas may appear in a variety of configurations—including exophytic papillary tumors (the most common configuration); flat patches of carcinoma in situ (CIS); nodular tumors; sessile growths; and mixed growths such as high-grade papillary tumors together with flat CIS Hematuria is the usual first sign of bladder cancer, present at least microscopically in almost all patients with cystoscopically detectable tumors (Messing and Valencourt, 1990) In some cases, bladder irritability accompanied by urgency, frequency and dysuria will be present in addition to Copyright © 1999, American Urological Association, Inc Staging For staging of bladder cancer, the original Jewett-Strong system (1946), modified by Marshall (1952, 1956), has generally given way to the TNM (tumor, node, metastasis) system developed jointly by the American Committee on Cancer Staging and the International Union Against Cancer (Hermanek and Sobin, 1992; Fleming, 1997) Depth of tumor penetration is the crucial element in both systems Table on page 16 shows the TNM classifications for primary tumors, adapted from the American Joint Committee on Cancer (AJCC) staging manual (Fleming, 1997) Page Executive Summary Basic characteristics of stages Ta, T1 and Tis Stage Ta tumors are confined to the urothelium (above the basement membrane) and have a papillary configuration described by Johansson and Cohen (1996) as resembling "seaweed" protruding into the lumen of the bladder Most Ta tumors are low grade Stage T1 tumors have penetrated below the basement membrane and infiltrated the lamina propria, but not so far as the detrusor muscle Most T1 tumors are papillary, but many of those that have penetrated the deepest into the lamina propria are nodular (Heney, Nocks, Daly, et al., 1982) In a stage by itself, CIS (stage Tis) has been defined as high-grade (anaplastic) carcinoma, which like stage Ta is confined to the urothelium, but with a flat, disordered, nonpapillary configuration and a likelihood of being underdiagnosed (Epstein, Amin, Reuter, et al., 1998) CIS can be focal, multifocal or diffuse On cystoscopic examination, it usually appears as a slightly raised, reddened patch of velvety mucosa but often is endoscopically invisible fulguration and/or laser therapy A careful cystoscopic examination of all bladder surfaces, the urethra and the prostate precedes resection (Koch and Smith, 1996) Findings with prognostic significance are noted during this examination Following resection, adjuvant intravesical chemotherapy or intravesical immunotherapy is commonly used to prevent recurrences Resection and fulguration of bladder tumors As stated previously, a TURBT has two main purposes: 1) complete eradication of all visible tumors; and 2) tissue resection for pathologic evaluation to determine grade and stage Fulguration may be used on small lesions, but tissue still needs to be obtained to determine grade and stage at time of initial presentation When a tumor is removed, a separate biopsy can be taken at the base with the resecting loop, after which healthyappearing muscle fibers should be visible at the base Necrotic-appearing tissue implies an invasive carcinoma The presence of fat implies a full-thickness bladder wall defect Archived Document— For Reference Only Grade classification Numerous classification systems for grading transitional cell carcinomas of the bladder have been developed and published over the past few decades Although no single system has yet emerged to win universal acceptance, the most widely used systems all share important characteristics In particular, they all tend to group bladder carcinomas similarly into three principal grades based mainly on degree of anaplasia (Bergkvist, Ljungqvist and Moberger, 1965; Epstein, Amin, Reuter, et al., 1998; Koss, 1975) The three grades—low (grade 1), intermediate (grade 2) and high (grade 3)—correspond respectively to well differentiated, moderately differentiated and poorly differentiated tumors Grade has been shown to be a highly predictive indicator of future tumor behavior with regard to both recurrence and progression Treatment alternatives In most cases of non-muscle-invasive bladder cancer, tumors are treated initially with TURBT, Page Executive Summary Laser therapy The Nd:YAG laser has so far proven to be the most versatile wavelength for treating bladder cancer, but other wavelengths also have been used (Koch and Smith, 1996; Smith, 1986) Results are comparable to electrocautery resection, with little difference in the recurrence rate (Beisland and Seland, 1986) However, tissue samples need to be obtained beforehand by means of cold-cup biopsies to determine tumor grade Assessing depth of tumor penetration to determine stage is more problematic with laser therapy Appropriate patients for this therapy have papillary, low-grade tumors and a history of low-grade, low-stage tumors (Koch and Smith, 1996) Intravesical chemotherapy and immunotherapy Intravesical chemotherapy or immunotherapy is most often used as adjuvant treatment to prevent tumor recurrence following the TURBT of primary non-muscle-invasive bladder tumors, including possible recurrence because of iatrogenic implantation of tumor cells Intravesical therapy is also used to treat known existing tumors in cases Copyright © 1999, American Urological Association, Inc of CIS, which frequently cannot be treated adequately by resection or fulguration because of diffuse involvement The chief intravesical agents currently available are thiotepa, doxorubicin, mitomycin C and bacillus Calmette-Guérin (BCG) Chapter of this report contains an evidencebased comparative outcomes analysis of these agents Thiotepa, introduced in 1961, is the oldest and one of the least expensive of the intravesical drugs It is an alkylating agent that acts by crosslinking nucleic acid Its low molecular weight of 189 allows partial absorption through the urothelium, with possible systemic toxicity Doxorubicin is an anthracycline antibiotic able to bind to DNA and inhibit synthesis It is not cell cycle specific, but appears to be most cytotoxic in the S phase Its molecular weight of 580 is high, and absorption and systemic toxicity are extremely rare Mitomycin C is an antibiotic that works by inhibiting DNA synthesis Because of its moderately high molecular weight of 329, there are few problems with transurothelial absorption, and myelosuppression is rare However, mitomycin C is a very expensive agent (see Table on page 25) BCG is a live attenuated strain of Mycobacterium bovis and was first used as a tuberculosis vaccine Its now widespread use as intravesical immunotherapy for management of noninvasive bladder cancer began in the 1970s It has since become a first-line treatment for CIS and has been shown to be effective as prophylaxis to prevent bladder cancer recurrences following TURBT (Cookson and Sarosdy, 1992; Coplen, Marcus, Myers, et al., 1990; DeJager, Guinan, Lamm, et al., 1991; Herr, Schwalb, Zhang, et al., 1995; Lamm, Blumenstein, Crawford, et al., 1995) Its mechanism of action is not fully understood, but clearly involves a strong inflammatory immunologic host response with release of interleukins and other cytokines (Morales, Eidinger and Bruce, 1976; Ratliff, Haaff and Catalona, 1986) The most common side effects of BCG are cystitis and hematuria The most serious is BCG sepsis BCG therapy is contraindicated in patients who are immunocompromised, have liver disease or a history of tuberculosis Treatment recommendations The panel generated its recommendations based on analysis of comparative outcomes data from both randomized controlled trials (RCTs) and clinical series and on expert opinion The recommendations apply to treatment of patients with non-muscle-invasive, transitional cell carcinoma of the bladder, including CIS as well as stages Ta and T1 tumors The panel evaluated comparative data for the following treatment methods in particular: • TURBT; • TURBT plus thiotepa; • TURBT plus doxorubicin; • TURBT plus mitomycin C; • TURBT plus BCG The terms "standard," "guideline" and "option," as used in the panel's recommendations, refer to the three levels of flexibility for practice policies defined in Chapter (page 9) A standard is the least flexible of the three, a guideline more flexible and an option the most flexible Options can exist because of insufficient evidence or because patient preferences are divided In the latter case particularly, the panel considered it important to take into account likely preferences of individual patients when selecting from among alternative interventions Archived Document— For Reference Only Index patients The specific types of patients to whom the panel's recommendations apply are termed index patients In recognition of the differences in decision-making that occur depending upon patient circumstances, the panel defined three different index patients: Index Patient No 1: A patient who presents with an abnormal growth on the urothelium, but who has not yet been diagnosed with bladder cancer; Index Patient No 2: A patient with established bladder cancer of any grade, stage Ta or T1, with or without CIS, who has not had prior intravesical therapy; and Index Patient No 3: A patient with CIS or high-grade T1 cancer who has had at least one course of intravesical therapy (continued on page 6) Copyright © 1999, American Urological Association, Inc Page Executive Summary Recommendations Recommendation for all index patients Standard: Physicians should discuss with the patient the treatment options and the benefits and harms, including side effects, of intravesical treatment, especially those side effects associated with a particular agent Recommendation for Index Patient No A patient who presents with an abnormal growth on the urothelium, but who has not yet been diagnosed with bladder cancer Standard: Archived Document— For Reference Only If the patient does not have an established histologic diagnosis, a biopsy should be obtained for pathologic analysis Recommendations for Index Patient No A patient with established bladder cancer of any grade, stage Ta or T1, with or without CIS, who has not had prior intravesical therapy Standard: Complete eradication of all visible tumors should be performed if surgically feasible and if the patient's medical condition permits Option: Surgical eradication can be performed by one of several methods, including electrocautery resection, fulguration or laser ablation (continued on next page) Page Executive Summary Copyright © 1999, American Urological Association, Inc Authors Procite Journal Year Vol Pages Title Archived Document— For Reference Only Page 48 Copyright © 1999 American Urological Association, Inc Authors Procite Journal Year Vol Pages Title Archived Document— For Reference Only Copyright © 1999 American Urological Association, Inc Page 49 Archived Document— For Reference Only Page 50 Copyright © 1999 American Urological Association, Inc Archived Document— For Reference Only Copyright © 1999 American Urological Association, Inc Page 51 Archived Document— For Reference Only Page 52 Copyright © 1999 American Urological Association, Inc Archived Document— For Reference Only Copyright © 1999 American Urological Association, Inc Page 53 Appendix B – Data extraction form Archived Document— For Reference Only Page 54 Copyright © 1999 American Urological Association, Inc Archived Document— For Reference Only Copyright © 1999 American Urological Association, Inc Page 55 Appendix C: Data analysis Table C-1 Comparative data from six BCG studies Study Interventions Patients Results Luftenegger, 1996 BCG (Pasteur) 120 mg for six weeks with and without intradermal BCG 78 patients without intradermal, 76 patients with No difference in recurrence at year follow-up, p=.61 Martinez-Pineiro, 1995 BCG (Connaught) 81mg for weeks followed by biweekly for 12 weeks vs 27mg for the same schedule 204 patients, high dose 210 patients, low dose followed 18 months Recurrence: 37 high dose 41 low dose Progression: high dose 10 low dose Differences not stat significant at p=.05 Archived Document— For Reference Only Kaisary, 1987 BCG (Glaxo) 60 mg for six weeks followed by intradermal, vs BCG (Pasteur) 120 mg for the same schedule 11 patients, Glaxo 10 patients, Pasteur followed 18 months recurrences, Glaxo 10 recurrences, Pasteur Hudson, 1987 BCG (Pasteur) 120mg for weeks, vs same plus maintenance instillation every months 21 patients, each group (note that 19 others in each group were lost to follow-up or excluded due to early recurrence) Mean follow-up 16 mo Recurrence: in non-maintenance group in maintenance group Badalament, 1987 BCG (Pasteur) 120mg for six weeks vs same schedule plus maintenance instillation every month 47 patients, maintenance 46 patients, non-maintenance, followed a mean of 22 months No difference in tumor reduction, p=.77, no difference in disease free interval, p=.8, no difference in progression, p=.5 Pagano, 1995 BCG (Pasteur) 75mg vs BCG (Pasteur) 150mg for weeks plus two year maintenance 90 patients, low dose 93 patients, high dose Higher disease free interval in low dose group (p=.0009)-primarily in CIS patients Progression rates the same in the two groups (9%) Each of the six studies in this table compared two groups of bladder cancer patients, all of whom were being treated with BCG The two groups differed in respective studies with regard to dosages administered, route of administration (with and without intradermal boosters), schedules and types of BCG strains yet outcomes did not differ significantly Results are summarized for each study in the fourth column on the right Page 56 Copyright © 1999 American Urological Association, Inc Tables C-2 and C-3: Articles Analyzed for Recurrence and Progression Data R ec u r ren c e BCG vs TURBT BCG vs Thiotepa Mitomycin C vs BCG Mitomycin C vs BCG CIS Lamm et al., 1981 Pagano et al., 1991 Sarosdy and Lamm, 1989 Krege et al., 1996 Lamm, 1985 Melekos et al., 1993 Brosman, 1982 Rodrigues and Lemos, 1983 Martinez-Pineiro et al., 1990 Debruyne et al., 1988 Krege et al., 1996 Lundholm et al., 1996 Vegt et al., 1995 Debruyne et al., 1989 Lamm et al., 1995 Lamm et al., 1995 Vegt et al., 1995 Rintala et al., 1989 Lundholm et al., 1996 BCG vs Doxorubicin Thiotepa vs TURBT Thiotepa vs Mitomycin C Thiotepa vs Doxorubicin Martinez-Pineiro et al., 1990 Lamm et al., 1991 Lamm et al., 1989 Schulman et al 1982 Koontz et al., 1981 Byar and Blackard, 1977 Hirao et al., 1987 Netto et al., 1983 Anonymous, 1985 Prout et al., 1983 Hirao et al., 1992 Zincke et al., 1983 Asahi et al.,1980 Hirao et al., 1987 Flanigan et al., 1986 Horn et al., 1981 Hirao et al., 1987 Martinez-Pineiro et al., 1990 Bouffioux et al., 1992 Zincke et al., 1983 Archived Document— For Reference Only Mitomycin C vs TURBT Mitomycin C vs Doxorubicin Doxorubicin vs TURBT Hirao et al., 1987 Huland and Otto, 1983 Kim and Lee, 1989 Nujima et al., 1983 Krege et al., 1996 Tolley et al.,1996 Akaza et al., 1987 Hirao et al., 1987 Akaza et al., 1987 Silberberg and Zarrabi, 1987 Hirao et al., 1987 Nujima et al., 1983 Kurth et al., 1984 Akaza et al., 1987 Rubben et al., 1988 Kurth et al., 1997 P ro g res s io n BCG vs TURB BCG vs Thiotepa Mitomycin C vs BCG Thiotepa vs TURBT Pagano et al., 1991 Melekos et al., 1993 Krege et al., 1996 Brosman, 1982 Martinez-Pineiro, et al., 1990 Lundholm et al., 1996 Vegt et al., 1995 Lamm et al., 1995 Byar and Blackard, 1977 Hirao et al., 1987 Anonymous, 1985 Prout et al., 1983 Thiotepa vs Mitomycin C Mitomycin C vs TURBT Mitomycin C vs Doxorubicin Doxorubicin vs TURBT Flanigan et al., 1986 Huland and Otto, 1983 Kim and Lee, 1989 Akaza et al., 1992 Akaza et al., 1992 Copyright © 1999 American Urological Association, Inc Hirao et al., 1987 Akaza et al., 1992 Kurth et al., 1997 Page 57 Index A ABO antigen, as prognostic indicator, 17 Adenocarcinoma, 14 Adriamycin See Doxorubicin Arthralgia, as complication of treatment, 22 B Bacillus Calmette-Guérin (BCG), as intravesical therapy and CIS tumors, 5, 7, 19, 30 and recurrence following intravesical therapy, 3, 7, 8, 19, 22, 25-26, 29, 30, 31 and Ta tumors, 5, 7, 30 and T1 tumors, 5, 7, 30 compared to other intravesical therapies, 7, 20, 26, 30 complications from, 3, 6, 19, 26, 27, 29 cost of, 25 description of, 3, 19 dosage of, 8, 19, 31 outcomes of, 3, 7, 9, 12, 22, 23-24, 25 recommendations for use as treatment, 5, 7, 8, 28, 29, 30, 31 Bacterial cystitis, as complication of treatment, 22 BCG sepsis, 3, 6, 19, 27, 29 BCG See Bacillus Calmette-Guérin Biopsy of bladder cancer tumors, 2, 4, 6, 14, 29 Bladder contracture, as complication of treatment, 22 Bladder irritability as complication of bladder cancer, 6, 29 as symptom of bladder cancer, 1, 14 Bladder perforation, as complication of treatment, 22 Blood group antigens, as prognostic indicators, 17 Blood in urine, as complication of treatment, 22 TM BTA stat test, 15, 20 TM BTA TRAK test, 15, 20 and treatment with BCG, 7, 19, 30 and treatment with mitomycin C, 7, 30 definition and description of, 1, 2, 13, 17 outcomes of treatment on, 3, 7, 11, 25 recommendations for treatment of, 3, 4, 5, 7, 28, 29, 30, 31 symptoms of, 14 Complications, 1, 3, 6, 11, 12, 26-27 See also specific complications Cost of treatment See specific treatment methods Cylophosphamide, in etiology of bladder cancer, 13 Cystectomy, 5, 7, 19, 20, 21, 30 Cystitis, as complication of treatment with BCG, 3, 19 Cystoscopy as diagnostic tool, 1, 2, 14 and recurrence of tumors, 20, 31 Cytokeratin, 15 Cytologic assessment and tumor grade, 15 as diagnostic tool, 1, 14, 15, 29 and recurrence of tumors, 15, 20 Archived Document— For Reference Only C Carcinoma in situ See CIS tumors Chemotherapy See Intravesical therapy Cigarette smoke, in etiology of bladder cancer, 13 CIS tumors and cystectomy, 5, 7, 30 and cytologic assessment, 15, 20 and intravesical therapy, 2-3, 18, 19, 20, 28, 30, 31 and staging, 16, 17 Page 58 D Death, 21, 22, 27 and BCG sepsis, 6, 29 Diagnostic evaluation, 1, 4, 6, 7, 14-15, 29 recommendations for, 4, 6, 7, 29 DNA ploidy status, as prognostic indicator, 17, 31 Doxorubicin as intravesical therapy, 3, 7, 19, 22, 26, 28, 30 compared to other intravesical therapies, 7, 26 cost of, 25 description of, 3, 19 dosage of, 19 outcomes of treatment, 3, 7, 9, 22, 23-24, 26, 28 recommendations for use as treatment, 7, 28 Dysuria as complication of treatment, 21, 22 as symptom of bladder cancer, 1, 14 E Electrocautery resection, 2, 4, 6, 18, 29, 30 Endoscopic ablation, recommendations for use, 6, 7, 29, 30 Epididymitis, 22, 26 Copyright © 1999 American Urological Association, Inc Epirubicin, 19 See also Doxorubicin F Fever, as complication of treatment, 22, 26 Flow cystometry, 17, 31 Frequency of urination as complication of treatment, 21, 22, 26 as symptom of bladder cancer, 1, 14 Fulguration, 2, 3, 4, 6, 18, 29, 30 H Hematuria as complication of treatment with BCG, 3, 19 as symptom of bladder cancer, 1, 14 Hepatitis, as complication of treatment, 22 I Immunostaining techniques, 15 Immunotherapy See Intravesical therapy Index patient definition of and criteria for, 3, 28-29 recommendations for, 4-8, 29-31 Industrial chemicals, in etiology of bladder cancer, 13 Interferon, 19-20 Intravesical drugs See specific drugs Intravesical therapy See also specific intravesical therapy treatment methods as treatment after endoscopic ablation, 4, 5, 6, 29, 30-31 as treatment after TURBT, 2-3, 18, 19, 22, 23-24, 25-26, 28, 29 costs of individual therapies, 22, 25 dosage of, 6, 8, 18-19, 29, 31 limitations to outcomes, 11, 25 outcomes of treatment, 9, 11, 25-26 recommendations for use as treatment, 3, 4, 5, 7-8, 28, 29, 30, 31 cost of treatment, 3, 19, 25 description of, 3, 19 outcomes of treatment, 3, 7, 9, 23-24, 26 recommendations for use as treatment, 5, 7, 19, 28, 30 Myelosuppression, as complication of treatment, 3, 18, 19, 22 N Nausea, as complication of treatment, 22 Nd:YAG laser, 2, 5, 18 NMP-22, 15, 20 Nocturia, as complication of treatment, 22, 26 Nuclear matrix protein test See NMP-22 O Outcomes See outcomes under specific treatment methods P p53 and pRb tumor-suppressor genes, as cause of bladder cancer, 13, 17 Pain, as complication of treatment, 22 Patient appropriate for laser therapy, informing about intravesical treatment, 4, 6, 29 spinal-cord injured patients, 14 Phenacetin-related analgesic abuse, as cause of bladder cancer, 13 Pneumonia or pneumonitis, as complication of treatment, 22 Progression of tumors and cystectomy, and intravesical therapy, 7, 12, 25, 26, 29, 30, 31 and prognostic indicators, 17, 31 and tumor grade, 2, 7, 16, 17, 22, 31 and TURBT followed by intravesical therapy, 6, 7, 25, 29 as outcome, 7, 9, 10, 11-12, 22, 25-26, 29, 30, 31 factors associated with increased risk, 7, 22, 30, 31 Prostatic urethral involvement, 17, 31 Prostatitis, as complication of treatment, 22, 26 Proto-oncogenes, in etiology of bladder cancer, 13 Pulmonary changes, as complication of treatment, 22 Archived Document— For Reference Only J Jewett-Strong staging system, 1, 15-16 L Laser ablation, 4, 30 Laser therapy, 2, 6-7, 15, 18, 29, 30 LewisX antigen, 15, 17 M Mitomycin C compared to other intravesical therapies, 7, 26, 30 Copyright © 1999 American Urological Association, Inc R Radiotherapy, in etiology of bladder cancer, 13 Rash, as complication of treatment, 22 Recurrence of tumors and cystoscopy, 20 and cytology, 15, 20 Page 59 and intravesical therapy, 5, 7-8, 12, 18, 19, 22, 2526, 29, 30, 31 and prognostic indicators, 17, 31 and treatment with BCG, 3, 8, 19, 22, 25, 26, 29, 30, 31 and tumor grade, 2, 7, 16, 17 and TURBT followed by intravesical therapy, 2, 6, 7, 25, 29, 30 and urine assay tests, 15 as outcome, 6, 7, 9, 10, 11-12, 21, 22, 25-26, 29, 30, 31 Risk factors for bladder cancer, 13 S Schistosoma haematobium, 14 Sepsis See BCG sepsis Squamous cell carcinoma, 14 Superficial cancer, i, 10, 11, 16 Systemic toxicity of doxorubicin, 3, 19 of thiotepa, 3, 18 as intravesical therapy, 3, 18, 25, 26, 28, 30 compared to other intravesical therapies, 7, 26, 30 cost of, 3, 18, 25 description of, 3, 18 dosage of, 18 outcomes of use as treatment, 3, 25, 26, 28 recommendations for treatment of, 7, 30 TIS (stage) tumors See CIS tumors TNM staging system, 1, 16 Transitional cell carcinoma, See also T1 (stage) tumors, Ta (stage, tumors, and CIS tumors definition and description of, 1, 6, 13-14, 29 grading of, 2, 17, 31 Transurethral resection and intravesical therapy, 2, 7, 21, 28, 30 and treatment with BCG, 3, 7, 9, 22, 28 and treatment with doxorubicin, 3, 7, 9, 22, 28 and treatment with mitomycin C, 3, 7, 9, 28 and treatment with thiotepa, 3, 7, 9, 25, 26, 28 as treatment, 22, 28, 31 definition and description of, 1, 2, 18 diagnosis of, 6, 14, 15, 18, 29 outcomes of use as treatment, 3, 7, 9, 12, 21, 25, 27 without adjuvant therapy, 3, 9, 12, 22, 25, 26, 30 Archived Document— For Reference Only T T1 (stage) tumors and cystectomy, 5, 30 and progression of, 16, 17, 22, 30, 31 and recurrence of, 16, 17, 30, 31 and TURBT, 1, 3, 15 and TURBT followed by intravesical therapy, definition and description of, 2, 13, 16 endoscopic ablation of, 5, 7, 29, 30 outcomes of treatment, 3, 11 recommendations for treatment of, 3, 4, 5, 6, 7-8, 28, 29, 30 staging of, 16 Ta (stage) tumors and cystoscopy, 20 and grade, 2, 16 and progression, 16, 17, 22, 30, 31 and recurrence, 16, 17, 19, 21, 22, 30 and staging, 16, 21 and TURBT, 1, 7, 15 and TURBT followed by intravesical treatment, 7, 30 definition and description of, 2, 13, 16 endoscopic ablation of, 5, 7, 29 outcomes of treatment, 3, 11, 21, 22 recommendation for treatment of, 3, 4, 5, 6, 7, 28, 29, 30 staging of, 16 Telomeric repeat amplification protocol assay test (TRAP test), 15 Thiotepa Page 60 U Urethral infection, as complication of treatment, 22, 26 Urgency as complication of treatment, 22 as symptom of bladder cancer, 1, 14 Urinary incontinence, as complication of treatment, 22 Urinary tract infections, 14 Urine assay tests See specific tests Urine cytology See Cytologic assessment Urothelial carcinoma, 31 V Valrubicin, 19, 31 Vomiting, as complication of treatment, 22 Copyright © 1999 American Urological Association, Inc Archived Document— For Reference Only An attempt has been made to recommend a range of generally acceptable modalities of treatment, taking into account variations in resources and in patient needs and preferences It is recommended that the practitioner articulate and document the basis for any significant deviation from these parameters Finally, it is recognized that conformance with these guidelines cannot ensure a successful result The parameters should not stifle innovation, but will, themselves, be updated and will change with both scientific knowledge and technological advances This material may not be reproduced in electronic or other format without written permission of the American Urological Association, Inc ISBN 0-9649702-S-2 For additional copies, physicians may contact: American Urological Association, Inc Health Policy Department 1000 Corporate Boulevard Linthicum, MD 21090 October 1999 (Stages Ta, T1 and Tis) Archived Document— For Reference Only Management of Non-Muscle-Invasive Bladder Cancer This report is intended to furnish to the skilled practitioner a consensus of clear principles and strategies for quality patient care, based on current professional literature, clinical experience, and expert opinion It does not establish a fixed set of rules or define the legal standard of care, preempting physician judgment in individual cases ... Stewart, et al 1996) These noninvasive cancers are the subject of this Report on the Management of Non-Muscle-Invasive Bladder Cancer (Stages Ta, T1 and Tis) The report was produced by the American Urological... resection, fulguration or application of laser energy Sometimes, the extent of disease or the location of the lesions may preclude complete eradication Also, co-morbid conditions must be considered... resection, fulguration or application of laser energy Sometimes, the extent of disease or the location of the lesions may preclude complete eradication Also, co-morbid conditions must be considered