Nội dung

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Treatment alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 Treatment recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 Chapter 1: Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 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 1. 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 1 on page 16 shows the TNM classifications for primary tumors, adapted from the American Joint Committee on Cancer (AJCC) staging manual (Fleming, 1997). Page 1 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 2 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 3 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 6 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 1 (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 3 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. 1 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. 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. 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 4 Executive Summary Copyright © 1999, American Urological Association, Inc.