Bladder Cancer Guidelines Panel Report on Report on The Management 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 Members: Consultants: Hanan S. Bell, PhD Patrick M. Florer Curtis Colby American Urological Association Inc., Bladder Cancer Bladder Cancer Non-Muscle-Invasive of (Stages Ta, T1 and Tis) Archived Document— For Reference Only
Transcript
Bladder Cancer Guidelines Panel
Report onReport on
The Management
Joseph A. Smith, Jr., MD, ChairRichard F. Labasky, MD, FacilitatorJames E. Montie, MDRandall G. Rowland, MDAbraham T.K. Cockett, MDJohn A. Fracchia, MD
Members:
Consultants:
Hanan S. Bell, PhDPatrick M. FlorerCurtis Colby
American
Urological
Association
Inc.,
Bladder CancerBladder CancerNon-Muscle-Invasiveof
(Stages Ta, T1 and Tis)
Archived Document— For Reference Only
Bladder Cancer Clinical Guidelines Panel Members and Consultants
The Bladder Cancer Clinical Guidelines Panel consists of board-certified urologists who are experts in the treatment of blad-der cancer. This Report on the Management of Non-Muscle-Invasive Bladder Cancer (stages Ta, T1 and Tis)was extensivelyreviewed by over 50 physicians throughout the country in February 1999. The Panel finalized its recommendations for theAmerican 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 acceptedfor publication in August 1999, and appeared in its November 1999 issue. A Doctor’s Guide for Patientsand Evidence WorkingPapershave 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 CancerClinical Guidelines Panel in producing this guideline.
Members Consultants
ISBN 0-9649702-5-2
Joseph A. Smith, Jr., M.D. (Panel Chair)Department HeadDepartment of UrologyVanderbilt University Medical CenterNashville, Tennessee
Richard F. Labasky, M.D.(Panel Facilitator)Assistant ProfessorDivision of UrologyUniversity of UtahSalt Lake City, Utah
James E. Montie, M.D.Professor and HeadSection of UrologyUniversity of MichiganAnn Arbor, Michigan
Randall G. Rowland, M.D.Professor and DirectorDivision of UrologyUniversity of KentuckyChandler Medical CenterLexington, Kentucky
Hanan S. Bell, Ph.D.(Consultant in Methodology)Seattle, Washington
Patrick M. Florer(Database Design andCoordination)Dallas, Texas
Curtis Colby(Editor)Washington, D.C.
Residents (Data Extraction)Jack BanielElie Benaim Clay GouldBlake HamiltonJeff HolzbeierlienFred LeachJohn Mansfield Mitchell S. SteinerBrad StonekingJoseph TrapassoMargaret Wolf
Abraham T.K. Cockett, M.D.(Physician Consultant)Department of UrologyUniversity of RochesterRochester, New York
John A. Fracchia, M.D.(Physician Consultant)Chief Section of UrologyDepartment of SurgeryLenox Hill HospitalNew York, New York
More than 50,000 new bladder cancer cases are diagnosed each year in the United States, andthe incidence rate (number of new cases per 100,000 persons per year) has been slowly rising, con-current with an aging population (Landis, Murray, Bolden, et al., 1999; Parker, Tong, Bolden, etal., 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 ofnew 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 can-cer will likely accelerate.
At any age, most bladder cancers, when initially diagnosed, have not invaded the detrusor mus-cle (Fischer, Waechter, Kraus, et al., 1998; Fleshner, Herr, Stewart, et al. 1996). These noninvasivecancers 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'sBladder Cancer Clinical Guidelines Panel.
The AUA charged the panel with the task of analyzing published outcomes data to assess po-tential benefits and possible adverse effects of treatment interventions and to produce practice poli-cy recommendations accordingly. The three types of outcomes the panel determined to be mostimportant for analysis are: 1) probability of tumor recurrence; 2) risk for tumor progression; and3) complications of treatment.
The panel developed practice policy recommendations for three types of patients: 1) a patientwho presents with an abnormal growth on the urothelium, but who has not yet been diagnosedwith bladder cancer; 2) a patient with established bladder cancer of any grade, stage Ta or T1, withor without carcinoma in situ (CIS), who has not had prior intravesical therapy; and 3) a patientwith 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-mus-cle-invasive stages of bladder cancer: Ta, T1 and Tis. The panel agrees with the InternationalSociety 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 re-spects they behave differently from one another and to group them in a single category is mislead-ing. (See the discussion on page 16.)
A summary of this report has been published in theJournal of Urology(November 1999). ADoctor's Guide for Patientsand Evidence Working Papersare available for purchase through theAUA.
To develop recommendations for treatment ofnon-muscle-invasive bladder cancer, the AUABladder Cancer Clinical Guidelines Panel re-viewed the literature on bladder cancer fromJanuary 1964 to January 1998 and extracted andmeta-analyzed all relevant data to estimate as ac-curately as possible both desirable and undesir-able outcomes of alternative treatment modalities.The panel followed an explicit approach to the de-velopment of practice policy recommendations(Eddy, 1992). This approach emphasizes the useof scientific evidence in estimating outcomes. Ifthe evidence has limitations, the limitations areclearly stated. When panel opinion is necessary,the explicit approach calls for an explanation ofwhy it is necessary and/or for discussion of thefactors considered. For a full description of themethodology, see Chapter 1.
More than 90 percent of all bladder cancers in the United States and Europe, both muscle-invasive and noninvasive, are transitional cell car-cinomas originating in the urothelium that formsthe bladder lining (Fleshner, Herr, Stewart, et al.,1996). Transitional cell carcinomas may appear ina variety of configurations—including exophyticpapillary tumors (the most common configura-tion); flat patches of carcinoma in situ (CIS);nodular tumors; sessile growths; and mixedgrowths such as high-grade papillary tumors to-gether with flat CIS.
Hematuria is the usual first sign of bladdercancer, present at least microscopically in almostall patients with cystoscopically detectable tumors(Messing and Valencourt, 1990). In some cases,bladder irritability accompanied by urgency, fre-quency and dysuria will be present in addition to
hematuria. This set of symptoms is associatedwith diffuse CIS or muscle-invasive disease.
Routine diagnostic methods for bladder cancerinclude: a thorough history, especially regardingexposure to known carcinogens; a physical exami-nation; urine analysis; and a cystoscopic examina-tion of the bladder and urethra. Diagnostic cysto-scopies today are usually outpatient proceduresdone with a flexible or rigid cystoscope under lo-cal anesthesia. Diagnostic tools available in addi-tion to cystoscopy include cytologic assessmentand several new urinary tests approved by theFDA for detection or monitoring of recurrences ofbladder cancer.
A transurethral resection of a bladder tumor(TURBT) is usually performed both to excise allvisible tumors and to provide specimens forpathologic evaluation to determine tumor stageand grade (Shelfo, Brady and Soloway, 1997).Additional loop or cold-cup biopsies may be tak-en to evaluate other areas of the urothelium, and abimanual palpation before and after resection mayprovide further information on tumor size anddepth of penetration. A repeat TURBT may beperformed in cases of incompletely resected Ta tu-mors and T1 tumors.
StagingFor staging of bladder cancer, the original
Jewett-Strong system (1946), modified byMarshall (1952, 1956), has generally given way tothe TNM (tumor, node, metastasis) system devel-oped jointly by the American Committee onCancer Staging and the International UnionAgainst Cancer (Hermanek and Sobin, 1992;Fleming, 1997). Depth of tumor penetration isthe crucial element in both systems. Table 1 onpage 16 shows the TNM classifications for prima-ry tumors, adapted from the American JointCommittee on Cancer (AJCC) staging manual(Fleming, 1997).
Stage Ta tumors are confined to the urothelium(above the basement membrane) and have a papil-lary configuration--described by Johansson andCohen (1996) as resembling "seaweed" protrudinginto the lumen of the bladder. Most Ta tumors arelow grade.
Stage T1 tumors have penetrated below thebasement membrane and infiltrated the laminapropria, but not so far as the detrusor muscle.Most T1 tumors are papillary, but many of thosethat have penetrated the deepest into the laminapropria are nodular (Heney, Nocks, Daly, et al.,1982).
In a stage by itself, CIS (stage Tis) has beendefined as high-grade (anaplastic) carcinoma,which like stage Ta is confined to the urothelium,but with a flat, disordered, nonpapillary configura-tion and a likelihood of being underdiagnosed(Epstein, Amin, Reuter, et al., 1998). CIS can befocal, multifocal or diffuse. On cystoscopic ex-amination, it usually appears as a slightly raised,reddened patch of velvety mucosa--but often isendoscopically invisible.
Grade classificationNumerous classification systems for grading
transitional cell carcinomas of the bladder havebeen developed and published over the past fewdecades. Although no single system has yetemerged to win universal acceptance, the mostwidely used systems all share important character-istics. In particular, they all tend to group bladdercarcinomas similarly into three principal gradesbased mainly on degree of anaplasia (Bergkvist,Ljungqvist and Moberger, 1965; Epstein, Amin,Reuter, et al., 1998; Koss, 1975). The threegrades—low (grade 1), intermediate (grade 2) andhigh (grade 3)—correspond respectively to welldifferentiated, moderately differentiated and poor-ly differentiated tumors. Grade has been shownto be a highly predictive indicator of future tumorbehavior with regard to both recurrence and pro-gression.
In most cases of non-muscle-invasive bladdercancer, tumors are treated initially with TURBT,
fulguration and/or laser therapy. A careful cysto-scopic examination of all bladder surfaces, theurethra and the prostate precedes resection (Kochand Smith, 1996). Findings with prognostic sig-nificance are noted during this examination.Following resection, adjuvant intravesicalchemotherapy or intravesical immunotherapy iscommonly used to prevent recurrences.
Resection and fulguration of bladder tumors
As stated previously, a TURBT has two mainpurposes: 1) complete eradication of all visible tu-mors; and 2) tissue resection for pathologic evalu-ation to determine grade and stage. Fulgurationmay be used on small lesions, but tissue stillneeds to be obtained to determine grade and stageat time of initial presentation. When a tumor isremoved, a separate biopsy can be taken at thebase with the resecting loop, after which healthy-appearing muscle fibers should be visible at thebase. Necrotic-appearing tissue implies an inva-sive carcinoma. The presence of fat implies afull-thickness bladder wall defect.
Laser therapyThe Nd:YAG laser has so far proven to be the
most versatile wavelength for treating bladdercancer, but other wavelengths also have been used(Koch and Smith, 1996; Smith, 1986). Resultsare comparable to electrocautery resection, withlittle difference in the recurrence rate (Beislandand Seland, 1986). However, tissue samples needto be obtained beforehand by means of cold-cupbiopsies to determine tumor grade. Assessingdepth of tumor penetration to determine stage ismore problematic with laser therapy. Appropriatepatients for this therapy have papillary, low-gradetumors and a history of low-grade, low-stage tu-mors (Koch and Smith, 1996).
Intravesical chemotherapy and immunotherapy
Intravesical chemotherapy or immunotherapyis most often used as adjuvant treatment to pre-vent tumor recurrence following the TURBT ofprimary non-muscle-invasive bladder tumors, in-cluding possible recurrence because of iatrogenicimplantation of tumor cells. Intravesical therapyis also used to treat known existing tumors in cases
of CIS, which frequently cannot be treated ade-quately by resection or fulguration because of dif-fuse involvement. The chief intravesical agentscurrently available are thiotepa, doxorubicin, mit-omycin C and bacillus Calmette-Guérin (BCG).Chapter 3 of this report contains an evidence-based comparative outcomes analysis of theseagents.
Thiotepa, introduced in 1961, is the oldest andone of the least expensive of the intravesicaldrugs. It is an alkylating agent that acts by cross-linking nucleic acid. Its low molecular weight of189 allows partial absorption through the urotheli-um, with possible systemic toxicity.
Doxorubicin is an anthracycline antibiotic ableto bind to DNA and inhibit synthesis. It is notcell cycle specific, but appears to be most cytotox-ic in the S phase. Its molecular weight of 580 ishigh, and absorption and systemic toxicity are ex-tremely rare.
Mitomycin C is an antibiotic that works byinhibiting DNA synthesis. Because of its moder-ately high molecular weight of 329, there arefew problems with transurothelial absorption,and myelosuppression is rare. However, mito-mycin C is a very expensive agent (see Table 6on page 25).
BCG is a live attenuated strain ofMycobacterium bovisand was first used as a tu-berculosis vaccine. Its now widespread use as in-travesical immunotherapy for management ofnoninvasive bladder cancer began in the 1970s. Ithas since become a first-line treatment for CISand has been shown to be effective as prophylaxisto prevent bladder cancer recurrences followingTURBT (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 under-stood, but clearly involves a strong inflammatoryimmunologic host response with release of inter-leukins and other cytokines (Morales, Eidingerand Bruce, 1976; Ratliff, Haaff and Catalona,1986). The most common side effects of BCGare cystitis and hematuria. The most serious isBCG sepsis. BCG therapy is contraindicated inpatients who are immunocompromised, have liverdisease or a history of tuberculosis.
The panel generated its recommendationsbased on analysis of comparative outcomes datafrom both randomized controlled trials (RCTs)and clinical series and on expert opinion. Therecommendations apply to treatment of patientswith non-muscle-invasive, transitional cell carci-noma of the bladder, including CIS as well asstages Ta and T1 tumors. The panel evaluatedcomparative data for the following treatmentmethods in particular:• TURBT;
• TURBT plus thiotepa;
• TURBT plus doxorubicin;
• TURBT plus mitomycin C;
• TURBT plus BCG.The terms "standard," "guideline" and "op-
tion," as used in the panel's recommendations, re-fer to the three levels of flexibility for practicepolicies defined in Chapter 1 (page 9). A standardis the least flexible of the three, a guideline moreflexible and an option the most flexible. Optionscan exist because of insufficient evidence or be-cause patient preferences are divided. In the lattercase particularly, the panel considered it importantto take into account likely preferences of individ-ual patients when selecting from among alterna-tive interventions.
Index patientsThe specific types of patients to whom the
panel's recommendations apply are termed indexpatients. In recognition of the differences in deci-sion-making that occur depending upon patientcircumstances, the panel defined three differentindex patients:
Index Patient No. 1: A patient who presentswith an abnormal growth on the urothelium, butwho has not yet been diagnosed with bladder can-cer;
Index Patient No. 2: A patient with estab-lished bladder cancer of any grade, stage Ta orT1, with or without CIS, who has not had priorintravesical therapy; and
Index Patient No. 3: A patient with CIS orhigh-grade T1 cancer who has had at least onecourse of intravesical therapy.
Physicians should discuss with the patient the treatment options and the benefits andharms, including side effects, of intravesical treatment, especially those side effectsassociated with a particular agent.
Recommendation for Index Patient No. 1
A patient who presents with an abnormal growth on the urothelium, but who has notyet been diagnosed with bladder cancer.
Standard:
If the patient does not have an established histologic diagnosis, a biopsy should be ob-tained for pathologic analysis.
Recommendations for Index Patient No. 2
A patient with established bladder cancer of any grade, stage Ta or T1, with or with-out CIS, who has not had prior intravesical therapy.
Standard:
Complete eradication of all visible tumors should be performed if surgically feasibleand if the patient's medical condition permits.
Option:
Surgical eradication can be performed by one of several methods, including electro-cautery resection, fulguration or laser ablation.
Adjuvant intravesical chemotherapy or immunotherapy is an option for treatment afterendoscopic removal of low-grade Ta bladder cancers.
Guideline:
Intravesical instillation of either BCG or mitomycin C is recommended for treatmentof CIS and for treatment after endoscopic removal of T1 tumors and high-grade Ta tu-mors.
Option:
Cystectomy may be considered for initial therapy in some patients with CIS or T1 tu-mors.
Recommendations for Index Patient No. 3
A patient with CIS or high-grade T1 cancer who has had at least one course of intrav-esical therapy.
Option:
Cystectomy may be considered as an option for patients with CIS or high-grade T1cancers that have persisted or recurred after an initial intravesical treatment.
Option:
Further intravesical therapy may be considered as an option for patients with CIS orhigh-grade T1 cancers that have persisted or recurred after an initial intravesical treat-ment.
This recommendation is based on the panel'sexpert opinion. Although all of the adjuvant treat-ments studied decrease the recurrence probabilityof bladder cancer when they are compared toTURBT alone, the published literature does notunequivocally support the conclusion that the rateof progression to muscle-invasive disease is al-tered. Patients contemplating intravesical therapyshould consider information about all expectedoutcomes including the possible side effects oftherapy. All of the treatments have in commonsome side effects, especially those related to blad-der irritation; other side effects are either uniqueor peculiar to a particular drug. The incidence ofserious or life-threatening side effects with any ofthe treatments is low, as shown in Table 5; but thepanel is aware of reports documenting systemic in-fection or even death from BCG sepsis in rare cir-cumstances.
In addition, there is little information definingthe optimal dose, number and timing of instilla-tions or the influence of long-term maintenancetherapy. Randomized studies supporting the useof maintenance BCG therapy have been conduct-ed, but the panel excluded them because their re-sults have been reported only in abstract form.Other trials would appear to support a role formaintenance therapy.
Recommendation for Index Patient No. 1
A patient who presents with an abnormalgrowth on the urothelium, but who has not yetbeen diagnosed with bladder cancer.
Although urine cytology and other novel tumormarkers, as discussed in Chapter 2 (page 17), canprovide suggestive evidence of bladder cancer, thedefinitive diagnosis is established by pathologicexamination of tissue removed by TURBT orbiopsy. Transitional cell carcinoma of the bladderoften has a characteristic appearance, but otherconditions can mimic the gross appearance ofbladder cancer. It is important, therefore, to proveby microscopic analysis that gross abnormalitiesare from transitional cell carcinoma. Intravesicalimmunotherapy or chemotherapy should not beused in the absence of a histologic diagnosis.
Recommendations for Index Patient No. 2
A patient with established bladder cancer ofany grade, stage Ta or T1, with or without CIS,who has not had prior intravesical therapy.
In a patient with known bladder cancer, endo-scopic ablation of all visible tumors should be per-formed. This can be accomplished with electro-cautery resection, fulguration or application oflaser energy. Sometimes, the extent of disease orthe location of the lesions may preclude completeeradication. Also, co-morbid conditions must beconsidered and may occasionally influence a deci-sion about whether or not to attempt endoscopicremoval of bladder tumors. This recommendationis based on the panel's expert opinion.
For bladder cancers that do not invade the de-trusor muscle, several methods for tumor destruc-tion provide apparently comparable results.Adequate tissue should be available for determina-tion of pathologic stage, but endoscopic ablative
Standard: Physicians should discuss with thepatient the treatment options and the benefitsand harms, including side effects, of intravesi-cal treatment, especially those side effects asso-ciated with a particular agent.
Standard: If the patient does not have an es-tablished histologic diagnosis, a biopsy shouldbe obtained for pathologic analysis.
Standard: Complete eradication of all visibletumors should be performed if surgicallyfeasible and if the patient's medical conditionpermits.
Option: Surgical eradication can be performedby one of several methods, including electro-cautery resection, fulguration or laser ablation.
techniques may not permit submission of all ma-terial for histologic evaluation. This recommen-dation is based on the panel's expert opinion.
A recommendation stronger than an option forthis group of patients (Index Patient No. 2) cannotbe supported by the evidence in the outcomes ta-bles (see page 23). Most studies combined pa-tients who had low-grade stage Ta tumors withpatients who had T1 lesions and higher-grade can-cers, creating difficulty in extracting informationabout this subgroup. However, based upon panelopinion, many patients with low-grade Ta tumorsdo not require adjuvant intravesical therapy.There is a low risk of disease progression (overallless than 10 percent) in this group, and there is lit-tle evidence that adjuvant therapy affects the pro-gression rate. For rapidly recurring low-grade Tatumors, adjuvant therapy may be useful. The out-comes tables show a decreased recurrence proba-bility for all the intravesical therapies studied,compared to TURBT alone.
Based on evidence from the literature and pan-el opinion, both BCG and mitomycin C are supe-rior to doxorubicin or thiotepa for reducing recur-rence of T1 and high-grade Ta tumors. There isno evidence that any intravesical therapy affectsthe ultimate rate of progression to muscle-invasivedisease.
Because there is risk of progression to muscle-invasive disease even after intravesical therapy,cystectomy may be considered as an initial treat-ment option in certain cases. Among factors asso-ciated with increased risk of progression are largetumor size, high grade, tumor location in a sitepoorly accessible to complete resection, diffusedisease, infiltration of lymphatic or vascularspaces and prostatic urethral involvement. Thisrecommendation is based on the panel's expertopinion.
Recommendations for Index Patient No. 3
A patient with CIS or high-grade T1 cancerwho has had at least one course of intravesicaltherapy.
This recommendation is based upon panelopinion rather than evidence in the outcomes ta-bles. However, other data in the literature doshow a substantial risk of progression to muscle-invasive cancer in patients with diffuse CIS andhigh-grade T1 tumors (Herr, 1997; Hudson andHerr, 1995; Kiemeney, Witjes, Heijbroek, et al.,1993). It is not certain whether intravesical thera-py alters this risk of progression. Thus, there aresome patients with symptomatic disease or high-grade tumors who may want to move directly tocystectomy. Physicians should present specificinformation about the risks of cystectomy andmethods for urinary reconstruction to patientswho are contemplating bladder removal.
Option: Adjuvant intravesical chemotherapy orimmunotherapy is an option for treatment afterendoscopic removal of low-grade Ta bladdercancers.
Guideline: Intravesical instillation of eitherBCG or mitomycin C is recommended fortreatment of CIS and for treatment after endo-scopic removal of T1 tumors and high-gradeTa tumors.
Option: Cystectomy may be considered forinitial therapy in some patients with CIS or T1tumors.
Option: Cystectomy may be considered as anoption for patients with CIS or high-grade T1cancers that have persisted or recurred after aninitial intravesical treatment.
Option: Further intravesical therapy may beconsidered as an option for patients with CISor high-grade T1 cancers that have persisted orrecurred after an initial intravesical treatment.
Archived Document— For Reference Only
This recommendation is also based on the pan-el's expert opinion. Optimal dosing schemes forintravesical chemotherapy and immunotherapyhave not been established, but weekly instillationsfor at least six weeks are used most often. There isadditional evidence showing that some patientswill respond to second induction regimens, particu-
larly with BCG. Repeat intravesical therapy maybe appropriate in patients who develop a late recur-rence after previous complete response to an in-travesical agent. Data are insufficient, however, toallow conclusions about the role of drug combina-tion regimens or alternating therapies.
To develop the recommendations in this Reporton the Management of Non-Muscle-InvasiveBladder Cancer (Stages Ta, T1 and Tis),the AUABladder Cancer Clinical Guidelines Panel used anexplicit approach (Eddy, 1992). This approach at-tempts to arrive at practice policy recommenda-tions through mechanisms that systematically takeinto account relevant factors for making selectionsbetween alternative interventions. Such factors in-clude estimation of the outcomes from the inter-ventions, consideration of patient preferences andassessment of the relative priority of the interven-tions for a share of limited health care resourceswhen possible. For estimating the outcomes of in-terventions, emphasis is placed on the use of sci-entific evidence. When panel opinion is neces-sary, the explicit approach calls for explainingwhy it was necessary and/or for discussion of thefactors considered.
In developing its recommendations, the panelmade an extensive effort to review the literatureon non-muscle-invasive bladder cancer and to esti-mate outcomes of alternative treatment modalitiesas accurately as possible. The panel membersthemselves served as proxies for patients in con-sidering preferences with regard to health and eco-nomic outcomes.
The review of the evidence began with a litera-ture search and extraction of data as described onpage 10. The data available in the literature weredisplayed in evidence tables. From these tables,with reference back to the original studies whennecessary, the panel developed comparative out-comes estimates for the following therapeutic al-ternatives for treating non-muscle-invasive bladdercancer:• Transurethral resection of bladder tumor
(TURBT) without adjuvant therapy;
• TURBT with thiotepa;
• TURBT with doxorubicin;
• TURBT with mitomycin C;
• TURBT with bacillus Calmette-Guérin (BCG).The panel utilized the FAST*PRO® meta-
analysis software described on pages 10-11 to
combine the outcomes evidence from the variousstudies. The resulting probability estimates aredisplayed in the outcomes tables on pages 23-24.Because tumor removal is the standard of practice,there is no evidence comparing removal versusnonremoval. Thus, this report concentrates oncomparison of the above listed adjuvant therapiesas used to reduce the likelihood of tumor recur-rence and progression.
The panel generated its recommendationsbased on the probability estimates shown in theoutcomes tables and on expert opinion. Theserecommendations were graded according to threelevels of flexibility as determined by strength ofevidence and the expected amount of variation inpatient preferences. The three levels of flexibilityare defined as follows (Eddy, 1992):1. Standard: A treatment policy is considered a
standard if the health and economic outcomesof the alternative interventions are sufficientlywell-known to permit meaningful decisionsand there is virtual unanimity about which in-tervention is preferred.
2. Guideline: A policy is considered a guidelineif 1) the health and economic outcomes of theinterventions are sufficiently well-known topermit meaningful decisions and 2) an appre-ciable but not unanimous majority agree onwhich intervention is preferred.
3. Option: A policy is considered an option if 1)the health and economic outcomes of the inter-ventions are not sufficiently well-known topermit meaningful decisions, 2) preferencesamong the outcomes are not known, 3) pa-tients' preferences are divided among the alter-native interventions and/or 4) patients are in-different about the alternative interventions.A standard has the least flexibility. A guide-
line has significantly more flexibility, and optionsare the most flexible. In this report, the terms areused to indicate the strength of the recommenda-tions. A recommendation was labeled a standard,for example, if the panel concluded that it shouldbe followed by virtually all health care providersfor virtually all patients. A guideline generally
denotes a recommendation supported by objectivedata but not with sufficient strength to warrant adesignation of standard. An option in this reportwould include treatments for which there appearsto be equal support in the literature or ones forwhich there is insufficient published informationto support a stronger recommendation. Also, asnoted in the above definition, options can exist be-cause of insufficient evidence or because patientpreferences are divided. In the latter case particu-larly, the panel considered it important to take intoaccount likely preferences of individual patientswith regard to health outcomes when selectingfrom among alternative interventions.
Literature searches were performed mostly us-ing the MEDLINE
®database. Some articles (in-
cluding some that predate the inception of MED-LINE
®in 1966) were added for review based on
panel members' own knowledge. The initialMEDLINE
®search was performed in 1989. A
subsequent literature search was performed in1992 with the search terms bladder neoplasms andcarcinoma, transitional cell. Several updatesearches were also performed, the last in 1998.All searches were restricted to English-languagearticles on human subjects. Update searches werefurther restricted to articles containing the termsuperficial in the bibliographic record. The result-ing database of search results was used as the ba-sis for selecting articles for data extraction. Noattempt was made to weight the articles by qualityof data.
The panel as a group reviewed the abstractsand selected the relevant articles for data extrac-tion. From a database of 5,712 citations, the panelselected 227 articles for retrieval and data extrac-tion. A comprehensive data-extraction form wasdevised by the panel to capture as much pertinentinformation as possible from each article.Appendix B contains a sample of this form.
Reviewers were recruited from residencies atthe panel members' medical centers and trained touse the review form. The articles selected by thepanel were retrieved and divided among the re-viewers, who extracted the articles and transcribed
the data onto the forms. The panel rejected 46 ar-ticles at this stage because of reasons such as in-adequate methods, no relevant data or superses-sion by a later article from the same source (seeAppendix A, Figure A-5). The result was 181 ar-ticles to be used as the source of data for this re-port. All data were entered into a MicrosoftAccess 97® database (Microsoft, Redmond,Washington), then double-checked at a later time.
The bar graph in Figure A-1 on page 50 cate-gorizes by year of publication the number of arti-cles reviewed and the number accepted for dataextraction. The articles extracted range in year ofpublication from 1964 to 1998. The graph inFigure A-2 categorizes the articles by source. Themajority came from the Journal of Urology,Urology and The British Journal of Urology.
The data resulting from the article-selectionand data-extraction process just described werecombined to generate the comparative probabilityestimates for alternative interventions displayed inthe outcomes tables (Tables 2-5) on pages 23-24.A variety of methods can be used to combine out-comes evidence from the literature to generateprobability estimates. The methods chosen de-pend on the nature and quality of the evidence.For example, if there is only one good randomizedcontrolled trial (RCT), the results of that one trialalone may be used in the outcomes tables. Otherstudies of lesser quality may be ignored.
For non-muscle-invasive bladder tumors, datafrom more than 30 RCTs were available to gener-ate comparative estimates of recurrence and pro-gression probabilities for the different treatmentalternatives. The small patient size of many ofthese studies, however, made them suboptimal forestimating probabilities of treatment complica-tions, particularly uncommon complications.Thus, the panel opted to include data from clinicalseries as well as from RCTs for generating com-plications estimates.
If a number of studies have some degree of rel-evance to a particular cell or cells in an outcomestable, meta-analytic methods may be used.Different specific methods are available dependingon the nature of the evidence. For this report, thepanel elected to use the Confidence ProfileMethod (Eddy 1989; Eddy, Hasselblad andShachter, 1990), utilizing FAST*PROTM computer
Literature search, article selection and data extraction Evidence combination
software (Eddy and Hasselblad, 1992). TheConfidence Profile Method allows analysis of databoth from RCTs and from single-arm studies thatare not controlled.
Two different meta-analytic approaches wereused. For estimates of recurrence and progres-sion, data from multi-armed RCTs were combinedmeta-analytically to determine the difference be-tween two treatment alternatives. All alternativeswere compared in pairs. For estimates of treat-ment complications, meta-analysis was performedto combine data from single arms of more thanone study, including the relevant single arms ofmulti-armed RCTs. An estimate of the probabilityof each complication was computed. Thus, theoutcomes table for treatment complications (Table5, page 24) shows the probabilities of a particularcomplication occurring for each treatment choice.In the tables for recurrence and progression (page23), the numbers represent the difference in prob-ability between two treatment interventions. Forexample, if 10 percent of patients given interven-tion A had a recurrence, and 13 percent of patientsgiven intervention B had a recurrence, the numberlisted in the outcomes table would be 3 percent.
Different study results may be caused by anumber of factors, including differences in patientpopulations, how an intervention was performedor the skill of those performing the intervention.Because of such differences, the meta-analyses allused a random effects or hierarchical Bayesianmodel in combining data from different studies.A random effects model assumes that for eachstudy there is an underlying true rate for the out-come being assessed. It further assumes that thisunderlying rate varies from study to study, andthat the variation in the true rate is normally dis-tributed.
The probability distributions produced by theConfidence Profile Method can be described usinga mean or median estimate of the probability anda confidence interval. In this report, the 95-per-cent confidence interval is such that the probabili-ty (Bayesian) of the true value being outside theinterval is 5 percent. The width of the confidenceinterval indicates the degree of uncertainty aboutthe estimated probability, reflecting such factors asdifferences in outcomes data being combined fromdifferent studies and differences in the size of thestudies.
The results presented in this document haveseveral limitations, mostly because of how dataare reported in the literature. Determination ofoutcomes by tumor stage is an important example.Such determination was limited by the fact thatmost studies, including RCTs, categorize patientswith CIS, Ta or T1 tumors as all having "superfi-cial bladder cancer," without reporting stage-spe-cific results. In addition, most studies do not seg-regate response by tumor grade. Yet, stage andgrade, even in the absence of muscle invasion, arestrong predictors of recurrence and progression.These problems limited the ability of the panel tomake strong, evidence-supported recommenda-tions.
A possible limitation in using RCTs for meta-analysis is that, by their nature, most RCTs com-pare two or more different treatments, whereas thecomparison of all alternative treatments may bewhat is desired for purposes of evidence-basedclinical practice guidelines. Ideally, this shouldnot be a problem because the two-way compar-isons should line up consistently in relation to oneanother, and it should be possible to generatenumbers that show with consistency the differ-ences among all of a given set of treatments.
For example, assume that a two-way compari-son based on meta-analysis of RCTs shows the es-timated probability of patient survival to be 20percent greater after treatment A than after treat-ment B. Another two-way comparison based onother RCTs shows this estimated probability to be10 percent greater after treatment B than aftertreatment C. Therefore, a comparison of treat-ments A and C should logically show a differenceof 30 percent in favor of treatment A. In reality,such consistency of results is uncommon whenbased on data from different studies. Among thereasons for possible inconsistencies are differ-ences in study designs, differences in the mea-sures used, patient differences and simple randomvariation.
With regard to intravesical drugs, studies differon dosages, strains, administration protocols andmixtures of patients. Nevertheless, the panel ulti-mately decided to combine data from studies thatdiffer in these areas, because such differences
software (Eddy and Hasselblad, 1992). TheConfidence Profile Method allows analysis of databoth from RCTs and from single-arm studies thatare not controlled.
Two different meta-analytic approaches wereused. For estimates of recurrence and progres-sion, data from multi-armed RCTs were combinedmeta-analytically to determine the difference be-tween two treatment alternatives. All alternativeswere compared in pairs. For estimates of treat-ment complications, meta-analysis was performedto combine data from single arms of more thanone study, including the relevant single arms ofmulti-armed RCTs. An estimate of the probabilityof each complication was computed. Thus, theoutcomes table for treatment complications (Table5, page 24) shows the probabilities of a particularcomplication occurring for each treatment choice.In the tables for recurrence and progression (page23), the numbers represent the difference in prob-ability between two treatment interventions. Forexample, if 10 percent of patients given interven-tion A had a recurrence, and 13 percent of patientsgiven intervention B had a recurrence, the numberlisted in the outcomes table would be 3 percent.
Different study results may be caused by anumber of factors, including differences in patientpopulations, how an intervention was performedor the skill of those performing the intervention.Because of such differences, the meta-analyses allused a random effects or hierarchical Bayesianmodel in combining data from different studies.A random effects model assumes that for eachstudy there is an underlying true rate for the out-come being assessed. It further assumes that thisunderlying rate varies from study to study, andthat the variation in the true rate is normally dis-tributed.
The probability distributions produced by theConfidence Profile Method can be described usinga mean or median estimate of the probability anda confidence interval. In this report, the 95-per-cent confidence interval is such that the probabili-ty (Bayesian) of the true value being outside theinterval is 5 percent. The width of the confidenceinterval indicates the degree of uncertainty aboutthe estimated probability, reflecting such factors asdifferences in outcomes data being combined fromdifferent studies and differences in the size of thestudies.
The results presented in this document haveseveral limitations, mostly because of how dataare reported in the literature. Determination ofoutcomes by tumor stage is an important example.Such determination was limited by the fact thatmost studies, including RCTs, categorize patientswith CIS, Ta or T1 tumors as all having "superfi-cial bladder cancer," without reporting stage-spe-cific results. In addition, most studies do not seg-regate response by tumor grade. Yet, stage andgrade, even in the absence of muscle invasion, arestrong predictors of recurrence and progression.These problems limited the ability of the panel tomake strong, evidence-supported recommenda-tions.
A possible limitation in using RCTs for meta-analysis is that, by their nature, most RCTs com-pare two or more different treatments, whereas thecomparison of all alternative treatments may bewhat is desired for purposes of evidence-basedclinical practice guidelines. Ideally, this shouldnot be a problem because the two-way compar-isons should line up consistently in relation to oneanother, and it should be possible to generatenumbers that show with consistency the differ-ences among all of a given set of treatments.
For example, assume that a two-way compari-son based on meta-analysis of RCTs shows the es-timated probability of patient survival to be 20percent greater after treatment A than after treat-ment B. Another two-way comparison based onother RCTs shows this estimated probability to be10 percent greater after treatment B than aftertreatment C. Therefore, a comparison of treat-ments A and C should logically show a differenceof 30 percent in favor of treatment A. In reality,such consistency of results is uncommon whenbased on data from different studies. Among thereasons for possible inconsistencies are differ-ences in study designs, differences in the mea-sures used, patient differences and simple randomvariation.
With regard to intravesical drugs, studies differon dosages, strains, administration protocols andmixtures of patients. Nevertheless, the panel ulti-mately decided to combine data from studies thatdiffer in these areas, because such differences
appear to have little or no effect on rates of recur-rence and progression. This is demonstrated bythe comparative data from BCG studies shown inTable C-1 in Appendix C. The panel also com-bined data from studies that differed in follow-upduration. The panel did this because those studiesthat had longer follow-up and showed actuarialdata indicated that differences in recurrence andprogression apparently develop early in the fol-low-up period and remain relatively constant overtime.
Differences in how authors define and recordcomplications are also a common problem. Someauthors report the most minor of complications,whereas other authors fail to report complicationsat all. If a complication is rare and the panel onlyanalyzes those papers that report the complica-tion, there will be a significant overestimation of
its frequency. The panel attempted to determineappropriate denominators for such complications,but the possibility of overestimation still exists.
Another common difficulty is negative publi-cation bias. Studies with poor results are lesslikely to be published because either they are nev-er submitted for publication or they are rejectedlater. For example, with regard to articles com-paring adjuvant therapies to TURBT alone, thereis the possibility that studies demonstrating nega-tive results for adjuvant therapies versus TURBTalone may never have been published.
Notwithstanding such limitations, the paneldid find high-quality outcomes data available ontreatment of non-muscle-invasive bladder cancerand in sufficient quantity for computing reliableprobability estimates to aid physicians and pa-tients in their treatment decision making.
Chapter 2: Non-muscle-invasive bladder cancer and its management
Chapter 2 provides an overview of the currentknowledge base for bladder carcinomas that havenot invaded the detrusor muscle (stages Ta, T1and Tis). This overview includes summary de-scriptions of known etiologic factors, tumor typesand characteristics, histology and natural history.Described also are current methods of diagnosis,staging and grade classification, as well as meth-ods for treating primary tumors and for predictinglikelihood of tumor recurrence and subsequentprogression.
Malignant transformation of a normal bladdercell begins with alteration of the cell's DNA.Epidemiologic evidence implicates chemical car-cinogens as a causative agent in many patients.Specifically, the evidence points to aromaticamines, such as 2-naphthylamine and 4-amino-biphenyl, which are present in cigarette smokeand various industrial chemicals. Cigarette smokemetabolites, secreted into smokers' urine, havebeen estimated to cause more than 50 percent ofthe bladder cancer cases in the United States andEurope (Bryan, 1993; Vineis, Martone andRandone, 1995). Occupational exposure to indus-trial chemicals has been estimated to account forup to 20 percent of bladder cancer cases in theUnited States, often with latency periods of morethan 30 years (Bryan, 1993; Cole, Hoover andFriedell, 1972; Silverman, Levin, Hoover, et al.,1989a, 1989b).
Other reported risk factors for bladder cancerinclude phenacetin-related analgesic abuse; thatis, consumption in excessive quantities over a 10-year period (Piper, Tonascia and Metanoski,1985). The average latency period is 22 years,and most patients have renal pelvic tumors as well(Johansson, Angervall, Bengtsson, et al., 1974).The drug cylophosphamide, which is used to treata variety of conditions including Hodgkin's dis-ease, can also lead to development of bladder can-cer; the causative agent is believed to be cy-
clophosphamide's urinary metabolite acrolein.The latency period is a relatively short 6-13 years,and most of the tumors are high grade when diag-nosed (Cohen, Garland, St. John, et al., 1992;Fernandes, Manivel, Reddy, et al., 1996; O'Keane,1988; Talar-Williams, Hijazi, Walther, et al.,1996). Bladder cancer can result from radiothera-py used to treat uterine or cervical cancer or otherpelvic tumors, and again the tumors tend to behigh grade when diagnosed (Quilty and Kerr,1987; Sella, Dexeus, Chong, et al., 1989).
Much of today's research regarding bladdercancer etiology focuses on the role of altered ge-netic mechanisms, some of which have been un-der study for years. Oncogenes are an example.These are altered forms of alleles called proto-oncogenes. Proto-oncogenes encode a growthfactor as well as receptor proteins and are neces-sary for normal cell development. The alteredforms, oncogenes, lead to unregulated cell divi-sion and, in bladder cancer, increased recurrenceand progression (Del Senno, Maestri, Piva, et al.,1989; Tiniakos, Mellon, Anderson, et al., 1994).
Tumor-suppressor genes such as p53 have alsobeen under intense study. One of the functions ofp53 is to direct DNA-damaged cells toward apop-tosis before the DNA can replicate, thus suppress-ing proliferation of cells that have genetic abnor-malities (Harris and Hollstein, 1993). If p53 itselfis damaged, it may no longer be able to function(Cordon-Cardo, 1995). Bladder cancers associat-ed with mutated p53 tend to behave quite aggres-sively (Cordon-Cardo, 1995; Esrig, Elmajian,Groshen, et al., 1994), and altered genes like p53may serve as markers to indicate the relative ag-gressiveness of individual tumors.
More than 90 percent of all bladder cancers inthe United States and Europe, both muscle inva-sive and noninvasive, are transitional cell
carcinomas originating in the urothelium thatforms the bladder lining (Fleshner, Herr, Stewart,et al., 1996). Transitional cell carcinomas mayappear in a variety of configurations--includingexophytic papillary tumors (the most commonconfiguration); flat patches of carcinoma in situ(CIS); nodular tumors; sessile growths; and mixedgrowths such as high-grade papillary tumors to-gether with flat CIS.
Less common types of bladder cancer includesquamous cell carcinoma, which accounts for 3 to7 percent of all bladder cancers in the UnitedStates, and adenocarcinoma, which accounts forless than 2 percent of primary bladder cancers(Kantor, Hartge, Hoover, et al., 1988; Koss, 1975;Lynch and Cohen, 1995). Adenocarcinoma is themost common type of cancer in exstrophic blad-ders (Bennett, Wheatley and Walton, 1984;Nielsen and Nielsen, 1983).
In the United States, squamous cell carcinomaof the bladder is associated with factors such aschronic urinary tract infections and chronic irrita-tion from long-term indwelling catheters and uri-nary calculi. Spinal-cord injured patients, in par-ticular, are at risk for squamous cell bladder can-cer (Navon, Soliman, Khonsari, et al., 1997). InNorth Africa, where squamous cell carcinoma isalso associated with bilharzial infection fromSchistosoma haematobium,this type of bladdercancer is much more prevalent than in the UnitedStates and Europe (Zhang and Steineck, 1997). InEgypt, squamous cell carcinoma accounts formore than 75 percent of all bladder cancers (El-Bolkainy, Mokhtar, Ghoneim, et al., 1981).
The bladder has three main histologic layers:1) the urothelium; 2) the suburothelial layer ofloose connective tissue called the lamina propria;and 3) the detrusor muscle (muscularis propria).The urothelium in the normal bladder consists ofthree to seven layers of transitional-type epithelialcells, which vary in appearance from cell layer tocell layer. Those in the luminal cell layer arelarge, flat umbrella cells bound together by tightjunctions. The urothelium's deepest layer is com-posed of basal cells resting on and attached to anextracellular-matrix basement membrane (basallamina). Between these cell layers are one to fiveintermediate layers.
Beyond the basement membrane is the laminapropria, extending to the detrusor muscle. As not-ed, the lamina propria consists of loose connectivetissue. This layer also contains blood vessels andlymphatic vessels that provide potential channelsfor cancer dissemination. At about one-third ofthe distance from the basement membrane to thedetrusor muscle is a discontinuous, wispy layer ofsmooth muscle called the muscularis mucosa.The muscularis mucosa, when parts of it are pre-sent in small, fragmented tumor specimens ob-tained by biopsy or transurethral resection, maybe difficult for the pathologist to distinguish fromdetrusor muscle. The result may be overstagingof a tumor erroneously thought to be muscle-inva-sive, but actually limited to the lamina propria.The detrusor muscle itself consists of interlacingbundles of smooth muscle with a covering of adi-pose tissue (or peritoneum).
Hematuria is the usual first sign of bladdercancer, present at least microscopically in almostall patients with cystoscopically detectable tumors(Messing and Valencourt, 1990). In some cases,bladder irritability accompanied by urgency, fre-quency and dysuria will be present in addition tohematuria. This set of symptoms is associatedwith diffuse CIS or muscle-invasive disease.
Routine diagnostic methods for bladder cancerinclude a thorough history, especially regardingexposure to known carcinogens; a physical exami-nation; urine analysis; and a cystoscopic examina-tion of the bladder and urethra. Diagnostic cysto-scopies today are usually outpatient proceduresdone with a flexible or rigid cystoscope under lo-cal anesthesia. Diagnostic tools available in addi-tion to cystoscopy include cytologic assessmentand several new urinary tests approved by theFDA for detection or monitoring of recurrences ofbladder cancer. These diagnostic aids will be dis-cussed later.
Also, because hematuria can originate else-where than in the bladder, imaging of the entireurinary tract may be warranted at the time ofhematuria evaluation (using a range of availableimaging techniques). Once a diagnosis of bladdercancer is established, upper tract imaging is usuallyperformed.
Urinary cytologyMicroscopic cytologic examination of bladder
cells, collected from voided urine or from bladderwashings (which potentially yield more cells), haslong been part of the diagnostic armamentariumfor bladder cancer. Cytology is frequently used aswell in post-treatment follow-up to detect possiblecancer recurrence (Grégoire, Fradet, Meyer, et al.,1997).
Cytologic assessment is least sensitive for de-tecting low-grade bladder tumors. Because thecells of these well-differentiated tumors oftenclosely resemble normal urothelial cells, malig-nant features may be difficult to recognize. In ad-dition, the cells are relatively cohesive and maynot shed into the urine in sufficient numbers foranalysis. Cytologic detection rates for low-gradetumors are generally less than 30 percent (Kannanand Bose, 1993; Murphy, Soloway, Jukkola, et al.,1984).
Cytology is much more effective for detectinghigh-grade tumors, the cells of which have sub-stantial abnormal characteristics. Also, reducedcellular cohesion in high-grade tumors producesgreater numbers of cells shed into the urine.Cytology is especially valuable for detecting CIS,with detection rates as high as 90 percent(Grégoire, Fradet, Meyer, et al., 1997; Messingand Catalona, 1998).
Now being investigated are ways to improvecytology performance such as through immunos-taining with either Lewis
xantigen or cytokeratin
20 (Klein, Zemer, Buchumensky, et al., 1998;Pode, Golijanin, Sherman, et al., 1998).
Recently developed urineassay tests
The bladder tumor antigen (BTA) test was thefirst of several tests developed to detect bladdercancer recurrence based on urinary presence ofcertain antigens, nuclear matrix proteins or othersubstances known to be associated with bladdermalignancies (Fradet, 1998; Grossman, 1998;Sardosdy, White, Soloway, et al., 1995). Theoriginal BTA test has been followed by two newerassays, BTA statTM and BTA TRAKTM, which mayoffer improved performance over the original(Ellis, Blumenstein, Ishak, et al., 1997; Sarosdy,Hudson, Ellis, et al., 1997).
A nuclear matrix protein test, NMP-22, hasbeen approved by the FDA to detect occult or
rapidly recurring bladder cancer after a transure-thral resection of a bladder tumor (TURBT).NMP-22 has been reported to be more sensitivebut less specific than cytology as a diagnostictool; however, experience with the test is still lim-ited (Stampfer, Carpinito, Rodriguez-Villanueva,et al., 1998).
Another test is based on telomerase activity.Telomerase is an enzyme responsible for chromo-some-end (telomere) maintenance and is com-monly active in cancer. The TRAP test, or telom-eric repeat amplification protocol assay, is report-ed to be highly sensitive but may require specialcollection techniques (Kavaler, Landman, Chang,et al., 1998; Linn, Lango, Halachmi, et al., 1997).
These and other tests now under development(including easy-to-use point-of-service dip-stick-type assays) appear promising but need to be test-ed themselves by time and experience to provetheir clinical utility (Bandalament, 1998;Grossman, 1998; Johnston, Morales, Emerson, etal., 1997). Most of these tests are limited by in-sufficient specificity to allow treatment decisionsbased on a positive test, although they appear tobe more sensitive than cytology for detecting tu-mors, especially low-grade lesions.
Diagnostic TURBTTURBT (described on page 18) is the usual
method for initial diagnosis of bladder cancer. ATURBT is performed both to excise all visible tu-mors and to provide specimens for pathologicevaluation to determine tumor stage and grade(Shelfo, Brady and Soloway, 1997). Additionalloop or cold-cup biopsies may be taken to evalu-ate other areas of the urothelium, and a bimanualpalpation before and after resection may providefurther information on tumor size and depth ofpenetration. A repeat TURBT may be performedin cases of incompletely resected Ta and T1 tu-mors.
Laser coagulation may be used to ablate tu-mors in some cases, especially recurrent lesions.If laser therapy is used, cold-cup biopsies may betaken for pathologic evaluation.
For staging of bladder cancer, the originalJewett-Strong system (1946), modified by
Staging
Archived Document— For Reference Only
Marshall (1952, 1956), has generally given way tothe TNM (tumor, node, metastasis) system devel-oped jointly by the American Committee onCancer Staging and the International UnionAgainst Cancer (Hermanek and Sobin, 1992;Fleming, 1997). Depth of tumor penetration isthe crucial element in both systems. Table 1shows the TNM classifications for primary tu-mors, adapted from the American JointCommittee on Cancer (AJCC) staging manual(Fleming, 1997).
Based on large data sets from hospitals in theUnited States and Germany, 30-35 percent ofbladder cancer patients at time of diagnosis pre-sent with stage Ta or Tis disease (confined to theurothelium); 25-30 percent have stage T1 disease(penetration into the lamina propria); and 30-35percent present with muscle-invasive disease instage T2 or higher (Fischer, Waechter, Kraus, etal., 1998; Fleshner, Herr, Stewart, et al., 1996).
Use of the term "superficial"As noted in the introduction to this report
(page i), the three non-muscle-invasive stages––Ta, T1 and Tis––are often grouped together underthe label "superficial." This is an imprecise label,and the AUA Bladder Cancer Guidelines Panelbelieves its use should be discouraged. All threestages are indeed superficial to the detrusor mus-cle, but otherwise differ markedly from one an-
other, particularly with regard to tumor recurrenceand progression (Epstein, Amin, Reuter, et al.,1998; Fitzpatrick, 1993; Levi, La Vecchia,Randimbison, et al., 1993).
Low-grade Ta tumors, for example, tend to re-cur as low-grade Ta tumors. Progression to mus-cle-invasive disease takes place in less than 10percent of patients with these tumors (Holmäng,Hedelin, Anderström, et al., 1997; Kiemeney,Witjes, Heijbroek, et al., 1993; Prout, Barton,Griffin, et al., 1992). By contrast, T1 tumors havea progression rate of 30-50 percent in spite oftherapy, and there is a high risk of death becauseof progression (as high as 30 percent as reportedin studies with long-term patient follow-up) (Herr,1997; Kiemeney, Witjes, Heijbroek, et al., 1993).Treatment recommendations may be substantiallydifferent for patients with Ta tumors than for pa-tients with T1 disease.
Basic characteristics of stages Ta, T1 and Tis
Stage Ta tumors are confined to the urothelium(above the basement membrane) and have a papil-lary configuration--described by Johansson andCohen (1996) as resembling "seaweed" protrudinginto the lumen of the bladder. Most Ta tumors arelow grade.
Stage T1 tumors have penetrated below thebasement membrane and infiltrated the laminapropria, but have not gone so far as the detrusormuscle. Most T1 tumors are papillary, but manyof those that have penetrated the deepest into thelamina propria are nodular (Heney, Nocks, Daly,et al., 1982).
Hasui, Osada, Kitada, et al. (1994) reportedsignificant increases in cancer recurrence and pro-gression when T1 tumors penetrated to the levelof the muscularis mucosa and beyond--a two-foldincrease in incidence of recurrence and an eight-fold increase in incidence of progression. Hasuiand colleagues, as well as other authors, have pro-posed subdividing the stage T1 classification intostages T1a and T1b, using the muscularis mucosaas the dividing line. Unfortunately, the muscu-laris mucosa makes an unreliable point of refer-ence, being discontinuous and often difficult toidentify; but there is growing evidence that tumorpenetration to this depth does have important im-plications, such as a higher risk of later detrusormuscle invasion (Epstein, Amin, Reuter, et al.,1998; Holmäng, Hedelin, Anderström, et al.,
1997). In addition, tumor infiltration of vascularor lymphatic spaces may portend a poor outcomeif unequivocally present, but it is often difficult todetermine with certainty.
In a stage by itself, CIS (stage Tis) has beendefined as high-grade (anaplastic) carcinoma,which, like stage Ta, is confined to the urotheli-um, but with a flat, disordered, nonpapillary con-figuration and a likelihood of being underdiag-nosed (Epstein, Amin, Reuter, et al., 1998). CIScan be focal, multifocal or diffuse. On cystoscop-ic examination, it usually appears as a slightlyraised, reddened patch of velvety mucosa—butoften it is endoscopically invisible. Much aboutthis peculiar cancer is poorly understood, includ-ing its natural history and the mechanism bywhich it spreads. The most ominous characteris-tic of CIS may be multicentricity (Koch andSmith, 1996). Even when the extent of spreadseems limited, additional areas frequently existnot only in other parts of the bladder, but in thedistal ureters, the urethra or the prostatic ducts.Prostatic urethral biopsy may yield additional in-formation in patients with diffuse CIS. If untreat-ed, CIS is likely to progress to muscle-invasivedisease in a substantial percentage of patients(Hudson and Herr, 1995).
Numerous classification systems for gradingtransitional cell carcinomas of the bladder havebeen developed and published over the past fewdecades. Although no single system has yetemerged to win universal acceptance, the mostwidely used systems all share important charac-teristics. In particular, they all tend to group blad-der carcinomas similarly into three principalgrades 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 respec-tively to well differentiated, moderately differenti-ated and poorly differentiated tumors. Grade hasbeen shown to be a highly predictive indicator offuture tumor behavior with regard to both recur-rence and progression.
In addition to grade, the most clinically usefulfactors for predicting recurrence and progressionin patients who present with non-muscle-invasivedisease are tumor stage, tumor size, number of tu-mors and the presence of CIS. Stage is particu-larly important. As reported previously (page 16),the likelihood of progression to muscle-invasivedisease is much greater for T1 tumors than for Tatumors (Herr, 1997; Holmäng, Hedelin,Anderström, et al., 1997; Kiemeney, Witjes,Heijbroek, et al., 1993; Prout, Barton, Griffin, etal., 1992). Moreover, the likelihood of muscle in-vasion appears to be greater still for T1 tumorsthat have penetrated beyond the muscularis mu-cosa (Epstein, Amin, Reuter, et al., 1998;Holmäng, Hedelin, Anderström, et al., 1997).
Other possible predictors of recurrence and/orprogression include DNA ploidy, blood groupantigens and various molecular markers. DNAploidy is measured by flow cytometry, often per-formed on tumor tissue embedded in paraffin.Diploid tumor cells tend to be low grade and lowstage, indicating a favorable prognosis, whereastetraploid and aneuploid tumors have a greaterlikelihood of progression and/or recurrence(Gustafson, Tribukait and Esposti, 1982a, 1982b).However, there is some question as to the inde-pendent prognostic value of ploidy over gradealone (Masters, Camplejohn, Parkinson, et al.,1989; Murphy, Chandler and Trafford, 1986;Tachibana, Deguchi, Baba, et al., 1991, 1993).
Loss of cell-surface blood group antigens,such as ABO antigens and the Lewis
xantigen, has
been associated with an unfavorable prognosis insome studies, but other studies have found no cor-relation with either recurrence or progression(Newman, Carlton and Johnson, 1980; Richie,Blute and Waisman, 1980; Yamada, Fukui,Kobayashi, et al., 1991).
Molecular markers, such as abnormal expres-sion of the tumor-suppressor genes p53 and pRb(see page 13), show considerable promise asprognostic indicators for bladder cancer, especial-ly for predicting aggressive tumor behavior(Cordon-Cardo, 1998; Cote, Dunn, Chatterjee, etal., 1998; Grossman, Liebert, Antelo, et al., 1998).Reliable methods for clinical use of such markersare still being developed.
In most cases of non-muscle-invasive bladdercancer, tumors are treated initially with TURBT,fulguration and/or laser therapy. A careful cysto-scopic examination of all bladder surfaces, theurethra and the prostate precedes resection (Kochand Smith, 1996). Findings with prognostic sig-nificance are noted during this examination.Noted, for example, is the position of tumors withreference to the bladder neck and ureteral orifices;tumor configuration, such as whether tumors arepapillary or sessile; and estimates of the numberof tumors and their sizes. Following resection ofall visible tumors, adjuvant intravesicalchemotherapy or intravesical immunotherapy iscommonly used to prevent recurrences (Messingand Catalona, 1998).
Resection and fulguration of bladder tumors
As stated on page 15, a TURBT has two mainpurposes: 1) complete eradication of all visible tu-mors; and 2) tissue resection for pathologic evalu-ation to determine grade and stage. Fulgurationmay be used on small lesions, but tissue still needsto be obtained to determine grade and stage attime of initial presentation.
Koch and Smith (1996), in describing surgicaltechnique, recommend use of a continuous flowresectoscope, which allows a relatively constantvolume in the bladder and thus minimizes move-ment of tumors away from and toward the resecto-scope. When a tumor is removed, a separate biop-sy can be taken at the base with the resecting loop.After which, healthy-appearing muscle fibersshould be visible at the base. Necrotic-appearingtissue implies an invasive carcinoma. The pres-ence of fat implies a full-thickness bladder walldefect.
Laser therapyThe Nd:YAG laser has so far proven to be the
most versatile wavelength for treating bladder can-cer, but other wavelengths also have been used(Koch and Smith, 1996; Smith, 1986). Results arecomparable to electrocautery resection, with littledifference in the recurrence rate (Beisland andSeland, 1986).
However, tissue samples need to be obtainedbeforehand by means of cold-cup biopsies to de-termine tumor grade. Assessing depth of tumorpenetration to determine stage is more problematicwith laser therapy. Appropriate patients for thistherapy have papillary, low-grade tumors and ahistory of low-grade, low-stage tumors (Koch andSmith, 1996).
Intravesical chemotherapy and immunotherapy
Intravesical chemotherapy or immunotherapyis most often used as adjuvant treatment to preventtumor recurrence following the transurethral resec-tion of primary non-muscle-invasive bladder tu-mors, including possible recurrence because of ia-trogenic implantation of tumor cells. Intravesicaltherapy is also used to treat known existing tumorsin cases of CIS, which frequently cannot be treat-ed adequately by resection or fulguration becauseof diffuse involvement. Intravesical therapy hasbecome the preferred primary treatment for CIS(Messing and Catalona, 1998). In addition, anagent intended for prophylaxis may in fact betreating undetected existing disease. Basic proper-ties of the chief intravesical agents currently avail-able are described later in this chapter. Chapter 3contains an evidence-based comparative outcomesanalysis of most of these agents.
Thiotepa
Introduced in 1961, thiotepa is the oldest andone of the least expensive of the intravesicaldrugs. It is an alkylating agent that acts by cross-linking nucleic acid. It is administered in dosesranging from 30 mg in 30 ml of sterile water orsaline to 60 mg in 60 ml of water or saline. Thelower dose appears to be as effective as the higherone in a comparative study, but the concentrationsin both were the same (Koontz, Prout, Smith, etal., 1981). The usual regimen consists of six toeight weekly instillations followed by monthly in-stillations for one year. Thiotepa's low molecularweight of 189 allows partial absorption throughthe urothelium, with possible systemic toxicity.There is a risk of myelosuppression especially atthe 60 mg dose level. White cell and plateletcounts are obtained before each instillation, andtreatment is delayed if necessary.
Mitomycin C is an antibiotic that works by in-hibiting DNA synthesis. Because of its moderate-ly high molecular weight of 329, there are fewproblems with transurothelial absorption, andmyelosuppression is rare. Dosage varies from 20mg to 60 mg per instillation; a commonly useddose is 40 mg in 40 ml of saline or sterile water,administered weekly for eight weeks followed bymonthly instillations for one year. Mitomycin Cis a very expensive agent. There is evidence thatmultiple follow-up instillations are only slightlymore beneficial than just a single instillation ad-ministered within 24 hours after TURBT (Tolley,Parmar, Grigor, et al., 1996).
Doxorubicin (adriamycin) and epirubicin
Doxorubicin is an anthracycline antibiotic ableto bind to DNA and inhibit synthesis. It is notcell cycle specific, but appears to be most cyto-toxic in the S phase. Its molecular weight of 580is high, and absorption and systemic toxicity areextremely rare. Doses vary widely, from 10 mgto 100 mg, in instillation schedules that rangefrom three times a week to once a month.Epirubicin, a derivative of doxorubicin, is an an-thracycline analog that appears to be somewhatbetter tolerated than doxorubicin (Kurth, Vijgh,Kate, et al., 1991). A study by the EuropeanOrganization for Research and Treatment ofCancer supports the possibility that epirubicinmay be most effective against cystoscopically in-visible tumors existing at the time of resection(Oosterlinck, Kurth, Schroder, et al., 1993). As of1999, epirubicin was not available in the UnitedStates, and the panel did not formally analyzeoutcomes data for this drug.
Bacillus Calmette-Guérin (BCG)
BCG, a live attenuated strain ofMycobacterium bovis, was first used as a tubercu-losis vaccine. Its now widespread use as intraves-ical immunotherapy for management of noninva-sive bladder cancer began in the 1970s, heraldedby the 1976 Morales study (Morales, Eidingerand Bruce, 1976). BCG has since become a first-line treatment for CIS and has been shown to beeffective as prophylaxis to prevent bladder cancerrecurrences following TURBT (Cookson andSarosdy, 1992; Coplen, Marcus, Myers, et al.,
1990; DeJager, Guinan, Lamm, et al., 1991; Herr,Schwalb, Zhang, et al., 1995; Lamm, Blumen-stein, Crawford, et al., 1995).
Several substrains of BCG have been used, in-cluding the Pasteur, Armand-Frappier, Tice,Evans, Tokyo, Dutch (RIVM) and Connaughtstrains. Although all of them are derived fromone original strain developed at the PasteurInstitute, the viability of BCG organisms per mil-ligram of vaccine may vary with different sub-strains and from lot to lot within the same sub-strain (Cummings, Hargreave, Webb, et al., 1989;Kelley, Ratliff, Catalona, et al., 1985; Messingand Catalona, 1998).
BCG's mechanism of action is not fully under-stood, but it clearly involves a strong inflammato-ry immunologic host response with release of in-terleukins and other cytokines (Morales, Eidingerand Bruce, 1976; Ratliff, Haaff and Catalona,1986). Most patients develop this inflammatoryimmunologic response during a typical course ofsix weekly instillations. Some patients do not re-quire that many instillations; other patients re-quire more than six (Brosman, 1992; Eure,Cundiff and Shellhammer, 1992; Haaff, Dresner,Ratliff, et al., 1986). Optimal dosing and instilla-tion schedules have not yet been established. Themost common side effects of BCG are cystitis andhematuria. The most serious is BCG sepsis.BCG therapy is contraindicated in patients whoare immunocompromised, who have liver diseaseor a history of tuberculosis. Also, there is agreater potential for sepsis if the drug is adminis-tered too soon after TURBT or traumatic catheter-ization.
Valrubicin and Interferon
Valrubicin and interferon are two newer agentsfor treating bladder cancer. Valrubicin, a semi-synthetic analog of doxorubicin, has receivedFDA approval for treatment of patients with CISwho have not responded to BCG therapy and inwhom immediate cystectomy would be associatedwith unacceptable morbidity or mortality. Thepanel did not formally review clinical studies us-ing valrubicin, but only about one of five patientswith BCG-refractory CIS was reported to havehad a complete response.
Interferons have antiproliferative, antiangio-genic and immunostimulatory properties; and re-combinant interferon alpha-2b has been effective
for treating CIS in some clinical trials (Glashan,1990). Interferon side effects tend to be minimal.However, as prophylaxis for noninvasive bladdercancer, interferons may not be as effective asBCG (Kalble, Beer and Staehler, 1994). Moreclinical studies are needed before this is deter-mined. Because not enough studies have beenpublished as yet, the panel did not have sufficientoutcomes evidence available to include interferonin the analysis described in Chapter 3.
Two key questions regarding follow-up aftertreatment for noninvasive bladder cancer are: 1)how long should follow-up be continued and 2)at what intensity? The classic follow-up protocolconsists of cystoscopic and cytologic examina-tions every three months for 18 to 24 months af-ter the initial tumor, then every six months for thefollowing two years and then annually(Fitzpatrick, 1993; Messing and Catalona, 1998).
The results of the first three-month cystoscopyoften predict the future recurrence pattern
(Fitzpatrick, West, Butler, et al., 1986). Less in-tense surveillance may be indicated if patientshad Ta papillary low-grade tumors that werecompletely resected and if the results of the firstthree-month cystoscopic examination were nega-tive (Abel, 1993; Gulliford, Burney andPetruckitch, 1993).
Bladder cancer, however, may recur even afterlong, disease-free intervals, indicating a need forlifelong surveillance (Cookson, Herr, Zhang, etal., 1997; Messing and Catalona, 1998;Thompson, Campbell, Kramer, et al., 1993).Surveillance includes periodic upper-tract imag-ing, especially if the treated cancer was CIS, oth-er high-grade tumors or tumors located near aureteral orifice (Cookson, Herr, Zhang, et al.,1997; Miller, Eure and Schellhammer, 1993).
The new urine assay tests described on page15, such as BTA stat
TM, BTA TRAK
TMand NMP-
22, may ultimately prove sensitive enough to re-place a portion of the routine follow-up cysto-scopic examinations.
The AUA Bladder Cancer Clinical GuidelinesPanel analyzed available outcomes data for boththe potential benefits and the potential complica-tions of alternative approaches to treating non-muscle-invasive bladder cancer. Results of thepanel's analysis are summarized as probabilityestimates in the comparative outcomes tables onpages 23-24 of this chapter. The data extractionand evidence combination processes that pro-duced the probability estimates are described on pages 10-11 of Chapter 1. The raw data arein a technical supplement to this report,Evidence Working Papers,which is availablefrom the AUA.
Types of outcomes include direct outcomesthat are experienced by the patient firsthand andthat affect the patient directly. Some, such as dy-suria or an increase in urinary frequency, may beshort-term side effects of treatment. Others, suchas urinary frequency due to bladder contractionfrom scarring, may occur on a continuing basislong after treatment has been completed. Directoutcomes are often of great importance to the pa-tient simply because they impact them. By con-trast, asymptomatic tumor recurrence, although anextremely important outcome, may not necessari-ly seem important to the patient because it is notexperienced directly. From the patient's stand-point, however, it is important as a proxy for fu-ture adverse events such as the likelihood of re-peated treatment and possibly more aggressivetreatments such as radical cystectomy.
The outcomes tables (Tables 2-5) on pages 23-24 summarize results following ConfidenceProfile (FAST*PROTM) meta-analyses of combinedoutcomes data from the bladder cancer treatmentliterature, as described in Chapter 1. Results aredisplayed in the tables as probability estimates.In most cases, a 95-percent confidence interval isreported along with a median estimate of the
probability. It should be noted that "median" inthese tables is the median of the probability distri-bution resulting from FAST*PRO® meta-analysis(Eddy, Hasselblad and Shachter, 1990); it is notthe median of an array of individual study results.The G/P columns in Table 5 show (G) the numberof patient groups for a given outcome and (P) thetotal number of patients in those groups. A cellmarked "No Data" indicates insufficient ex-tractable data for a given outcome.
For assessing potential benefits and possibleadverse effects of interventions for treatment ofnon-muscle-invasive bladder cancer, the panel de-termined that the following outcomes are the mostimportant:• Probability of tumor recurrence;
• Risk for tumor progression; and
• Complications of treatment.
RecurrenceNon-muscle-invasive bladder cancer has a high
rate of new tumor formation within the bladder.New tumor formations following treatment aregenerally termed "recurrences" (although in manycases they might be more accurately termed "re-occurrences"). Recurrent tumors may have pro-gressed to a higher grade and/or higher stage, butmost recurrences of non-muscle-invasive bladdercancer (especially of initially diagnosed grade 1,stage Ta disease) are not muscle invasive and car-ry relatively little risk of metastasis or death.However, recurrent disease will likely require arepetition of therapy.
For the patient and physician assessing treat-ment alternatives, the probability of recurrencefollowing treatment is obviously an important out-come to consider. The first two outcomes tables,Tables 2 and 3 on page 23, display comparativedifferences in the estimated probability of recur-rence following use of intravesical agents as adju-vant therapy after transurethral resection of blad-der tumor (TURBT). The comparative differences
Chapter 3: Outcomes analysis for treatments of non-muscle-invasive bladder cancer
in Table 2 are statistically significant; those inTable 3 are not.
Each intravesical agent in the tables is com-pared to TURBT alone and to each of the otheragents, based on data from multi-armed random-ized controlled trials (RCTs). All of the agents,when used as adjuvant therapy after TURBT, areshown to result in a lower estimated probability ofrecurrence compared to use of TURBT alone.Some of the differences in Table 2 are quite large.An example is the use of TURBT plus BCG ver-sus the use of TURBT alone. With a median dif-ference of 30 percent (95% CI 19-39 percent), thetable shows a significantly lower estimated proba-bility of recurrence in favor of TURBT plus BCG.(All median differences in Tables 2-4 are in favorof the first intervention listed in each pair.)
The last column of Table 2 displays anotherway of showing the results. "Number needed totreat" (NNT) is the number of patients who mustbe treated with the superior treatment of each pairin order to reduce by one the estimated number ofpatients with recurrences. For example, in"TURBT plus doxorubicin versus TURBT alone,"the NNT is 10. Thus, if 10 patients are treatedwith the superior treatment of this pair, TURBTplus doxorubicin, and another 10 patients withTURBT alone, one less recurrence can be expect-ed in the patient group receiving TURBT plusdoxorubicin.
The recurrence tables are further discussed onpages 25-26 of this chapter. The basic methodol-ogy is described on page 11 of Chapter 1.
ProgressionThe risk for progression of non-muscle-
invasive bladder cancer, depends on a number offactors, including size and number of tumorsand, especially, their grade and stage. Low-grade, stage Ta tumors, although they have a tendency to recur, have a low risk for progres-sion to muscle invasion, whereas progressionrates of 30-50 percent have been reported forhigh-grade, stage T1 disease (Herr, 1997).
Most of the available studies reporting resultsof treatment do not adequately address the risk forlong-term progression, notwithstanding the impor-tance of this outcome. Consequently, the resultsdisplayed in Table 4 (page 23) are based on fewerRCTs than were available for calculating the re-sults shown in Table 2-3 (page 23).
Complications of treatment
After review and evaluation of all possible ad-verse outcomes from treatment for non-muscle-in-vasive bladder cancer, the panel grouped theseoutcomes into three general categories: 1) Localbladder symptoms; 2) Systemic symptoms; and 3)Other. Their estimated probabilities for occur-rence with particular treatments are displayed inTable 5 on page 24.
Local bladder symptoms are the most commonadverse outcomes experienced by patients under-going treatment for non-muscle-invasive bladdercancer. The most frequently observed immediatesymptoms are irritative lower urinary tract prob-lems including dysuria, frequency/nocturia, ur-gency, pain and cramping and passing of debris inthe urine, including blood or clots. Patients mayalso experience bacterial cystitis, urinary inconti-nence or bladder perforation. Long-term adverseoutcomes related to local bladder symptoms in-clude bladder contracture.
Although local bladder symptoms can be se-vere, systemic symptoms are more threatening.These include flu-like symptoms such as arthral-gia, fever, chills and malaise. Systemic infectiouscomplications may also result from treatment.Among these problems are pulmonary or hepaticchanges, pneumonia, pneumonitis, hepatitis, epi-didymitis, prostatitis and urethral infection. Also,patients might experience nausea, vomiting, rashor indirect adverse outcomes such as myelosup-pression.
Some patients might experience adverse out-comes severe enough that the intervention must beinterrupted or even stopped entirely. In rare cir-cumstances, deaths have been reported with inter-ventions used for non-muscle-invasive bladdercancer, although the frequency of death is notgenerally recorded.
Cost, inconvenience and quality-of-life issues
Cost, inconvenience and quality-of-life issuesare certainly important to patients. Few meaning-ful data are readily available from the literature toaddress these issues for non-muscle-invasive blad-der cancer, and for the most part, these are areasin need of future research. Nevertheless, in regardto cost, panel members knew from their own ex-periences that there are major differences between
intravesical agents, usually with mitomycin C be-ing by far the most expensive. Table 6 showscomparative 1999 patient charges from a universi-ty-based hospital setting of one of the panel mem-bers. Generalization is not possible, however, ascosts of intravesical agents may vary substantiallyboth regionally and from institution to institution.
There are many retrospective studies reportingoutcomes of interventions for non-muscle-invasivebladder cancer. However, RCTs are the most use-ful for analysis, eliminating many of the problemsencountered with uncontrolled or poorly con-trolled studies. Accordingly, the panel decided toextract data only from RCTs for comparison oftreatments with regard to lowering the probabilityof recurrence and progression.
Yet, even with the advantage of having RCTsavailable for analysis, the panel found the evalua-tion process complicated for the following rea-sons:1. The patients in the different studies varied by
stage, grade, prior treatments and tumor histo-ry, presence or absence of CIS and length oftime with bladder cancer. The patient mixwas generally undifferentiated, and the studiesdid not break down outcomes relative to pa-tient characteristics.
2. The treatment protocols differed in the numberand timing of medication instillations, dosesand frequency. However, even where differentdosing regimens were compared within or be-tween studies, no significant outcome differ-ences were noted for different treatment regi-mens (see Table C-1 in Appendix C).
3. The outcomes measured were reported in vari-ous ways. Recurrence rates were reportedvariably as number of patients with recur-rences, number of recurrences, number of oc-currences per unit of time or time of first re-currence. For progression, some studies re-ported patients with different types ofprogression without indicating whether therewas overlap among these patients.
4. The follow-up times varied significantly, bothwithin and between studies.
5. In some studies, patients unsuccessful withone treatment were crossed over to take othertreatments.Despite these limitations, the panel found the
analysis useful. One important conclusion thepanel drew from the data evaluation was thattreatment-related reductions in the probability ofrecurrence were detected within the first year ofobservation in most studies. Furthermore, the ob-served reductions were carried forward into sub-sequent years; that is, differences observed withinthe first year remained stable over time.
Thiotepa after TURBT was compared withTURBT alone in 10 RCTs. Meta-analysis ofthese studies demonstrated that thiotepa afterTURBT lowers the probability of recurrence morethan TURBT alone (Table 2, page 23). The medi-an estimate of the difference is approximately 19percent (95% CI 9-28 percent). However, com-parative evaluation of these two treatments withregard to progression (Table 4, page 23) showedno difference between them.
The administration of BCG after TURBT wascompared with TURBT alone in six studies. Asnoted previously (page 22), the meta-analysisyielded a 30 percent reduction in the probabilityof recurrence using the BCG intervention (95%CI 19-39 percent). For progression (Table 4, page23), the two treatments were compared in threestudies, yielding an estimated difference of 8 per-cent in favor of BCG (95% CI -0.2-15 percent).However, with the confidence interval overlappingzero, this difference is not statistically significant.
Outcomes summary:recurrence and progression
Variability of outcomes data
Table 6:Sample costs of intravesical agents
Intravesical Patient Agent Charge
Mitomycin C (2 mg vial) $385.20Thiotepa (15 mg vial) 253.55BCG (1 ampule) 137.75Doxorubicin (2 mg/ml; 25 ml vial=50 mg) 83.75
Mitomycin C administration after TURBTyielded a reduction in recurrence probability ofapproximately 15 percent (95% CI 7-22 percent)over TURBT alone. For preventing progression,there was no benefit to mitomycin C administra-tion after TURBT versus TURBT alone.
The administration of doxorubicin afterTURBT yielded a reduction of 10 percent in prob-ability of recurrence (95% CI 2-17 percent) overTURBT alone. There was no evident reduction inprobability of progression using doxorubicin afterTURBT versus TURBT alone.
Three studies compared the administration ofBCG versus thiotepa, each after TURBT. Thesestudies showed a clear benefit to BCG overthiotepa with a median difference in recurrenceprobability of 30 percent (95% CI 10-47 percent).
Doxorubicin was also compared with BCG,each after TURBT, in four studies. The advantagewent to BCG over doxorubicin in reduction of re-currence probability, with a median difference of23 percent (95% CI 13-32 percent).
Other intervention comparisons (Table 3, page23) of mitomycin C versus thiotepa, doxorubicinversus thiotepa, mitomycin C versus BCG andmitomycin C versus doxorubicin yielded no statis-tically significant advantage for one treatmentover another in reducing the probability of recur-rence.
A comparative assessment of the probability ofprogression reduction with the various treatmentmodalities showed no evident differences amongthem in the RCTs (Table 4, page 23).
The probability estimates for complicationsfrom each of the interventions are displayed inTable 5 on page 24. The table shows median esti-mates of the probability of the complications oc-curring, along with 95-percent confidence inter-vals. The complications data were obtained fromthe randomized controlled trials as well as fromthe non-randomized trials. The panel decidedthat, for complications, the data reported in allstudies were of value in assessing frequency ofcomplications for a given intervention, regardlessof whether the patients were involved in RCTs.
A major difficulty in listing complicationsstems from the familiar problem of how data are
summarized in the literature. Some studies classi-fy complications such as frequency and nocturiaseparately, whereas other studies combine themunder single headings. Likewise, cutoff points forsignificant fever vary from study to study, andsome studies do not include a definition of fever.Thus, the data analysis required some judgment,and the combinations of data required some arbi-trary assignments by the data extractors and thepanel. The panel specifically addressed outliersand made decisions whether to accept the data atface value or to exclude these data in situationswhere they could not be accurately or usefullycategorized.
Some specific complications are not includedin all studies. This might have been because theynever occurred or because they were never trackedor recorded, depending upon the protocol struc-ture. Such arbitrary deletions in the studies canaffect the overall analysis of the complications.However, there is no way to account for these dif-ferences in reporting. It is important to recognizethat some complications do not apply to each ofthe treatment modalities, and that each interven-tion has its own unique spectrum of complicationsas well as complications in common with otherinterventions. For example, almost all of the in-terventions induce some problem with local blad-der symptoms, but only BCG is likely to induceevidence of systemic infection.
The panel decided to delete certain complica-tions entirely from the analysis. Among thesewere granulomas, bladder mucosal erythema andhypotension. Such complications were deletedbecause they had no clinical significance to thepatient in the short or long term, or were so un-usual that they would not affect treatment deci-sions by patients or recommendations by thephysician. The complication of urethral stricturewas deleted from the complications listing be-cause it was reported in so few patients.
Other complications were combined to easeinterpretation. An example of this is epididymitisbeing included together with prostatitis and ure-thral infections.
Certain review articles were of value for pro-viding data about complications. However, sucharticles were examined carefully to ensure thatthere was no duplication of data from other stud-ies in the review that would overweight certaincomplications.
Death associated with any of the interventionsfor non-muscle-invasive bladder cancer is ex-tremely unusual. There are certainly risks associ-ated with the anesthesia and surgical procedurefor TURBT. Overall, however, in the panel's ex-pert opinion, the risk of death would be much lessthan 1 percent for each of the interventions. Thepanel believes that such a low rate is not likely tobe a significant factor in the selection of therapyby a patient or in its recommendation by a physi-cian.
Local bladder effects occur with the greatestfrequency and are direct outcomes felt by pa-tients. Thus, they are the adverse outcomes most
likely to govern a patient's decision to select oneintervention over another. Systemic complica-tions affect a minority of patients, yet can be quiteprofound with BCG therapy. The risk of BCGsepsis may be a factor that influences patient pref-erences or physician recommendations.
In general, the balance between likely benefi-cial outcomes (such as reduced recurrence rates)and likely adverse outcomes (such as local com-plications) will dictate which intervention a pa-tient will select for treatment of non-muscle-inva-sive bladder cancer.
The AUA Bladder Cancer Clinical GuidelinesPanel generated the recommendations in thischapter based upon analysis of comparative out-comes data from both randomized controlled tri-als (RCTs) and clinical series and upon expertopinion. The recommendations apply to treat-ment of patients with non-muscle-invasive, transi-tional cell carcinoma of the bladder, includingCIS (CIS) as well as stages Ta and T1 tumors.The panel evaluated comparative data for the fol-lowing treatment methods in particular:• Transurethral resection of bladder tumor
(TURBT);
• TURBT plus thiotepa;
• TURBT plus doxorubicin;
• TURBT plus mitomycin C;
• TURBT plus bacillus Calmette-Guérin (BCG).
As explained in Chapter 1 (page 9), panel rec-ommendations were graded according to threelevels of flexibility as determined by strength ofevidence and the expected amount of variation inpatient preferences. The definitions of these threelevels of flexibility are repeated as follows fromChapter 1:1. Standard: A treatment policy is considered a
standard if the health and economic outcomesof the alternative interventions are sufficientlywell-known to permit meaningful decisionsand there is virtual unanimity about which in-tervention is preferred.
2. Guideline: A policy is considered a guidelineif 1) the health and economic outcomes of theinterventions are sufficiently well-known topermit meaningful decisions and 2) an appre-ciable but not unanimous majority agree onwhich intervention is preferred.
3. Option: A policy is considered an option if 1)the health and economic outcomes of the in-terventions are not sufficiently well-known topermit meaningful decisions, 2) preferencesamong the outcomes are not known, 3) pa-tients' preferences are divided among the alter-native interventions and/or 4) patients are in-different about the alternative interventions.A standard has the least flexibility. A guide-
line has significantly more flexibility, and optionsare the most flexible. In this report, the terms areused to indicate the strength of the recommenda-tions. A recommendation was labeled a standard,for example, if the panel concluded that it shouldbe followed by virtually all health care providersfor virtually all patients. A guideline generallydenotes a recommendation supported by objectivedata but not with sufficient strength to warrant adesignation of standard. An option in this reportwould include treatments for which there appearsto be equal support in the literature or ones forwhich there is insufficient published informationto support a stronger recommendation. Also, asnoted in the above definition, options can exist be-cause of insufficient evidence or because patientpreferences are divided. In the latter case particu-larly, the panel considered it important to take in-to account likely preferences of individual pa-tients with regard to health outcomes when select-ing from among alternative interventions.
The specific types of patients to whom thepanel's recommendations apply are termed indexpatients. In recognition of the differences in deci-sion making that occur depending upon patientcircumstances, the panel defined three differentindex patients:
Index Patient No. 1: A patient who presentswith an abnormal growth on the urothelium, butwho has not yet been diagnosed with bladder cancer;
Index Patient No. 2: A patient with estab-lished bladder cancer of any grade, stage Ta or
Chapter 4: Recommendations for management of non-muscle-invasive bladder cancer
T1, with or without CIS, who has not had priorintravesical therapy; and
Index Patient No. 3: A patient with CIS orhigh-grade T1 cancer who has had at least onecourse of intravesical therapy.
Recommendation for all index patients
This recommendation is based on the panel'sexpert opinion. Although all of the adjuvant treat-ments studied decrease the recurrence probabilityof bladder cancer when they are compared toTURBT alone, the published literature does notunequivocally support the conclusion that the rateof progression to muscle-invasive disease is al-tered. Patients contemplating intravesical therapyshould consider information about all expectedoutcomes, including the possible side effects oftherapy. All of the treatments have in commonsome side effects, especially those related to blad-der irritation; other side effects are either uniqueor peculiar to a particular drug. The incidence ofserious or life-threatening side effects with any ofthe treatments is low, as shown in Table 5 (page24); the panel is aware of reports documentingsystemic infection or even death from BCG sepsisin rare circumstances.
In addition, there is little information definingthe optimal dose, number and timing of instilla-tions or the influence of long-term maintenancetherapy. Randomized studies supporting the useof maintenance BCG therapy have been conduct-ed, but the panel excluded them because their re-sults have been reported only in abstract form.Other trials would appear to support a role formaintenance therapy.
Recommendationfor Index Patient No. 1
A patient who presents with an abnormalgrowth on the urothelium, but who has not yetbeen diagnosed with bladder cancer.
.
Although urine cytology and other novel tu-mor markers, as discussed in Chapter 2 (page 15),can provide suggestive evidence of bladder can-cer, the definitive diagnosis is established bypathologic examination of tissue removed byTURBT or biopsy. Transitional cell carcinoma ofthe bladder often has a characteristic appearance,but other conditions can mimic the gross appear-ance of bladder cancer. It is important, therefore,to prove by microscopic analysis that gross abnor-malities are from transitional cell carcinoma.Intravesical immunotherapy or chemotherapyshould not be used in the absence of a histologicdiagnosis.
Recommendations for Index Patient No. 2
A patient with established bladder cancer ofany grade, stage Ta or T1, with or without CIS,who has not had prior intravesical therapy.
In a patient with known bladder cancer, endo-scopic ablation of all visible tumors should beperformed. This can be accomplished with elec-trocautery resection, fulguration or application oflaser energy. Sometimes, the extent of disease orthe location of the lesions may preclude completeeradication. Also, co-morbid conditions must beconsidered and may occasionally influence a deci-sion about whether to attempt endoscopic removalof bladder tumors. This recommendation is basedon the panel's expert opinion.
Treatment recommendations
Standard: Physicians should discuss with the pa-tient the treatment options and the benefits andharms, including side effects, of intravesical treat-ment, especially those side effects associated witha particular agent.
Standard: If the patient does not have an estab-lished histologic diagnosis, a biopsy should be ob-tained for pathologic analysis
Standard: Complete eradication of all visible tu-mors should be performed if surgically feasibleand if the patient's medical condition permits.
For bladder cancers that do not invade the de-trusor muscle, several methods for tumor destruc-tion provide apparently comparable results.Adequate tissue should be available for determi-nation of pathologic stage, but endoscopic abla-tive techniques may not permit submission of allmaterial for histologic evaluation. This recom-mendation is based on the panel's expert opinion.
A recommendation stronger than an option forthis group of patients (Index Patient No. 2) cannotbe supported by the evidence in the outcomes ta-bles. Most studies combined patients who hadlow-grade stage Ta tumors with patients who hadT1 lesions and higher-grade cancers, creating dif-ficulty in extracting information about this sub-group. However, based upon panel opinion, manypatients with low-grade Ta tumors do not requireadjuvant intravesical therapy. There is a low riskof disease progression (overall less than 10 per-cent) in this group and little evidence that adju-vant therapy affects the progression rate. Forrapidly recurring low-grade Ta tumors, adjuvanttherapy may be useful. The outcomes tables showa decreased recurrence probability for all the in-travesical therapies studied, compared to TURBTalone.
Based on evidence from the literature and pan-el opinion, both BCG and mitomycin C are supe-rior to doxorubicin or thiotepa for reducing recur-rence of these tumors. There is no evidence thatany intravesical therapy affects the ultimate rateof progression to muscle-invasive disease.
Because there is risk of progression to muscle-invasive disease even after intravesical therapy,cystectomy may be considered as an initial treat-ment option in certain cases. Among factors asso-ciated with increased risk of progression are largetumor size, high grade, tumor location in a sitepoorly accessible to complete resection, diffusedisease, infiltration of lymphatic or vascularspaces and prostatic urethral involvement. Thisrecommendation is based on the panel's expertopinion.
Recommendations for Index Patient No. 3
A patient with CIS or high-grade T1 cancerwho has had at least one course of intravesicaltherapy.
This recommendation is based upon panelopinion rather than evidence in the outcomes ta-bles. However, other data in the literature doshow a substantial risk of progression to muscle-invasive cancer in patients with diffuse CIS andhigh-grade T1 tumors (Herr, 1997; Hudson andHerr, 1995; Kiemeney, Witjes, Heijbroek, et al.,1993). It is not certain whether intravesical thera-py alters this risk of progression. Thus, there aresome patients with symptomatic disease or high-grade tumors who may want to move directly tocystectomy. Physicians should present specificinformation about the risks of cystectomy andmethods for urinary reconstruction to patientswho are contemplating bladder removal.
Option: Surgical eradication can be performed byone of several methods including electrocautery re-section, fulguration or laser ablation.
Option: Adjuvant intravesical chemotherapy orimmunotherapy is an option for treatment after en-doscopic removal of low-grade Ta bladder cancers.
Guideline: Intravesical instillation of either BCGor mitomycin C is recommended for treatment ofCIS and for treatment after endoscopic removal ofT1 tumors and high-grade Ta tumors.
Option: Cystectomy may be considered for initialtherapy in some patients with CIS or T1 tumors.
Option: Further intravesical therapy may be con-sidered as an option for patients with CIS or high-grade T1 cancers that have persisted or recurred af-ter an initial intravesical treatment.
Option: Cystectomy may be considered as an op-tion for patients with CIS or high-grade T1 cancersthat have persisted or recurred after an initial in-travesical treatment.
This recommendation is also based on the pan-el's expert opinion. Optimal dosing schemes forintravesical chemotherapy and immunotherapyhave not been established, but weekly instillationsfor at least six weeks are used most often. Thereis additional evidence showing that some patientswill respond to second induction regimens, partic-ularly with BCG. Repeat intravesical therapymay be appropriate in patients who develop a laterecurrence after previous complete response to anintravesical agent. Data are insufficient, however,to allow conclusions about the role of drug com-bination regimens or alternating therapies. Also,as of this writing, there are preliminary data aboutuse of valrubicin for this patient. The panel didnot formally review clinical studies for valrubicin.
Large, often multicenter RCTs have helped de-fine the roles of TURBT and intravesical therapyfor the treatment of bladder cancer. Much addi-tional work is needed, however. Many studieshave focused primarily on recurrence, whereasprogression may be an outcome of more signifi-cance to the patient. Many of the treatmentschemes, including those for dose and frequency,have been chosen arbitrarily. Studies have fre-quently combined patients who have substantiallydifferent tumor parameters, which limits the abili-ty to analyze selected patient groups.
Many patients with CIS or stage Ta/T1 bladdercancer never develop disease progression or mus-cle-invasive cancer. Better methods are needed,however, to identify those more likely to developdisease progression.
The prognostic significance of tumor grade iswell recognized, as there is a clear increase in riskof progression with higher-grade tumors. DNAploidy status, determined by flow cystometry, hasnot provided useful information independent oftumor grade in most studies. Factors that predict
recurrence (such as tumor size, number or a historyof frequent recurrences) may not necessarily pre-dict progression.
Tumor stage at the time of presentation is animportant factor. Only a small percentage of pa-tients with Ta tumors show progression. A T1 le-sion, especially when high grade or with associat-ed CIS, places the patient at much greater risk.Recent efforts to substratify stage T1 cancer basedupon depth of infiltration must be further clarified.
The risk and significance of urothelial carcino-ma outside the bladder must be further deter-mined. Especially in patients with CIS, urothelialcancers within the ureter or intrarenal collectingsystem may occur at a frequency far exceedingthe previously accepted predictions of occurrence(about 5 percent of patients). Periodic monitoringof the upper urinary tract is necessary, and studiesare needed to better determine the efficacy of ad-ministration of chemotherapy or immunotherapyto the upper urinary tract. Prostatic urethral in-volvement may occur, especially in patients withCIS, even in the absence of identifiable diseasewithin the bladder.
Advances in molecular biology and geneticshave identified a number of markers that may beuseful for both detection and prognosis of bladdercancer. These may allow identification of patientsat high risk for recurrence or progression andcould alter time-honored regimens for follow-upof patients with bladder cancer. Historically, cys-toscopic bladder surveillance has been performedevery three months for at least a year and with de-clining frequency after that point in patients withstage Ta or T1 bladder cancer. Prognostic mark-ers may in the future allow follow-up surveillanceto be customized to individual patient risk.
The role of treatment regimens using alternat-ing or combined drugs must be determined. Earlyinstillation of drugs, sometimes immediately afterTURBT, may improve results, but randomizedstudies are needed to explore this possibility.Also, as new drugs or treatment strategies emerge,adequate studies to determine their role must beperformed.
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BCG (Glaxo) 60 mg forsix weeks followed byintradermal, vs. BCG(Pasteur) 120 mg for thesame schedule
11 patients, Glaxo
10 patients, Pasteur
followed 18 months
9 recurrences, Glaxo
10 recurrences, Pasteur
BCG (Pasteur) 120mgfor 6 weeks, vs. sameplus maintenance instil-lation every 3 months
21 patients, each group(note that 19 others ineach group were lost tofollow-up or excludeddue to early recurrence)Mean follow-up 16 mo.
Recurrence:
6 in non-maintenance group
5 in maintenance group
47 patients, maintenance
46 patients, non-mainte-nance, followed a meanof 22 months
No difference in tumor re-duction, p=.77, no differ-ence in disease free interval,p=.8, no difference in pro-gression, p=.5
90 patients, low dose
93 patients, high dose
Higher disease free intervalin low dose group(p=.0009)-primarily in CISpatients. Progression ratesthe 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 treatedwith BCG. The two groups differed in respective studies with regard to dosages administered, route of administra-tion (with and without intradermal boosters), schedules and types of BCG strains yet outcomes did not differ signif-icantly. Results are summarized for each study in the fourth column on the right.
Lamm et al., 1981Pagano et al., 1991Sarosdy and Lamm, 1989Krege et al., 1996Lamm, 1985Melekos et al., 1993
BCG vs TURBT BCG vs. Thiotepa Mitomycin C vs. BCG Mitomycin C vs. BCG CIS
Brosman, 1982Rodrigues and Lemos, 1983Martinez-Pineiro et al., 1990
Debruyne et al., 1988Krege et al., 1996 Lundholm et al., 1996 Vegt et al., 1995 Debruyne et al., 1989 Lamm et al., 1995
Lamm et al., 1995Vegt et al., 1995 Rintala et al., 1989Lundholm et al., 1996
BCG vs Doxorubicin Thiotepa vs. TURBT Thiotepa vs. Mitomycin C Thiotepa vs. Doxorubicin
Martinez-Pineiro et al., 1990 Lamm et al., 1991Lamm et al., 1989
Schulman et al. 1982 Koontz et al., 1981Byar and Blackard, 1977Hirao et al., 1987 Netto et al., 1983Anonymous, 1985 Prout et al., 1983Hirao et al., 1992Zincke et al., 1983Asahi et al.,1980
Hirao et al., 1987Huland and Otto, 1983 Kim and Lee, 1989Nujima et al., 1983Krege et al., 1996Tolley et al.,1996Akaza et al., 1987
Hirao et al., 1987Flanigan et al., 1986
Horn et al., 1981 Hirao et al., 1987 Martinez-Pineiro et al., 1990Bouffioux et al., 1992Zincke et al., 1983
Mitomycin C vs. TURBT Mitomycin C vs. Doxorubicin Doxorubicin vs. TURBT
Hirao et al., 1987Akaza et al., 1987Silberberg and Zarrabi, 1987
Hirao et al., 1987Nujima et al., 1983Kurth et al., 1984Akaza et al., 1987Rubben et al., 1988Kurth et al., 1997
Progression
Pagano et al., 1991Melekos et al., 1993Krege et al., 1996
BCG vs. TURB BCG vs. Thiotepa Mitomycin C vs. BCG Thiotepa vs. TURBT
Brosman, 1982Martinez-Pineiro, et al.,1990
Lundholm et al., 1996 Vegt et al., 1995 Lamm et al., 1995
Byar and Blackard, 1977Hirao et al., 1987 Anonymous, 1985Prout 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, 1989Akaza et al., 1992
Akaza et al., 1992 Hirao et al., 1987 Akaza et al., 1992Kurth et al., 1997
Tables C-2 and C-3: Articles Analyzed for Recurrence and Progression Data
AABO antigen, as prognostic indicator, 17Adenocarcinoma, 14Adriamycin. See DoxorubicinArthralgia, as complication of treatment, 22
B Bacillus Calmette-Guérin (BCG), as intravesical therapy
and CIS tumors, 5, 7, 19, 30and recurrence following intravesical therapy, 3, 7, 8,
19, 22, 25-26, 29, 30, 31and Ta tumors, 5, 7, 30and T1 tumors, 5, 7, 30compared to other intravesical therapies, 7, 20, 26, 30complications from, 3, 6, 19, 26, 27, 29cost of, 25 description of, 3, 19dosage of, 8, 19, 31outcomes of, 3, 7, 9, 12, 22, 23-24, 25recommendations for use as treatment, 5, 7, 8, 28,
29, 30, 31Bacterial cystitis, as complication of treatment, 22BCG sepsis, 3, 6, 19, 27, 29BCG. See Bacillus Calmette-GuérinBiopsy of bladder cancer tumors, 2, 4, 6, 14, 29Bladder contracture, as complication of treatment, 22
Bladder irritabilityas complication of bladder cancer, 6, 29as symptom of bladder cancer, 1, 14
Bladder perforation, as complication of treatment, 22Blood group antigens, as prognostic indicators, 17Blood in urine, as complication of treatment, 22BTA stat
TMtest, 15, 20
BTA TRAKTM
test, 15, 20
CCarcinoma in situ. See CIS tumorsChemotherapy. See Intravesical therapyCigarette smoke, in etiology of bladder cancer, 13CIS tumors
and treatment with BCG, 7, 19, 30and treatment with mitomycin C, 7, 30definition and description of, 1, 2, 13, 17outcomes of treatment on, 3, 7, 11, 25recommendations for treatment of, 3, 4, 5, 7, 28, 29,
30, 31symptoms of, 14
Complications, 1, 3, 6, 11, 12, 26-27. See also specific complications
Cost of treatment. See specific treatment methodsCylophosphamide, in etiology of bladder cancer, 13Cystectomy, 5, 7, 19, 20, 21, 30Cystitis, as complication of treatment with BCG, 3, 19Cystoscopy
as diagnostic tool, 1, 2, 14and recurrence of tumors, 20, 31
Cytokeratin, 15Cytologic assessment
and tumor grade, 15as diagnostic tool, 1, 14, 15, 29and recurrence of tumors, 15, 20
FFever, as complication of treatment, 22, 26Flow cystometry, 17, 31Frequency of urination
as complication of treatment, 21, 22, 26as symptom of bladder cancer, 1, 14
Fulguration, 2, 3, 4, 6, 18, 29, 30
HHematuria
as complication of treatment with BCG, 3, 19as symptom of bladder cancer, 1, 14
Hepatitis, as complication of treatment, 22
IImmunostaining techniques, 15Immunotherapy. See Intravesical therapyIndex patient
definition of and criteria for, 3, 28-29recommendations for, 4-8, 29-31
Industrial chemicals, in etiology of bladder cancer, 13Interferon, 19-20Intravesical drugs. See specific drugsIntravesical therapy. See also specific intravesical
compared to other intravesical therapies, 7, 26, 30
cost of treatment, 3, 19, 25description of, 3, 19outcomes of treatment, 3, 7, 9, 23-24, 26recommendations for use as treatment, 5, 7, 19, 28, 30
Myelosuppression, as complication of treatment, 3, 18,19, 22
NNausea, as complication of treatment, 22Nd:YAG laser, 2, 5, 18NMP-22, 15, 20Nocturia, as complication of treatment, 22, 26Nuclear matrix protein test. See NMP-22
OOutcomes. See outcomes under specific treatment
methods
Pp53 and pRb tumor-suppressor genes, as cause of
bladder cancer, 13, 17Pain, as complication of treatment, 22Patient
appropriate for laser therapy, 2informing about intravesical treatment, 4, 6, 29spinal-cord injured patients, 14Phenacetin-related analgesic abuse, as cause of blad-
der cancer, 13Pneumonia or pneumonitis, as complication of treat-
ment, 22Progression of tumorsand cystectomy, 7and intravesical therapy, 7, 12, 25, 26, 29, 30, 31and prognostic indicators, 17, 31and tumor grade, 2, 7, 16, 17, 22, 31and TURBT followed by intravesical therapy, 6, 7,
Prostatic urethral involvement, 17, 31Prostatitis, as complication of treatment, 22, 26Proto-oncogenes, in etiology of bladder cancer, 13Pulmonary changes, as complication of treatment, 22
RRadiotherapy, in etiology of bladder cancer, 13Rash, as complication of treatment, 22Recurrence of tumors
Transurethral resectionand intravesical therapy, 2, 7, 21, 28, 30and treatment with BCG, 3, 7, 9, 22, 28and treatment with doxorubicin, 3, 7, 9, 22, 28and treatment with mitomycin C, 3, 7, 9, 28and treatment with thiotepa, 3, 7, 9, 25, 26, 28as treatment, 22, 28, 31definition and description of, 1, 2, 18diagnosis of, 6, 14, 15, 18, 29outcomes of use as treatment, 3, 7, 9, 12, 21, 25, 27without adjuvant therapy, 3, 9, 12, 22, 25, 26, 30
UUrethral infection, as complication of treatment, 22, 26Urgency
as complication of treatment, 22as symptom of bladder cancer, 1, 14
Urinary incontinence, as complication of treatment, 22Urinary tract infections, 14Urine assay tests. See specific testsUrine cytology. See Cytologic assessmentUrothelial carcinoma, 31
VValrubicin, 19, 31Vomiting, as complication of treatment, 22
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