Arc Bladder Cancer PDF

American
Urological
Association
Inc.,
Report on
The
Management
of
Non-Muscle-Invasive
Bladder Cancer
(Stages Ta, T1 and Tis)
Archived Document
For Reference Only
Bladder Cancer Guidelines Panel

Members:
Joseph A. Smith, Jr., MD, Chair
Richard F. Labasky, MD, Facilitator
James E. Montie, MD
Randall G. Rowland, MD
Abraham T.K. Cockett, MD
John A. Fracchia, MD
Consultants:
Hanan S. Bell, PhD
Patrick M. Florer
Curtis Colby
Bladder Cancer Clinical Guidelines Panel Members and Consultants

Members
Joseph A. Smith, Jr., M.D.
(Panel Chair)
Department Head
Department of Urology
Vanderbilt University Medical Center
Nashville, Tennessee
Richard F. Labasky, M.D.
(Panel Facilitator)
Assistant Professor
Division of Urology
University of Utah
Salt Lake City, Utah
James E. Montie, M.D.
Professor and Head
Section of Urology
University of Michigan
Ann Arbor, Michigan
Consultants
Abraham T.K. Cockett, M.D.
(Physician Consultant)
Department of Urology
University of Rochester
Rochester, New York
John A. Fracchia, M.D.
(Physician Consultant)
Chief
Section of Urology
Department of Surgery
Lenox Hill Hospital
New York, New York
Hanan S. Bell, Ph.D.

(Consultant in Methodology)
Seattle, Washington
Patrick M. Florer
(Database Design and
Coordination)
Dallas, Texas
Curtis Colby
(Editor)
Washington, D.C.
Residents (Data Extraction)
Jack Baniel
Elie Benaim
Clay Gould
Blake Hamilton
Jeff Holzbeierlien
Fred Leach
John Mansfield
Mitchell S. Steiner
Brad Stoneking
Joseph Trapasso
Margaret Wolf
Archived Document
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Randall G. Rowland, M.D.
Professor and Director
Division of Urology
University of Kentucky
Chandler Medical Center
Lexington, Kentucky
The Bladder Cancer Clinical Guidelines Panel consists of board-certified urologists who are experts in the treatment of bladder cancer. This Report on the Management of Non-Muscle-Invasive Bladder Cancer (stages Ta, T1 and Tis) was extensively
reviewed by over 50 physicians throughout the country in February 1999. The Panel finalized its recommendations for the
American Urological Association (AUA) Practice Parameters, Guidelines and Standards Committee, chaired by Joseph W.
Segura, MD, in July 1999. The AUA Board of Directors approved these practice guidelines in August 1999.
The Summary Report also underwent independent scrutiny by the Editorial Board of the Journal of Urology, was accepted
for publication in August 1999, and appeared in its November 1999 issue. A Doctors Guide for Patients and Evidence Working
Papers have also been developed; both are available from the AUA.
The AUA expresses its gratitude for the dedication and leadership demonstrated by the members of the Bladder Cancer
Clinical Guidelines Panel in producing this guideline.
ISBN 0-9649702-5-2
Introduction
More than 50,000 new bladder cancer cases are diagnosed each year in the United States, and
the incidence rate (number of new cases per 100,000 persons per year) has been slowly rising, concurrent with an aging population (Landis, Murray, Bolden, et al., 1999; Parker, Tong, Bolden, et
al., 1996, 1997; Wingo, Tong, Bolden, et al., 1995).
Bladder cancer is largely a disease afflicting the late middle age and old age populations.
Although the disease does occur in young personseven in childrenmore than 70 percent of
new cases are diagnosed in persons aged 65 and older (Lynch and Cohen, 1995; Yancik and Ries,
1994). As the baby boom generation ages over the next two decades, the incidence of bladder cancer will likely accelerate.
At any age, most bladder cancers, when initially diagnosed, have not invaded the detrusor muscle (Fischer, Waechter, Kraus, et al., 1998; Fleshner, Herr, Stewart, et al. 1996). These noninvasive
cancers are the subject of this Report on the Management of Non-Muscle-Invasive Bladder Cancer
(Stages Ta, T1 and Tis). The report was produced by the American Urological Association's
Bladder Cancer Clinical Guidelines Panel.
The AUA charged the panel with the task of analyzing published outcomes data to assess potential benefits and possible adverse effects of treatment interventions and to produce practice policy recommendations accordingly. The three types of outcomes the panel determined to be most
important for analysis are: 1) probability of tumor recurrence; 2) risk for tumor progression; and
3) complications of treatment.
The panel developed practice policy recommendations for three types of patients: 1) a patient
who presents with an abnormal growth on the urothelium, but who has not yet been diagnosed
with bladder cancer; 2) a patient with established bladder cancer of any grade, stage Ta or T1, with
or without carcinoma in situ (CIS), who has not had prior intravesical therapy; and 3) a patient
with CIS or high-grade T1 cancer who has had at least one course of intravesical therapy.
The panel avoided use of the term "superficial" in this report to categorize the three non-muscle-invasive stages of bladder cancer: Ta, T1 and Tis. The panel agrees with the International
Society of Urological Pathology's recommendation that such use of the term should be discouraged
(Epstein, Amin, Reuter, et al., 1998). Ta, T1 and Tis tumors have often been grouped together as
"superficial" cancers because they are all superficial to the detrusor muscle, but in most other respects they behave differently from one another and to group them in a single category is misleading. (See the discussion on page 16.)
A summary of this report has been published in the Journal of Urology (November 1999). A
Doctor's Guide for Patients and Evidence Working Papers are available for purchase through the
AUA.
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Copyright 1999 American Urological Association, Inc.
Page i
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Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i
Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Treatment alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Treatment recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Chapter 1: Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
Literature search, article selection and data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
Evidence combination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Chapter 2: Non-muscle-invasive bladder cancer and its management . . . . . . . . . . . . . . . . . . . . . . . . .13
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Major types of bladder cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
Grade classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
Prognostic indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
Treatment alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18
Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20
Chapter 3: Outcomes analysis for treatments of non-muscle-invasive bladder cancer . . . . . . . . . . . . .21
The outcome tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
Variability of outcomes data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
Outcomes summary:recurrence and progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
Outcomes summary: treatment complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
Chapter 4: Recommendations for management of non-muscle-invasive bladder cancer . . . . . . . . . . . .28
Treatment policies: levels of flexibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28
Index patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28
Treatment recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29
Areas for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33
Appendix A Data Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38
Appendix B Data extraction form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54
Appendix C Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58
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Managing Editor
Lisa Emmons
Graphic Desgner
Gary Weems
Copy Editor
Lisa Goetz
Copyright 1999
American Urological Association, Inc.
Executive Summary:
Report on the management of non-muscle-invasive
bladder cancer (stages Ta, T1 and Tis)
Methodology
To develop recommendations for treatment of
non-muscle-invasive bladder cancer, the AUA
Bladder Cancer Clinical Guidelines Panel reviewed the literature on bladder cancer from
January 1964 to January 1998 and extracted and
meta-analyzed all relevant data to estimate as accurately as possible both desirable and undesirable outcomes of alternative treatment modalities.
The panel followed an explicit approach to the development of practice policy recommendations
(Eddy, 1992). This approach emphasizes the use
of scientific evidence in estimating outcomes. If
the evidence has limitations, the limitations are
clearly stated. When panel opinion is necessary,
the explicit approach calls for an explanation of
why it is necessary and/or for discussion of the
factors considered. For a full description of the
methodology, see Chapter 1.
hematuria. This set of symptoms is associated

with diffuse CIS or muscle-invasive disease.
Routine diagnostic methods for bladder cancer
include: a thorough history, especially regarding
exposure to known carcinogens; a physical examination; urine analysis; and a cystoscopic examination of the bladder and urethra. Diagnostic cystoscopies today are usually outpatient procedures
done with a flexible or rigid cystoscope under local anesthesia. Diagnostic tools available in addition to cystoscopy include cytologic assessment
and several new urinary tests approved by the
FDA for detection or monitoring of recurrences of
bladder cancer.
A transurethral resection of a bladder tumor
(TURBT) is usually performed both to excise all
visible tumors and to provide specimens for
pathologic evaluation to determine tumor stage
and grade (Shelfo, Brady and Soloway, 1997).
Additional loop or cold-cup biopsies may be taken to evaluate other areas of the urothelium, and a
bimanual palpation before and after resection may
provide further information on tumor size and
depth of penetration. A repeat TURBT may be
performed in cases of incompletely resected Ta tumors and T1 tumors.
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Background
More than 90 percent of all bladder cancers
in the United States and Europe, both muscleinvasive and noninvasive, are transitional cell carcinomas originating in the urothelium that forms
the bladder lining (Fleshner, Herr, Stewart, et al.,
1996). Transitional cell carcinomas may appear in
a variety of configurationsincluding exophytic
papillary tumors (the most common configuration); flat patches of carcinoma in situ (CIS);
nodular tumors; sessile growths; and mixed
growths such as high-grade papillary tumors together with flat CIS.
Hematuria is the usual first sign of bladder
cancer, present at least microscopically in almost
all patients with cystoscopically detectable tumors
(Messing and Valencourt, 1990). In some cases,
bladder irritability accompanied by urgency, frequency and dysuria will be present in addition to
Copyright 1999, American Urological Association, Inc.
Staging
For staging of bladder cancer, the original
Jewett-Strong system (1946), modified by
Marshall (1952, 1956), has generally given way to
the TNM (tumor, node, metastasis) system developed jointly by the American Committee on
Cancer Staging and the International Union
Against Cancer (Hermanek and Sobin, 1992;
Fleming, 1997). Depth of tumor penetration is
the crucial element in both systems. Table 1 on
page 16 shows the TNM classifications for primary tumors, adapted from the American Joint
Committee on Cancer (AJCC) staging manual
(Fleming, 1997).
Page 1 Executive Summary
Basic characteristics of
stages Ta, T1 and Tis
Stage Ta tumors are confined to the urothelium
(above the basement membrane) and have a papillary configuration--described by Johansson and
Cohen (1996) as resembling "seaweed" protruding
into the lumen of the bladder. Most Ta tumors are
low grade.
Stage T1 tumors have penetrated below the
basement membrane and infiltrated the lamina
propria, but not so far as the detrusor muscle.
Most T1 tumors are papillary, but many of those
that have penetrated the deepest into the lamina
propria are nodular (Heney, Nocks, Daly, et al.,
1982).
In a stage by itself, CIS (stage Tis) has been
defined as high-grade (anaplastic) carcinoma,
which like stage Ta is confined to the urothelium,
but with a flat, disordered, nonpapillary configuration and a likelihood of being underdiagnosed
(Epstein, Amin, Reuter, et al., 1998). CIS can be
focal, multifocal or diffuse. On cystoscopic examination, it usually appears as a slightly raised,
reddened patch of velvety mucosa--but often is
endoscopically invisible.
fulguration and/or laser therapy. A careful cystoscopic examination of all bladder surfaces, the
urethra and the prostate precedes resection (Koch
and Smith, 1996). Findings with prognostic significance are noted during this examination.
Following resection, adjuvant intravesical
chemotherapy or intravesical immunotherapy is
commonly used to prevent recurrences.
Resection and fulguration of

bladder tumors
As stated previously, a TURBT has two main
purposes: 1) complete eradication of all visible tumors; and 2) tissue resection for pathologic evaluation to determine grade and stage. Fulguration
may be used on small lesions, but tissue still
needs to be obtained to determine grade and stage
at time of initial presentation. When a tumor is
removed, a separate biopsy can be taken at the
base with the resecting loop, after which healthyappearing muscle fibers should be visible at the
base. Necrotic-appearing tissue implies an invasive carcinoma. The presence of fat implies a
full-thickness bladder wall defect.
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Grade classification
Numerous classification systems for grading

transitional cell carcinomas of the bladder have
been developed and published over the past few
decades. Although no single system has yet
emerged to win universal acceptance, the most
widely used systems all share important characteristics. In particular, they all tend to group bladder
carcinomas similarly into three principal grades
based mainly on degree of anaplasia (Bergkvist,
Ljungqvist and Moberger, 1965; Epstein, Amin,
Reuter, et al., 1998; Koss, 1975). The three
gradeslow (grade 1), intermediate (grade 2) and
high (grade 3)correspond respectively to well
differentiated, moderately differentiated and poorly differentiated tumors. Grade has been shown
to be a highly predictive indicator of future tumor
behavior with regard to both recurrence and progression.
Treatment alternatives
In most cases of non-muscle-invasive bladder
cancer, tumors are treated initially with TURBT,
Laser therapy
The Nd:YAG laser has so far proven to be the

most versatile wavelength for treating bladder
cancer, but other wavelengths also have been used
(Koch and Smith, 1996; Smith, 1986). Results
are comparable to electrocautery resection, with
little difference in the recurrence rate (Beisland
and Seland, 1986). However, tissue samples need
to be obtained beforehand by means of cold-cup
biopsies to determine tumor grade. Assessing
depth of tumor penetration to determine stage is
more problematic with laser therapy. Appropriate
patients for this therapy have papillary, low-grade
tumors and a history of low-grade, low-stage tumors (Koch and Smith, 1996).
Intravesical chemotherapy and

immunotherapy
Intravesical chemotherapy or immunotherapy
is most often used as adjuvant treatment to prevent tumor recurrence following the TURBT of
primary non-muscle-invasive bladder tumors, including possible recurrence because of iatrogenic
implantation of tumor cells. Intravesical therapy
is also used to treat known existing tumors in cases
of CIS, which frequently cannot be treated adequately by resection or fulguration because of diffuse involvement. The chief intravesical agents
currently available are thiotepa, doxorubicin, mitomycin C and bacillus Calmette-Gurin (BCG).
Chapter 3 of this report contains an evidencebased comparative outcomes analysis of these
agents.
Thiotepa, introduced in 1961, is the oldest and
one of the least expensive of the intravesical
drugs. It is an alkylating agent that acts by crosslinking nucleic acid. Its low molecular weight of
189 allows partial absorption through the urothelium, with possible systemic toxicity.
Doxorubicin is an anthracycline antibiotic able
to bind to DNA and inhibit synthesis. It is not
cell cycle specific, but appears to be most cytotoxic in the S phase. Its molecular weight of 580 is
high, and absorption and systemic toxicity are extremely rare.
Mitomycin C is an antibiotic that works by
inhibiting DNA synthesis. Because of its moderately high molecular weight of 329, there are
few problems with transurothelial absorption,
and myelosuppression is rare. However, mitomycin C is a very expensive agent (see Table 6
on page 25).
BCG is a live attenuated strain of
Mycobacterium bovis and was first used as a tuberculosis vaccine. Its now widespread use as intravesical immunotherapy for management of
noninvasive bladder cancer began in the 1970s. It
has since become a first-line treatment for CIS
and has been shown to be effective as prophylaxis
to prevent bladder cancer recurrences following
TURBT (Cookson and Sarosdy, 1992; Coplen,
Marcus, Myers, et al., 1990; DeJager, Guinan,
Lamm, et al., 1991; Herr, Schwalb, Zhang, et al.,
1995; Lamm, Blumenstein, Crawford, et al.,
1995). Its mechanism of action is not fully understood, but clearly involves a strong inflammatory
immunologic host response with release of interleukins and other cytokines (Morales, Eidinger
and Bruce, 1976; Ratliff, Haaff and Catalona,
1986). The most common side effects of BCG
are cystitis and hematuria. The most serious is
BCG sepsis. BCG therapy is contraindicated in
patients who are immunocompromised, have liver
disease or a history of tuberculosis.
Treatment recommendations
The panel generated its recommendations
based on analysis of comparative outcomes data
from both randomized controlled trials (RCTs)
and clinical series and on expert opinion. The
recommendations apply to treatment of patients
with non-muscle-invasive, transitional cell carcinoma of the bladder, including CIS as well as
stages Ta and T1 tumors. The panel evaluated
comparative data for the following treatment
methods in particular:
TURBT;
TURBT plus thiotepa;
TURBT plus doxorubicin;
TURBT plus mitomycin C;
TURBT plus BCG.
The terms "standard," "guideline" and "option," as used in the panel's recommendations, refer to the three levels of flexibility for practice
policies defined in Chapter 1 (page 9). A standard
is the least flexible of the three, a guideline more
flexible and an option the most flexible. Options
can exist because of insufficient evidence or because patient preferences are divided. In the latter
case particularly, the panel considered it important
to take into account likely preferences of individual patients when selecting from among alternative interventions.
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Index patients
The specific types of patients to whom the
panel's recommendations apply are termed index
patients. In recognition of the differences in decision-making that occur depending upon patient
circumstances, the panel defined three different
index patients:
Index Patient No. 1: A patient who presents
with an abnormal growth on the urothelium, but
who has not yet been diagnosed with bladder cancer;
Index Patient No. 2: A patient with established bladder cancer of any grade, stage Ta or
T1, with or without CIS, who has not had prior
intravesical therapy; and
Index Patient No. 3: A patient with CIS or
high-grade T1 cancer who has had at least one
course of intravesical therapy.
(continued on page 6)
Recommendations
Recommendation for all index patients
Standard:
Physicians should discuss with the patient the treatment options and the benefits and
harms, including side effects, of intravesical treatment, especially those side effects
associated with a particular agent.
Recommendation for Index Patient No. 1

A patient who presents with an abnormal growth on the urothelium, but who has not
yet been diagnosed with bladder cancer.
Standard:
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If the patient does not have an established histologic diagnosis, a biopsy should be obtained for pathologic analysis.
Recommendations for Index Patient No. 2
A patient with established bladder cancer of any grade, stage Ta or T1, with or without CIS, who has not had prior intravesical therapy.
Standard:
Complete eradication of all visible tumors should be performed if surgically feasible

and if the patient's medical condition permits.
Option:
Surgical eradication can be performed by one of several methods, including electrocautery resection, fulguration or laser ablation.
(continued on next page)
Recommendations
(continued)
Option:
Adjuvant intravesical chemotherapy or immunotherapy is an option for treatment after
endoscopic removal of low-grade Ta bladder cancers.
Guideline:
Intravesical instillation of either BCG or mitomycin C is recommended for treatment
of CIS and for treatment after endoscopic removal of T1 tumors and high-grade Ta tumors.
Option:
Cystectomy may be considered for initial therapy in some patients with CIS or T1 tumors.
Recommendations for Index Patient No. 3
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A patient with CIS or high-grade T1 cancer who has had at least one course of intravesical therapy.
Option:
Cystectomy may be considered as an option for patients with CIS or high-grade T1

cancers that have persisted or recurred after an initial intravesical treatment.
Option:
Further intravesical therapy may be considered as an option for patients with CIS or
high-grade T1 cancers that have persisted or recurred after an initial intravesical treatment.
Recommendation for all

index patients
Standard: Physicians should discuss with the
patient the treatment options and the benefits
and harms, including side effects, of intravesical treatment, especially those side effects associated with a particular agent.
This recommendation is based on the panel's
expert opinion. Although all of the adjuvant treatments studied decrease the recurrence probability
of bladder cancer when they are compared to
TURBT alone, the published literature does not
unequivocally support the conclusion that the rate
of progression to muscle-invasive disease is altered. Patients contemplating intravesical therapy
should consider information about all expected
outcomes including the possible side effects of
therapy. All of the treatments have in common
some side effects, especially those related to bladder irritation; other side effects are either unique
or peculiar to a particular drug. The incidence of
serious or life-threatening side effects with any of
the treatments is low, as shown in Table 5; but the
panel is aware of reports documenting systemic infection or even death from BCG sepsis in rare circumstances.
In addition, there is little information defining
the optimal dose, number and timing of instillations or the influence of long-term maintenance
therapy. Randomized studies supporting the use
of maintenance BCG therapy have been conducted, but the panel excluded them because their results have been reported only in abstract form.
Other trials would appear to support a role for
maintenance therapy.
Although urine cytology and other novel tumor

markers, as discussed in Chapter 2 (page 17), can
provide suggestive evidence of bladder cancer, the
definitive diagnosis is established by pathologic
examination of tissue removed by TURBT or
biopsy. Transitional cell carcinoma of the bladder
often has a characteristic appearance, but other
conditions can mimic the gross appearance of
bladder cancer. It is important, therefore, to prove
by microscopic analysis that gross abnormalities
are from transitional cell carcinoma. Intravesical
immunotherapy or chemotherapy should not be
used in the absence of a histologic diagnosis.
Recommendations for
Index Patient No. 2
A patient with established bladder cancer of
any grade, stage Ta or T1, with or without CIS,
who has not had prior intravesical therapy.
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Recommendation for
Index Patient No. 1
A patient who presents with an abnormal
growth on the urothelium, but who has not yet
been diagnosed with bladder cancer.
Standard: If the patient does not have an established histologic diagnosis, a biopsy should
be obtained for pathologic analysis.
Standard: Complete eradication of all visible

tumors should be performed if surgically
feasible and if the patient's medical condition
permits.
In a patient with known bladder cancer, endoscopic ablation of all visible tumors should be performed. This can be accomplished with electrocautery resection, fulguration or application of
laser energy. Sometimes, the extent of disease or
the location of the lesions may preclude complete
eradication. Also, co-morbid conditions must be
considered and may occasionally influence a decision about whether or not to attempt endoscopic
removal of bladder tumors. This recommendation
is based on the panel's expert opinion.
Option: Surgical eradication can be performed

by one of several methods, including electrocautery resection, fulguration or laser ablation.
For bladder cancers that do not invade the detrusor muscle, several methods for tumor destruction provide apparently comparable results.
Adequate tissue should be available for determination of pathologic stage, but endoscopic ablative
techniques may not permit submission of all material for histologic evaluation. This recommendation is based on the panel's expert opinion.
Option: Adjuvant intravesical chemotherapy or
immunotherapy is an option for treatment after
endoscopic removal of low-grade Ta bladder
cancers.
A recommendation stronger than an option for
this group of patients (Index Patient No. 2) cannot
be supported by the evidence in the outcomes tables (see page 23). Most studies combined patients who had low-grade stage Ta tumors with
patients who had T1 lesions and higher-grade cancers, creating difficulty in extracting information
about this subgroup. However, based upon panel
opinion, many patients with low-grade Ta tumors
do not require adjuvant intravesical therapy.
There is a low risk of disease progression (overall
less than 10 percent) in this group, and there is little evidence that adjuvant therapy affects the progression rate. For rapidly recurring low-grade Ta
tumors, adjuvant therapy may be useful. The outcomes tables show a decreased recurrence probability for all the intravesical therapies studied,
compared to TURBT alone.
Because there is risk of progression to muscleinvasive disease even after intravesical therapy,
cystectomy may be considered as an initial treatment option in certain cases. Among factors associated with increased risk of progression are large
tumor size, high grade, tumor location in a site
poorly accessible to complete resection, diffuse
disease, infiltration of lymphatic or vascular
spaces and prostatic urethral involvement. This
recommendation is based on the panel's expert
opinion.
Recommendations for
Index Patient No. 3
A patient with CIS or high-grade T1 cancer
who has had at least one course of intravesical
therapy.
Option: Cystectomy may be considered as an

option for patients with CIS or high-grade T1
cancers that have persisted or recurred after an
initial intravesical treatment.
Archived Document
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Guideline: Intravesical instillation of either
BCG or mitomycin C is recommended for
treatment of CIS and for treatment after endoscopic removal of T1 tumors and high-grade
Ta tumors.
Based on evidence from the literature and panel opinion, both BCG and mitomycin C are superior to doxorubicin or thiotepa for reducing recurrence of T1 and high-grade Ta tumors. There is
no evidence that any intravesical therapy affects
the ultimate rate of progression to muscle-invasive
disease.
Option: Cystectomy may be considered for
initial therapy in some patients with CIS or T1
tumors.
This recommendation is based upon panel

opinion rather than evidence in the outcomes tables. However, other data in the literature do
show a substantial risk of progression to muscleinvasive cancer in patients with diffuse CIS and
high-grade T1 tumors (Herr, 1997; Hudson and
Herr, 1995; Kiemeney, Witjes, Heijbroek, et al.,
1993). It is not certain whether intravesical therapy alters this risk of progression. Thus, there are
some patients with symptomatic disease or highgrade tumors who may want to move directly to
cystectomy. Physicians should present specific
information about the risks of cystectomy and
methods for urinary reconstruction to patients
who are contemplating bladder removal.
Option: Further intravesical therapy may be

considered as an option for patients with CIS
or high-grade T1 cancers that have persisted or
recurred after an initial intravesical treatment.
This recommendation is also based on the panel's expert opinion. Optimal dosing schemes for
intravesical chemotherapy and immunotherapy
have not been established, but weekly instillations
for at least six weeks are used most often. There is
additional evidence showing that some patients
will respond to second induction regimens, particu-
larly with BCG. Repeat intravesical therapy may

be appropriate in patients who develop a late recurrence after previous complete response to an intravesical agent. Data are insufficient, however, to
allow conclusions about the role of drug combination regimens or alternating therapies.
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Page 8
Chapter 1: Methodology
To develop the recommendations in this Report

on the Management of Non-Muscle-Invasive
Bladder Cancer (Stages Ta, T1 and Tis), the AUA
Bladder Cancer Clinical Guidelines Panel used an
explicit approach (Eddy, 1992). This approach attempts to arrive at practice policy recommendations through mechanisms that systematically take
into account relevant factors for making selections
between alternative interventions. Such factors include estimation of the outcomes from the interventions, consideration of patient preferences and
assessment of the relative priority of the interventions for a share of limited health care resources
when possible. For estimating the outcomes of interventions, emphasis is placed on the use of scientific evidence. When panel opinion is necessary, the explicit approach calls for explaining
why it was necessary and/or for discussion of the
factors considered.
In developing its recommendations, the panel
made an extensive effort to review the literature
on non-muscle-invasive bladder cancer and to estimate outcomes of alternative treatment modalities
as accurately as possible. The panel members
themselves served as proxies for patients in considering preferences with regard to health and economic outcomes.
The review of the evidence began with a literature search and extraction of data as described on
page 10. The data available in the literature were
displayed in evidence tables. From these tables,
with reference back to the original studies when
necessary, the panel developed comparative outcomes estimates for the following therapeutic alternatives for treating non-muscle-invasive bladder
cancer:
Transurethral resection of bladder tumor
(TURBT) without adjuvant therapy;
TURBT with thiotepa;
TURBT with doxorubicin;
TURBT with mitomycin C;
TURBT with bacillus Calmette-Gurin (BCG).
The panel utilized the FAST*PRO metaanalysis software described on pages 10-11 to
combine the outcomes evidence from the various

studies. The resulting probability estimates are
displayed in the outcomes tables on pages 23-24.
Because tumor removal is the standard of practice,
there is no evidence comparing removal versus
nonremoval. Thus, this report concentrates on
comparison of the above listed adjuvant therapies
as used to reduce the likelihood of tumor recurrence and progression.
The panel generated its recommendations
based on the probability estimates shown in the
outcomes tables and on expert opinion. These
recommendations were graded according to three
levels of flexibility as determined by strength of
evidence and the expected amount of variation in
patient preferences. The three levels of flexibility
are defined as follows (Eddy, 1992):
1. Standard: A treatment policy is considered a
standard if the health and economic outcomes
of the alternative interventions are sufficiently
well-known to permit meaningful decisions
and there is virtual unanimity about which intervention is preferred.
2. Guideline: A policy is considered a guideline
if 1) the health and economic outcomes of the
interventions are sufficiently well-known to
permit meaningful decisions and 2) an appreciable but not unanimous majority agree on
which intervention is preferred.
3. Option: A policy is considered an option if 1)
the health and economic outcomes of the interventions are not sufficiently well-known to
permit meaningful decisions, 2) preferences
among the outcomes are not known, 3) patients' preferences are divided among the alternative interventions and/or 4) patients are indifferent about the alternative interventions.
A standard has the least flexibility. A guideline has significantly more flexibility, and options
are the most flexible. In this report, the terms are
used to indicate the strength of the recommendations. A recommendation was labeled a standard,
for example, if the panel concluded that it should
be followed by virtually all health care providers
for virtually all patients. A guideline generally
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Page 9
denotes a recommendation supported by objective

data but not with sufficient strength to warrant a
designation of standard. An option in this report
would include treatments for which there appears
to be equal support in the literature or ones for
which there is insufficient published information
to support a stronger recommendation. Also, as
noted in the above definition, options can exist because of insufficient evidence or because patient
preferences are divided. In the latter case particularly, the panel considered it important to take into
account likely preferences of individual patients
with regard to health outcomes when selecting
from among alternative interventions.
Literature search,
article selection and
data extraction
the data onto the forms. The panel rejected 46 articles at this stage because of reasons such as inadequate methods, no relevant data or supersession by a later article from the same source (see
Appendix A, Figure A-5). The result was 181 articles to be used as the source of data for this report. All data were entered into a Microsoft
Access 97 database (Microsoft, Redmond,
Washington), then double-checked at a later time.
The bar graph in Figure A-1 on page 50 categorizes by year of publication the number of articles reviewed and the number accepted for data
extraction. The articles extracted range in year of
publication from 1964 to 1998. The graph in
Figure A-2 categorizes the articles by source. The
majority came from the Journal of Urology,
Urology and The British Journal of Urology.
Evidence combination
The data resulting from the article-selection
and data-extraction process just described were
combined to generate the comparative probability
estimates for alternative interventions displayed in
the outcomes tables (Tables 2-5) on pages 23-24.
A variety of methods can be used to combine outcomes evidence from the literature to generate
probability estimates. The methods chosen depend on the nature and quality of the evidence.
For example, if there is only one good randomized
controlled trial (RCT), the results of that one trial
alone may be used in the outcomes tables. Other
studies of lesser quality may be ignored.
For non-muscle-invasive bladder tumors, data
from more than 30 RCTs were available to generate comparative estimates of recurrence and progression probabilities for the different treatment
alternatives. The small patient size of many of
these studies, however, made them suboptimal for
estimating probabilities of treatment complications, particularly uncommon complications.
Thus, the panel opted to include data from clinical
series as well as from RCTs for generating complications estimates.
If a number of studies have some degree of relevance to a particular cell or cells in an outcomes
table, meta-analytic methods may be used.
Different specific methods are available depending
on the nature of the evidence. For this report, the
panel elected to use the Confidence Profile
Method (Eddy 1989; Eddy, Hasselblad and
Shachter, 1990), utilizing FAST*PRO computer
Archived Document
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Literature searches
were performed mostly us
ing the MEDLINE database. Some articles (including
some that predate the inception of MED
LINE in 1966) were added for review based on
panel members'
own knowledge. The initial
MEDLINE search was performed in 1989. A

subsequent literature search was performed in
1992 with the search terms bladder neoplasms and
carcinoma, transitional cell. Several update
searches were also performed, the last in 1998.
All searches were restricted to English-language
articles on human subjects. Update searches were
further restricted to articles containing the term
superficial in the bibliographic record. The resulting database of search results was used as the basis for selecting articles for data extraction. No
attempt was made to weight the articles by quality
of data.
The panel as a group reviewed the abstracts
and selected the relevant articles for data extraction. From a database of 5,712 citations, the panel
selected 227 articles for retrieval and data extraction. A comprehensive data-extraction form was
devised by the panel to capture as much pertinent
information as possible from each article.
Appendix B contains a sample of this form.
Reviewers were recruited from residencies at
the panel members' medical centers and trained to
use the review form. The articles selected by the
panel were retrieved and divided among the reviewers, who extracted the articles and transcribed
TM
Page 10
software
software
(Eddy
(Eddy
andand
Hasselblad,
Hasselblad,
1992).
1992).
TheThe
Confidence Profile Method allows analysis of data
both from RCTs and from single-arm studies that
are not controlled.
Two different meta-analytic approaches were
used. For estimates of recurrence and progression, data from multi-armed RCTs were combined
meta-analytically to determine the difference between two treatment alternatives. All alternatives
were compared in pairs. For estimates of treatment complications, meta-analysis was performed
to combine data from single arms of more than
one study, including the relevant single arms of
multi-armed RCTs. An estimate of the probability
of each complication was computed. Thus, the
outcomes table for treatment complications (Table
5, page 24) shows the probabilities of a particular
complication occurring for each treatment choice.
In the tables for recurrence and progression (page
23), the numbers represent the difference in probability between two treatment interventions. For
example, if 10 percent of patients given intervention A had a recurrence, and 13 percent of patients
given intervention B had a recurrence, the number
listed in the outcomes table would be 3 percent.
Different study results may be caused by a
number of factors, including differences in patient
populations, how an intervention was performed
or the skill of those performing the intervention.
Because of such differences, the meta-analyses all
used a random effects or hierarchical Bayesian
model in combining data from different studies.
A random effects model assumes that for each
study there is an underlying true rate for the outcome being assessed. It further assumes that this
underlying rate varies from study to study, and
that the variation in the true rate is normally distributed.
The probability distributions produced by the
Confidence Profile Method can be described using
a mean or median estimate of the probability and
a confidence interval. In this report, the 95-percent confidence interval is such that the probability (Bayesian) of the true value being outside the
interval is 5 percent. The width of the confidence
interval indicates the degree of uncertainty about
the estimated probability, reflecting such factors as
differences in outcomes data being combined from
different studies and differences in the size of the
studies.
Limitations
The results presented in this document have
several limitations, mostly because of how data
are reported in the literature. Determination of
outcomes by tumor stage is an important example.
Such determination was limited by the fact that
most studies, including RCTs, categorize patients
with CIS, Ta or T1 tumors as all having "superficial bladder cancer," without reporting stage-specific results. In addition, most studies do not segregate response by tumor grade. Yet, stage and
grade, even in the absence of muscle invasion, are
strong predictors of recurrence and progression.
These problems limited the ability of the panel to
make strong, evidence-supported recommendations.
A possible limitation in using RCTs for metaanalysis is that, by their nature, most RCTs compare two or more different treatments, whereas the
comparison of all alternative treatments may be
what is desired for purposes of evidence-based
clinical practice guidelines. Ideally, this should
not be a problem because the two-way comparisons should line up consistently in relation to one
another, and it should be possible to generate
numbers that show with consistency the differences among all of a given set of treatments.
For example, assume that a two-way comparison based on meta-analysis of RCTs shows the estimated probability of patient survival to be 20
percent greater after treatment A than after treatment B. Another two-way comparison based on
other RCTs shows this estimated probability to be
10 percent greater after treatment B than after
treatment C. Therefore, a comparison of treatments A and C should logically show a difference
of 30 percent in favor of treatment A. In reality,
such consistency of results is uncommon when
based on data from different studies. Among the
reasons for possible inconsistencies are differences in study designs, differences in the measures used, patient differences and simple random
variation.
With regard to intravesical drugs, studies differ
on dosages, strains, administration protocols and
mixtures of patients. Nevertheless, the panel ultimately decided to combine data from studies that
differ in these areas, because such differences
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Page 11
appear to have little or no effect on rates of recurrence and progression. This is demonstrated by
the comparative data from BCG studies shown in
Table C-1 in Appendix C. The panel also combined data from studies that differed in follow-up
duration. The panel did this because those studies
that had longer follow-up and showed actuarial
data indicated that differences in recurrence and
progression apparently develop early in the follow-up period and remain relatively constant over
time.
Differences in how authors define and record
complications are also a common problem. Some
authors report the most minor of complications,
whereas other authors fail to report complications
at all. If a complication is rare and the panel only
analyzes those papers that report the complication, there will be a significant overestimation of
its frequency. The panel attempted to determine

appropriate denominators for such complications,
but the possibility of overestimation still exists.
Another common difficulty is negative publication bias. Studies with poor results are less
likely to be published because either they are never submitted for publication or they are rejected
later. For example, with regard to articles comparing adjuvant therapies to TURBT alone, there
is the possibility that studies demonstrating negative results for adjuvant therapies versus TURBT
alone may never have been published.
Notwithstanding such limitations, the panel
did find high-quality outcomes data available on
treatment of non-muscle-invasive bladder cancer
and in sufficient quantity for computing reliable
probability estimates to aid physicians and patients in their treatment decision making.
Archived Document
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Page 12
Chapter 2: Non-muscle-invasive bladder cancer

and its management
Chapter 2 provides an overview of the current
knowledge base for bladder carcinomas that have
not invaded the detrusor muscle (stages Ta, T1
and Tis). This overview includes summary descriptions of known etiologic factors, tumor types
and characteristics, histology and natural history.
Described also are current methods of diagnosis,
staging and grade classification, as well as methods for treating primary tumors and for predicting
likelihood of tumor recurrence and subsequent
progression.
Etiology
clophosphamide's urinary metabolite acrolein.

The latency period is a relatively short 6-13 years,
and most of the tumors are high grade when diagnosed (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 radiotherapy used to treat uterine or cervical cancer or other
pelvic tumors, and again the tumors tend to be
high grade when diagnosed (Quilty and Kerr,
1987; Sella, Dexeus, Chong, et al., 1989).
Much of today's research regarding bladder
cancer etiology focuses on the role of altered genetic mechanisms, some of which have been under study for years. Oncogenes are an example.
These are altered forms of alleles called protooncogenes. Proto-oncogenes encode a growth
factor as well as receptor proteins and are necessary for normal cell development. The altered
forms, oncogenes, lead to unregulated cell division and, in bladder cancer, increased recurrence
and progression (Del Senno, Maestri, Piva, et al.,
1989; Tiniakos, Mellon, Anderson, et al., 1994).
Tumor-suppressor genes such as p53 have also
been under intense study. One of the functions of
p53 is to direct DNA-damaged cells toward apoptosis before the DNA can replicate, thus suppressing proliferation of cells that have genetic abnormalities (Harris and Hollstein, 1993). If p53 itself
is damaged, it may no longer be able to function
(Cordon-Cardo, 1995). Bladder cancers associated with mutated p53 tend to behave quite aggressively (Cordon-Cardo, 1995; Esrig, Elmajian,
Groshen, et al., 1994), and altered genes like p53
may serve as markers to indicate the relative aggressiveness of individual tumors.
Archived Document
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Malignant transformation of a normal bladder
cell begins with alteration of the cell's DNA.
Epidemiologic evidence implicates chemical carcinogens as a causative agent in many patients.
Specifically, the evidence points to aromatic
amines, such as 2-naphthylamine and 4-aminobiphenyl, which are present in cigarette smoke
and various industrial chemicals. Cigarette smoke
metabolites, secreted into smokers' urine, have
been estimated to cause more than 50 percent of
the bladder cancer cases in the United States and
Europe (Bryan, 1993; Vineis, Martone and
Randone, 1995). Occupational exposure to industrial chemicals has been estimated to account for
up to 20 percent of bladder cancer cases in the
United States, often with latency periods of more
than 30 years (Bryan, 1993; Cole, Hoover and
Friedell, 1972; Silverman, Levin, Hoover, et al.,
1989a, 1989b).
Other reported risk factors for bladder cancer
include phenacetin-related analgesic abuse; that
is, consumption in excessive quantities over a 10year 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 treat
a variety of conditions including Hodgkin's disease, can also lead to development of bladder cancer; the causative agent is believed to be cy-
Major types of
bladder cancer
More than 90 percent of all bladder cancers in
the United States and Europe, both muscle invasive and noninvasive, are transitional cell
Page 13
carcinomas originating in the urothelium that

forms the bladder lining (Fleshner, Herr, Stewart,
et al., 1996). Transitional cell carcinomas may
appear in a variety of configurations--including
exophytic papillary tumors (the most common
configuration); flat patches of carcinoma in situ
(CIS); nodular tumors; sessile growths; and mixed
growths such as high-grade papillary tumors together with flat CIS.
Less common types of bladder cancer include
squamous cell carcinoma, which accounts for 3 to
7 percent of all bladder cancers in the United
States, and adenocarcinoma, which accounts for
less than 2 percent of primary bladder cancers
(Kantor, Hartge, Hoover, et al., 1988; Koss, 1975;
Lynch and Cohen, 1995). Adenocarcinoma is the
most common type of cancer in exstrophic bladders (Bennett, Wheatley and Walton, 1984;
Nielsen and Nielsen, 1983).
In the United States, squamous cell carcinoma
of the bladder is associated with factors such as
chronic urinary tract infections and chronic irritation from long-term indwelling catheters and urinary calculi. Spinal-cord injured patients, in particular, are at risk for squamous cell bladder cancer (Navon, Soliman, Khonsari, et al., 1997). In
North Africa, where squamous cell carcinoma is
also associated with bilharzial infection from
Schistosoma haematobium, this type of bladder
cancer is much more prevalent than in the United
States and Europe (Zhang and Steineck, 1997). In
Egypt, squamous cell carcinoma accounts for
more than 75 percent of all bladder cancers (ElBolkainy, Mokhtar, Ghoneim, et al., 1981).
Beyond the basement membrane is the lamina

propria, extending to the detrusor muscle. As noted, the lamina propria consists of loose connective
tissue. This layer also contains blood vessels and
lymphatic vessels that provide potential channels
for cancer dissemination. At about one-third of
the distance from the basement membrane to the
detrusor muscle is a discontinuous, wispy layer of
smooth muscle called the muscularis mucosa.
The muscularis mucosa, when parts of it are present in small, fragmented tumor specimens obtained by biopsy or transurethral resection, may
be difficult for the pathologist to distinguish from
detrusor muscle. The result may be overstaging
of a tumor erroneously thought to be muscle-invasive, but actually limited to the lamina propria.
The detrusor muscle itself consists of interlacing
bundles of smooth muscle with a covering of adipose tissue (or peritoneum).
Diagnosis
Archived Document
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Histology
The bladder has three main histologic layers:
1) the urothelium; 2) the suburothelial layer of
loose connective tissue called the lamina propria;
and 3) the detrusor muscle (muscularis propria).
The urothelium in the normal bladder consists of
three to seven layers of transitional-type epithelial
cells, which vary in appearance from cell layer to
cell layer. Those in the luminal cell layer are
large, flat umbrella cells bound together by tight
junctions. The urothelium's deepest layer is composed of basal cells resting on and attached to an
extracellular-matrix basement membrane (basal
lamina). Between these cell layers are one to five
intermediate layers.
Page 14
Hematuria is the usual first sign of bladder

cancer, present at least microscopically in almost
all patients with cystoscopically detectable tumors
(Messing and Valencourt, 1990). In some cases,
bladder irritability accompanied by urgency, frequency and dysuria will be present in addition to
hematuria. This set of symptoms is associated
with diffuse CIS or muscle-invasive disease.
Routine diagnostic methods for bladder cancer
include a thorough history, especially regarding
exposure to known carcinogens; a physical examination; urine analysis; and a cystoscopic examination of the bladder and urethra. Diagnostic cystoscopies today are usually outpatient procedures
done with a flexible or rigid cystoscope under local anesthesia. Diagnostic tools available in addition to cystoscopy include cytologic assessment
and several new urinary tests approved by the
FDA for detection or monitoring of recurrences of
bladder cancer. These diagnostic aids will be discussed later.
Also, because hematuria can originate elsewhere than in the bladder, imaging of the entire
urinary tract may be warranted at the time of
hematuria evaluation (using a range of available
imaging techniques). Once a diagnosis of bladder
cancer is established, upper tract imaging is usually
performed.
Urinary cytology
Microscopic cytologic examination of bladder
cells, collected from voided urine or from bladder
washings (which potentially yield more cells), has
long been part of the diagnostic armamentarium
for bladder cancer. Cytology is frequently used as
well in post-treatment follow-up to detect possible
cancer recurrence (Grgoire, Fradet, Meyer, et al.,
1997).
Cytologic assessment is least sensitive for detecting low-grade bladder tumors. Because the
cells of these well-differentiated tumors often
closely resemble normal urothelial cells, malignant features may be difficult to recognize. In addition, the cells are relatively cohesive and may
not shed into the urine in sufficient numbers for
analysis. Cytologic detection rates for low-grade
tumors are generally less than 30 percent (Kannan
and Bose, 1993; Murphy, Soloway, Jukkola, et al.,
1984).
Cytology is much more effective for detecting
high-grade tumors, the cells of which have substantial abnormal characteristics. Also, reduced
cellular cohesion in high-grade tumors produces
greater numbers of cells shed into the urine.
Cytology is especially valuable for detecting CIS,
with detection rates as high as 90 percent
(Grgoire, Fradet, Meyer, et al., 1997; Messing
and Catalona, 1998).
Now being investigated are ways to improve
cytology performance such
as through immunosx
taining with either Lewis antigen or cytokeratin
20 (Klein, Zemer, Buchumensky, et al., 1998;
Pode, Golijanin, Sherman, et al., 1998).
rapidly recurring bladder cancer after a transurethral resection of a bladder tumor (TURBT).
NMP-22 has been reported to be more sensitive
but less specific than cytology as a diagnostic
tool; however, experience with the test is still limited (Stampfer, Carpinito, Rodriguez-Villanueva,
et al., 1998).
Another test is based on telomerase activity.
Telomerase is an enzyme responsible for chromosome-end (telomere) maintenance and is commonly active in cancer. The TRAP test, or telomeric repeat amplification protocol assay, is reported to be highly sensitive but may require special
collection 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-sticktype assays) appear promising but need to be tested themselves by time and experience to prove
their clinical utility (Bandalament, 1998;
Grossman, 1998; Johnston, Morales, Emerson, et
al., 1997). Most of these tests are limited by insufficient specificity to allow treatment decisions
based on a positive test, although they appear to
be more sensitive than cytology for detecting tumors, especially low-grade lesions.
Archived Document
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Recently developed urine
assay tests
The bladder tumor antigen (BTA) test was the
first of several tests developed to detect bladder
cancer recurrence based on urinary presence of
certain antigens, nuclear matrix proteins or other
substances known to be associated with bladder
malignancies (Fradet, 1998; Grossman, 1998;
Sardosdy, White, Soloway, et al., 1995). The
original BTA test has been followed by two newer
assays, BTA stat and BTA TRAK , which may
offer improved performance over the original
(Ellis, Blumenstein, Ishak, et al., 1997; Sarosdy,
Hudson, Ellis, et al., 1997).
A nuclear matrix protein test, NMP-22, has
been approved by the FDA to detect occult or
TM
Diagnostic TURBT
TURBT (described on page 18) is the usual

method for initial diagnosis of bladder cancer. A
TURBT is performed both to excise all visible tumors and to provide specimens for pathologic
evaluation to determine tumor stage and grade
(Shelfo, Brady and Soloway, 1997). Additional
loop or cold-cup biopsies may be taken to evaluate other areas of the urothelium, and a bimanual
palpation before and after resection may provide
further information on tumor size and depth of
penetration. A repeat TURBT may be performed
in cases of incompletely resected Ta and T1 tumors.
Laser coagulation may be used to ablate tumors in some cases, especially recurrent lesions.
If laser therapy is used, cold-cup biopsies may be
taken for pathologic evaluation.
TM
Staging
For staging of bladder cancer, the original
Jewett-Strong system (1946), modified by
Page 15
Table 1:
Staging of primary bladder cancer tumors (T)
Ta: Noninvasive papillary carcinoma
Tis: CIS (anaplastic "flat tumor" confined to
urothelium)
T1: Tumor invades lamina propria
T2: Tumor invades muscularis propria
T2a: Invades superficial muscularis propria
T2b: Invades deep muscularis propria
T3: Tumor invades perivesical fat
T3a: Invades microscopic perivesical fat
T3b: Invades macroscopic perivesical fat
(extravesical mass)
T4: Tumor invades prostate, uterus, vagina,
pelvic wall or abdominal wall
T4a: Invades adjacent organs (uterus,
ovaries, prostate stoma)
T4b: Invades pelvic wall and/or abdominal
wall
other, particularly with regard to tumor recurrence

and progression (Epstein, Amin, Reuter, et al.,
1998; Fitzpatrick, 1993; Levi, La Vecchia,
Randimbison, et al., 1993).
Low-grade Ta tumors, for example, tend to recur as low-grade Ta tumors. Progression to muscle-invasive disease takes place in less than 10
percent of patients with these tumors (Holmng,
Hedelin, Anderstrm, et al., 1997; Kiemeney,
Witjes, Heijbroek, et al., 1993; Prout, Barton,
Griffin, et al., 1992). By contrast, T1 tumors have
a progression rate of 30-50 percent in spite of
therapy, and there is a high risk of death because
of progression (as high as 30 percent as reported
in studies with long-term patient follow-up) (Herr,
1997; Kiemeney, Witjes, Heijbroek, et al., 1993).
Treatment recommendations may be substantially
different for patients with Ta tumors than for patients with T1 disease.
Basic characteristics of
stages Ta, T1 and Tis
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Marshall (1952, 1956), has generally given way to
the TNM (tumor, node, metastasis) system developed jointly by the American Committee on
Cancer Staging and the International Union
Against Cancer (Hermanek and Sobin, 1992;
Fleming, 1997). Depth of tumor penetration is
the crucial element in both systems. Table 1
shows the TNM classifications for primary tumors, adapted from the American Joint
Committee on Cancer (AJCC) staging manual
(Fleming, 1997).
Based on large data sets from hospitals in the
United States and Germany, 30-35 percent of
bladder cancer patients at time of diagnosis present with stage Ta or Tis disease (confined to the
urothelium); 25-30 percent have stage T1 disease
(penetration into the lamina propria); and 30-35
percent present with muscle-invasive disease in
stage T2 or higher (Fischer, Waechter, Kraus, et
al., 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 Tisare often grouped together under
the label "superficial." This is an imprecise label,
and the AUA Bladder Cancer Guidelines Panel
believes its use should be discouraged. All three
stages are indeed superficial to the detrusor muscle, but otherwise differ markedly from one an-
Page 16
Stage Ta tumors are confined to the urothelium

(above the basement membrane) and have a papillary configuration--described by Johansson and
Cohen (1996) as resembling "seaweed" protruding
into the lumen of the bladder. Most Ta tumors are
low grade.
Stage T1 tumors have penetrated below the
basement membrane and infiltrated the lamina
propria, but have not gone so far as the detrusor
muscle. Most T1 tumors are papillary, but many
of those that have penetrated the deepest into the
lamina propria are nodular (Heney, Nocks, Daly,
et al., 1982).
Hasui, Osada, Kitada, et al. (1994) reported
significant increases in cancer recurrence and progression when T1 tumors penetrated to the level
of the muscularis mucosa and beyond--a two-fold
increase in incidence of recurrence and an eightfold increase in incidence of progression. Hasui
and colleagues, as well as other authors, have proposed subdividing the stage T1 classification into
stages T1a and T1b, using the muscularis mucosa
as the dividing line. Unfortunately, the muscularis mucosa makes an unreliable point of reference, being discontinuous and often difficult to
identify; but there is growing evidence that tumor
penetration to this depth does have important implications, such as a higher risk of later detrusor
muscle invasion (Epstein, Amin, Reuter, et al.,
1998; Holmng, Hedelin, Anderstrm, et al.,
1997). In addition, tumor infiltration of vascular

or lymphatic spaces may portend a poor outcome
if unequivocally present, but it is often difficult to
determine with certainty.
In a stage by itself, CIS (stage Tis) has been
defined as high-grade (anaplastic) carcinoma,
which, like stage Ta, is confined to the urothelium, but with a flat, disordered, nonpapillary configuration and a likelihood of being underdiagnosed (Epstein, Amin, Reuter, et al., 1998). CIS
can be focal, multifocal or diffuse. On cystoscopic examination, it usually appears as a slightly
raised, reddened patch of velvety mucosabut
often it is endoscopically invisible. Much about
this peculiar cancer is poorly understood, including its natural history and the mechanism by
which it spreads. The most ominous characteristic of CIS may be multicentricity (Koch and
Smith, 1996). Even when the extent of spread
seems limited, additional areas frequently exist
not only in other parts of the bladder, but in the
distal ureters, the urethra or the prostatic ducts.
Prostatic urethral biopsy may yield additional information in patients with diffuse CIS. If untreated, CIS is likely to progress to muscle-invasive
disease in a substantial percentage of patients
(Hudson and Herr, 1995).
Prognostic indicators
In addition to grade, the most clinically useful
factors for predicting recurrence and progression
in patients who present with non-muscle-invasive
disease are tumor stage, tumor size, number of tumors and the presence of CIS. Stage is particularly important. As reported previously (page 16),
the likelihood of progression to muscle-invasive
disease is much greater for T1 tumors than for Ta
tumors (Herr, 1997; Holmng, Hedelin,
Anderstrm, et al., 1997; Kiemeney, Witjes,
Heijbroek, et al., 1993; Prout, Barton, Griffin, et
al., 1992). Moreover, the likelihood of muscle invasion appears to be greater still for T1 tumors
that have penetrated beyond the muscularis mucosa (Epstein, Amin, Reuter, et al., 1998;
Holmng, Hedelin, Anderstrm, et al., 1997).
Other possible predictors of recurrence and/or
progression include DNA ploidy, blood group
antigens and various molecular markers. DNA
ploidy is measured by flow cytometry, often performed on tumor tissue embedded in paraffin.
Diploid tumor cells tend to be low grade and low
stage, indicating a favorable prognosis, whereas
tetraploid and aneuploid tumors have a greater
likelihood of progression and/or recurrence
(Gustafson, Tribukait and Esposti, 1982a, 1982b).
However, there is some question as to the independent prognostic value of ploidy over grade
alone (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,
x
such as ABO antigens and the Lewis antigen, has
been associated with an unfavorable prognosis in
some studies, but other studies have found no correlation 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 expression of the tumor-suppressor genes p53 and pRb
(see page 13), show considerable promise as
prognostic indicators for bladder cancer, especially for predicting aggressive tumor behavior
(Cordon-Cardo, 1998; Cote, Dunn, Chatterjee, et
al., 1998; Grossman, Liebert, Antelo, et al., 1998).
Reliable methods for clinical use of such markers
are still being developed.
Archived Document
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Grade classification
Numerous classification systems for grading

transitional cell carcinomas of the bladder have
been developed and published over the past few
decades. Although no single system has yet
emerged to win universal acceptance, the most
widely used systems all share important characteristics. In particular, they all tend to group bladder carcinomas similarly into three principal
grades based mainly on degree of anaplasia
(Bergkvist, Ljungqvist and Moberger, 1965;
Epstein, Amin, Reuter, et al., 1998; Koss, 1975).
The three gradeslow (grade 1), intermediate
(grade 2) and high (grade 3)correspond respectively to well differentiated, moderately differentiated and poorly differentiated tumors. Grade has
been shown to be a highly predictive indicator of
future tumor behavior with regard to both recurrence and progression.
Page 17
Treatment alternatives
In most cases of non-muscle-invasive bladder
cancer, tumors are treated initially with TURBT,
fulguration and/or laser therapy. A careful cystoscopic examination of all bladder surfaces, the
urethra and the prostate precedes resection (Koch
and Smith, 1996). Findings with prognostic significance are noted during this examination.
Noted, for example, is the position of tumors with
reference to the bladder neck and ureteral orifices;
tumor configuration, such as whether tumors are
papillary or sessile; and estimates of the number
of tumors and their sizes. Following resection of
all visible tumors, adjuvant intravesical
chemotherapy or intravesical immunotherapy is
commonly used to prevent recurrences (Messing
Resection and fulguration

of bladder tumors
However, tissue samples need to be obtained

beforehand by means of cold-cup biopsies to determine tumor grade. Assessing depth of tumor
penetration to determine stage is more problematic
with laser therapy. Appropriate patients for this
therapy have papillary, low-grade tumors and a
history of low-grade, low-stage tumors (Koch and
Smith, 1996).
Intravesical chemotherapy
and immunotherapy
Intravesical chemotherapy or immunotherapy
is most often used as adjuvant treatment to prevent
tumor recurrence following the transurethral resection of primary non-muscle-invasive bladder tumors, including possible recurrence because of iatrogenic implantation of tumor cells. Intravesical
therapy is also used to treat known existing tumors
in cases of CIS, which frequently cannot be treated adequately by resection or fulguration because
of diffuse involvement. Intravesical therapy has
become the preferred primary treatment for CIS
(Messing and Catalona, 1998). In addition, an
agent intended for prophylaxis may in fact be
treating undetected existing disease. Basic properties of the chief intravesical agents currently available are described later in this chapter. Chapter 3
contains an evidence-based comparative outcomes
analysis of most of these agents.
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As stated on page 15, a TURBT has two main
purposes: 1) complete eradication of all visible tumors; and 2) tissue resection for pathologic evaluation to determine grade and stage. Fulguration
may be used on small lesions, but tissue still needs
to be obtained to determine grade and stage at
time of initial presentation.
Koch and Smith (1996), in describing surgical
technique, recommend use of a continuous flow
resectoscope, which allows a relatively constant
volume in the bladder and thus minimizes movement of tumors away from and toward the resectoscope. When a tumor is removed, a separate biopsy can be taken at the base with the resecting loop.
After which, healthy-appearing muscle fibers
should be visible at the base. Necrotic-appearing
tissue implies an invasive carcinoma. The presence of fat implies a full-thickness bladder wall
defect.
Laser therapy
The Nd:YAG laser has so far proven to be the
most versatile wavelength for treating bladder cancer, but other wavelengths also have been used
(Koch and Smith, 1996; Smith, 1986). Results are
comparable to electrocautery resection, with little
difference in the recurrence rate (Beisland and
Seland, 1986).
Page 18
Thiotepa
Introduced in 1961, thiotepa is the oldest and

one of the least expensive of the intravesical
drugs. It is an alkylating agent that acts by crosslinking nucleic acid. It is administered in doses
ranging from 30 mg in 30 ml of sterile water or
saline to 60 mg in 60 ml of water or saline. The
lower dose appears to be as effective as the higher
one in a comparative study, but the concentrations
in both were the same (Koontz, Prout, Smith, et
al., 1981). The usual regimen consists of six to
eight weekly instillations followed by monthly instillations for one year. Thiotepa's low molecular
weight of 189 allows partial absorption through
the urothelium, with possible systemic toxicity.
There is a risk of myelosuppression especially at
the 60 mg dose level. White cell and platelet
counts are obtained before each instillation, and
treatment is delayed if necessary.
Mitomycin C
Mitomycin C is an antibiotic that works by inhibiting DNA synthesis. Because of its moderately high molecular weight of 329, there are few
problems with transurothelial absorption, and
myelosuppression is rare. Dosage varies from 20
mg to 60 mg per instillation; a commonly used
dose is 40 mg in 40 ml of saline or sterile water,
administered weekly for eight weeks followed by
monthly instillations for one year. Mitomycin C
is a very expensive agent. There is evidence that
multiple follow-up instillations are only slightly
more beneficial than just a single instillation administered within 24 hours after TURBT (Tolley,
Parmar, Grigor, et al., 1996).
Doxorubicin (adriamycin) and epirubicin
Doxorubicin is an anthracycline antibiotic able

to bind to DNA and inhibit synthesis. It is not
cell cycle specific, but appears to be most cytotoxic in the S phase. Its molecular weight of 580
is high, and absorption and systemic toxicity are
extremely rare. Doses vary widely, from 10 mg
to 100 mg, in instillation schedules that range
from three times a week to once a month.
Epirubicin, a derivative of doxorubicin, is an anthracycline analog that appears to be somewhat
better tolerated than doxorubicin (Kurth, Vijgh,
Kate, et al., 1991). A study by the European
Organization for Research and Treatment of
Cancer supports the possibility that epirubicin
may be most effective against cystoscopically invisible tumors existing at the time of resection
(Oosterlinck, Kurth, Schroder, et al., 1993). As of
1999, epirubicin was not available in the United
States, and the panel did not formally analyze
outcomes data for this drug.
1990; DeJager, Guinan, Lamm, et al., 1991; Herr,

Schwalb, Zhang, et al., 1995; Lamm, Blumenstein, Crawford, et al., 1995).
Several substrains of BCG have been used, including the Pasteur, Armand-Frappier, Tice,
Evans, Tokyo, Dutch (RIVM) and Connaught
strains. Although all of them are derived from
one original strain developed at the Pasteur
Institute, the viability of BCG organisms per milligram of vaccine may vary with different substrains and from lot to lot within the same substrain (Cummings, Hargreave, Webb, et al., 1989;
Kelley, Ratliff, Catalona, et al., 1985; Messing
BCG's mechanism of action is not fully understood, but it clearly involves a strong inflammatory immunologic host response with release of interleukins and other cytokines (Morales, Eidinger
and Bruce, 1976; Ratliff, Haaff and Catalona,
1986). Most patients develop this inflammatory
immunologic response during a typical course of
six weekly instillations. Some patients do not require that many instillations; other patients require more than six (Brosman, 1992; Eure,
Cundiff and Shellhammer, 1992; Haaff, Dresner,
Ratliff, et al., 1986). Optimal dosing and instillation schedules have not yet been established. The
most common side effects of BCG are cystitis and
hematuria. The most serious is BCG sepsis.
BCG therapy is contraindicated in patients who
are immunocompromised, who have liver disease
or a history of tuberculosis. Also, there is a
greater potential for sepsis if the drug is administered too soon after TURBT or traumatic catheterization.
Archived Document
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Bacillus Calmette-Gurin (BCG)
BCG, a live attenuated strain of

Mycobacterium bovis, was first used as a tuberculosis vaccine. Its now widespread use as intravesical immunotherapy for management of noninvasive bladder cancer began in the 1970s, heralded
by the 1976 Morales study (Morales, Eidinger
and Bruce, 1976). BCG has since become a firstline treatment for CIS and has been shown to be
effective as prophylaxis to prevent bladder cancer
recurrences following TURBT (Cookson and
Sarosdy, 1992; Coplen, Marcus, Myers, et al.,
Valrubicin and Interferon
Valrubicin and interferon are two newer agents

for treating bladder cancer. Valrubicin, a semisynthetic analog of doxorubicin, has received
FDA approval for treatment of patients with CIS
who have not responded to BCG therapy and in
whom immediate cystectomy would be associated
with unacceptable morbidity or mortality. The
panel did not formally review clinical studies using valrubicin, but only about one of five patients
with BCG-refractory CIS was reported to have
had a complete response.
Interferons have antiproliferative, antiangiogenic and immunostimulatory properties; and recombinant interferon alpha-2b has been effective
Page 19
for treating CIS in some clinical trials (Glashan,

1990). Interferon side effects tend to be minimal.
However, as prophylaxis for noninvasive bladder
cancer, interferons may not be as effective as
BCG (Kalble, Beer and Staehler, 1994). More
clinical studies are needed before this is determined. Because not enough studies have been
published as yet, the panel did not have sufficient
outcomes evidence available to include interferon
in the analysis described in Chapter 3.
Follow-up
Two key questions regarding follow-up after
treatment for noninvasive bladder cancer are: 1)
how long should follow-up be continued and 2)
at what intensity? The classic follow-up protocol
consists of cystoscopic and cytologic examinations every three months for 18 to 24 months after the initial tumor, then every six months for the
following two years and then annually
(Fitzpatrick, 1993; Messing and Catalona, 1998).
The results of the first three-month cystoscopy
often predict the future recurrence pattern
(Fitzpatrick, West, Butler, et al., 1986). Less intense surveillance may be indicated if patients
had Ta papillary low-grade tumors that were
completely resected and if the results of the first
three-month cystoscopic examination were negative (Abel, 1993; Gulliford, Burney and
Petruckitch, 1993).
Bladder cancer, however, may recur even after
long, disease-free intervals, indicating a need for
lifelong surveillance (Cookson, Herr, Zhang, et
al., 1997; Messing and Catalona, 1998;
Thompson, Campbell, Kramer, et al., 1993).
Surveillance includes periodic upper-tract imaging, especially if the treated cancer was CIS, other high-grade tumors or tumors located near a
ureteral orifice (Cookson, Herr, Zhang, et al.,
1997; Miller, Eure and Schellhammer, 1993).
The new urine assay
tests described
on page
TM
TM
15, such as BTA stat , BTA TRAK and NMP22, may ultimately prove sensitive enough to replace a portion of the routine follow-up cystoscopic examinations.
Archived Document
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Page 20
Chapter 3: Outcomes analysis for treatments of

non-muscle-invasive bladder cancer
The AUA Bladder Cancer Clinical Guidelines
Panel analyzed available outcomes data for both
the potential benefits and the potential complications of alternative approaches to treating nonmuscle-invasive bladder cancer. Results of the
panel's analysis are summarized as probability
estimates in the comparative outcomes tables on
pages 23-24 of this chapter. The data extraction
and evidence combination processes that produced the probability estimates are described
on pages 10-11 of Chapter 1. The raw data are
in a technical supplement to this report,
Evidence Working Papers, which is available
from the AUA.
Types of outcomes include direct outcomes
that are experienced by the patient firsthand and
that affect the patient directly. Some, such as dysuria or an increase in urinary frequency, may be
short-term side effects of treatment. Others, such
as urinary frequency due to bladder contraction
from scarring, may occur on a continuing basis
long after treatment has been completed. Direct
outcomes are often of great importance to the patient simply because they impact them. By contrast, asymptomatic tumor recurrence, although an
extremely important outcome, may not necessarily seem important to the patient because it is not
experienced directly. From the patient's standpoint, however, it is important as a proxy for future adverse events such as the likelihood of repeated treatment and possibly more aggressive
treatments such as radical cystectomy.
probability. It should be noted that "median" in

these tables is the median of the probability distribution resulting from FAST*PRO meta-analysis
(Eddy, Hasselblad and Shachter, 1990); it is not
the median of an array of individual study results.
The G/P columns in Table 5 show (G) the number
of patient groups for a given outcome and (P) the
total number of patients in those groups. A cell
marked "No Data" indicates insufficient extractable data for a given outcome.
For assessing potential benefits and possible
adverse effects of interventions for treatment of
non-muscle-invasive bladder cancer, the panel determined that the following outcomes are the most
important:
Probability of tumor recurrence;
Risk for tumor progression; and
Complications of treatment.
Archived Document
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The outcomes tables

The outcomes tables (Tables 2-5) on pages 2324 summarize results following Confidence
Profile (FAST*PRO ) meta-analyses of combined
outcomes data from the bladder cancer treatment
literature, as described in Chapter 1. Results are
displayed in the tables as probability estimates.
In most cases, a 95-percent confidence interval is
reported along with a median estimate of the
TM
Recurrence
Non-muscle-invasive bladder cancer has a high

rate of new tumor formation within the bladder.
New tumor formations following treatment are
generally termed "recurrences" (although in many
cases they might be more accurately termed "reoccurrences"). Recurrent tumors may have progressed to a higher grade and/or higher stage, but
most recurrences of non-muscle-invasive bladder
cancer (especially of initially diagnosed grade 1,
stage Ta disease) are not muscle invasive and carry relatively little risk of metastasis or death.
However, recurrent disease will likely require a
repetition of therapy.
For the patient and physician assessing treatment alternatives, the probability of recurrence
following treatment is obviously an important outcome to consider. The first two outcomes tables,
Tables 2 and 3 on page 23, display comparative
differences in the estimated probability of recurrence following use of intravesical agents as adjuvant therapy after transurethral resection of bladder tumor (TURBT). The comparative differences
Page 21
in Table 2 are statistically significant; those in

Table 3 are not.
Each intravesical agent in the tables is compared to TURBT alone and to each of the other
agents, based on data from multi-armed randomized controlled trials (RCTs). All of the agents,
when used as adjuvant therapy after TURBT, are
shown to result in a lower estimated probability of
recurrence 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 versus the use of TURBT alone. With a median difference of 30 percent (95% CI 19-39 percent), the
table shows a significantly lower estimated probability of recurrence in favor of TURBT plus BCG.
(All median differences in Tables 2-4 are in favor
of the first intervention listed in each pair.)
The last column of Table 2 displays another
way of showing the results. "Number needed to
treat" (NNT) is the number of patients who must
be treated with the superior treatment of each pair
in order to reduce by one the estimated number of
patients with recurrences. For example, in
"TURBT plus doxorubicin versus TURBT alone,"
the NNT is 10. Thus, if 10 patients are treated
with the superior treatment of this pair, TURBT
plus doxorubicin, and another 10 patients with
TURBT alone, one less recurrence can be expected in the patient group receiving TURBT plus
doxorubicin.
The recurrence tables are further discussed on
pages 25-26 of this chapter. The basic methodology is described on page 11 of Chapter 1.
Complications
of treatment
After review and evaluation of all possible adverse outcomes from treatment for non-muscle-invasive bladder cancer, the panel grouped these
outcomes into three general categories: 1) Local
bladder symptoms; 2) Systemic symptoms; and 3)
Other. Their estimated probabilities for occurrence with particular treatments are displayed in
Table 5 on page 24.
Local bladder symptoms are the most common
adverse outcomes experienced by patients undergoing treatment for non-muscle-invasive bladder
cancer. The most frequently observed immediate
symptoms are irritative lower urinary tract problems including dysuria, frequency/nocturia, urgency, pain and cramping and passing of debris in
the urine, including blood or clots. Patients may
also experience bacterial cystitis, urinary incontinence or bladder perforation. Long-term adverse
outcomes related to local bladder symptoms include bladder contracture.
Although local bladder symptoms can be severe, systemic symptoms are more threatening.
These include flu-like symptoms such as arthralgia, fever, chills and malaise. Systemic infectious
complications may also result from treatment.
Among these problems are pulmonary or hepatic
changes, pneumonia, pneumonitis, hepatitis, epididymitis, prostatitis and urethral infection. Also,
patients might experience nausea, vomiting, rash
or indirect adverse outcomes such as myelosuppression.
Some patients might experience adverse outcomes severe enough that the intervention must be
interrupted or even stopped entirely. In rare circumstances, deaths have been reported with interventions used for non-muscle-invasive bladder
cancer, although the frequency of death is not
generally recorded.
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Progression
The risk for progression of non-muscleinvasive bladder cancer, depends on a number of
factors, including size and number of tumors
and, especially, their grade and stage. Lowgrade, stage Ta tumors, although they have a
tendency to recur, have a low risk for progression to muscle invasion, whereas progression
rates of 30-50 percent have been reported for
high-grade, stage T1 disease (Herr, 1997).
Most of the available studies reporting results
of treatment do not adequately address the risk for
long-term progression, notwithstanding the importance of this outcome. Consequently, the results
displayed in Table 4 (page 23) are based on fewer
RCTs than were available for calculating the results shown in Table 2-3 (page 23).
Page 22
Cost, inconvenience and

quality-of-life issues
Cost, inconvenience and quality-of-life issues
are certainly important to patients. Few meaningful data are readily available from the literature to
address these issues for non-muscle-invasive bladder cancer, and for the most part, these are areas
in need of future research. Nevertheless, in regard
to cost, panel members knew from their own experiences that there are major differences between
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Page 23
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Page 24
Table 6:
Sample costs of intravesical agents
Intravesical
Agent
Mitomycin C (2 mg vial)
Thiotepa (15 mg vial)
BCG (1 ampule)
Doxorubicin (2 mg/ml;
25 ml vial=50 mg)
Patient
Charge
$385.20
253.55
137.75
83.75
intravesical agents, usually with mitomycin C being by far the most expensive. Table 6 shows
comparative 1999 patient charges from a university-based hospital setting of one of the panel members. Generalization is not possible, however, as
costs of intravesical agents may vary substantially
both regionally and from institution to institution.
Variability of
outcomes data
3. The outcomes measured were reported in various ways. Recurrence rates were reported
variably as number of patients with recurrences, number of recurrences, number of occurrences per unit of time or time of first recurrence. For progression, some studies reported patients with different types of
progression without indicating whether there
was overlap among these patients.
4. The follow-up times varied significantly, both
within and between studies.
5. In some studies, patients unsuccessful with
one treatment were crossed over to take other
treatments.
Despite these limitations, the panel found the
analysis useful. One important conclusion the
panel drew from the data evaluation was that
treatment-related reductions in the probability of
recurrence were detected within the first year of
observation in most studies. Furthermore, the observed reductions were carried forward into subsequent years; that is, differences observed within
the first year remained stable over time.
Archived Document
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There are many retrospective studies reporting
outcomes of interventions for non-muscle-invasive
bladder cancer. However, RCTs are the most useful for analysis, eliminating many of the problems
encountered with uncontrolled or poorly controlled studies. Accordingly, the panel decided to
extract data only from RCTs for comparison of
treatments with regard to lowering the probability
of recurrence and progression.
Yet, even with the advantage of having RCTs
available for analysis, the panel found the evaluation process complicated for the following reasons:
1. The patients in the different studies varied by
stage, grade, prior treatments and tumor history, presence or absence of CIS and length of
time with bladder cancer. The patient mix
was generally undifferentiated, and the studies
did not break down outcomes relative to patient characteristics.
2. The treatment protocols differed in the number
and timing of medication instillations, doses
and frequency. However, even where different
dosing regimens were compared within or between studies, no significant outcome differences were noted for different treatment regimens (see Table C-1 in Appendix C).
Outcomes summary:
recurrence and progression
Thiotepa after TURBT was compared with

TURBT alone in 10 RCTs. Meta-analysis of
these studies demonstrated that thiotepa after
TURBT lowers the probability of recurrence more
than TURBT alone (Table 2, page 23). The median estimate of the difference is approximately 19
percent (95% CI 9-28 percent). However, comparative evaluation of these two treatments with
regard to progression (Table 4, page 23) showed
no difference between them.
The administration of BCG after TURBT was
compared with TURBT alone in six studies. As
noted previously (page 22), the meta-analysis
yielded a 30 percent reduction in the probability
of recurrence using the BCG intervention (95%
CI 19-39 percent). For progression (Table 4, page
23), the two treatments were compared in three
studies, yielding an estimated difference of 8 percent in favor of BCG (95% CI -0.2-15 percent).
However, with the confidence interval overlapping
zero, this difference is not statistically significant.
Page 25
Mitomycin C administration after TURBT

yielded a reduction in recurrence probability of
approximately 15 percent (95% CI 7-22 percent)
over TURBT alone. For preventing progression,
there was no benefit to mitomycin C administration after TURBT versus TURBT alone.
The administration of doxorubicin after
TURBT yielded a reduction of 10 percent in probability of recurrence (95% CI 2-17 percent) over
TURBT alone. There was no evident reduction in
probability of progression using doxorubicin after
TURBT versus TURBT alone.
Three studies compared the administration of
BCG versus thiotepa, each after TURBT. These
studies showed a clear benefit to BCG over
thiotepa with a median difference in recurrence
probability of 30 percent (95% CI 10-47 percent).
Doxorubicin was also compared with BCG,
each after TURBT, in four studies. The advantage
went to BCG over doxorubicin in reduction of recurrence probability, with a median difference of
23 percent (95% CI 13-32 percent).
Other intervention comparisons (Table 3, page
23) of mitomycin C versus thiotepa, doxorubicin
versus thiotepa, mitomycin C versus BCG and
mitomycin C versus doxorubicin yielded no statistically significant advantage for one treatment
over another in reducing the probability of recurrence.
A comparative assessment of the probability of
progression reduction with the various treatment
modalities showed no evident differences among
them in the RCTs (Table 4, page 23).
summarized in the literature. Some studies classify complications such as frequency and nocturia
separately, whereas other studies combine them
under single headings. Likewise, cutoff points for
significant fever vary from study to study, and
some studies do not include a definition of fever.
Thus, the data analysis required some judgment,
and the combinations of data required some arbitrary assignments by the data extractors and the
panel. The panel specifically addressed outliers
and made decisions whether to accept the data at
face value or to exclude these data in situations
where they could not be accurately or usefully
categorized.
Some specific complications are not included
in all studies. This might have been because they
never occurred or because they were never tracked
or recorded, depending upon the protocol structure. Such arbitrary deletions in the studies can
affect the overall analysis of the complications.
However, there is no way to account for these differences in reporting. It is important to recognize
that some complications do not apply to each of
the treatment modalities, and that each intervention has its own unique spectrum of complications
as well as complications in common with other
interventions. For example, almost all of the interventions induce some problem with local bladder symptoms, but only BCG is likely to induce
evidence of systemic infection.
The panel decided to delete certain complications entirely from the analysis. Among these
were granulomas, bladder mucosal erythema and
hypotension. Such complications were deleted
because they had no clinical significance to the
patient in the short or long term, or were so unusual that they would not affect treatment decisions by patients or recommendations by the
physician. The complication of urethral stricture
was deleted from the complications listing because it was reported in so few patients.
Other complications were combined to ease
interpretation. An example of this is epididymitis
being included together with prostatitis and urethral infections.
Certain review articles were of value for providing data about complications. However, such
articles were examined carefully to ensure that
there was no duplication of data from other studies in the review that would overweight certain
complications.
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Outcomes summary:
treatment complications
The probability estimates for complications
from each of the interventions are displayed in
Table 5 on page 24. The table shows median estimates of the probability of the complications occurring, along with 95-percent confidence intervals. The complications data were obtained from
the randomized controlled trials as well as from
the non-randomized trials. The panel decided
that, for complications, the data reported in all
studies were of value in assessing frequency of
complications for a given intervention, regardless
of whether the patients were involved in RCTs.
A major difficulty in listing complications
stems from the familiar problem of how data are
Page 26
Death associated with any of the interventions

for non-muscle-invasive bladder cancer is extremely unusual. There are certainly risks associated with the anesthesia and surgical procedure
for TURBT. Overall, however, in the panel's expert opinion, the risk of death would be much less
than 1 percent for each of the interventions. The
panel believes that such a low rate is not likely to
be a significant factor in the selection of therapy
by a patient or in its recommendation by a physician.
Local bladder effects occur with the greatest
frequency and are direct outcomes felt by patients. Thus, they are the adverse outcomes most
likely to govern a patient's decision to select one

intervention over another. Systemic complications affect a minority of patients, yet can be quite
profound with BCG therapy. The risk of BCG
sepsis may be a factor that influences patient preferences or physician recommendations.
In general, the balance between likely beneficial outcomes (such as reduced recurrence rates)
and likely adverse outcomes (such as local complications) will dictate which intervention a patient will select for treatment of non-muscle-invasive bladder cancer.
Archived Document
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Page 27
Chapter 4: Recommendations for management of

non-muscle-invasive bladder cancer
The AUA Bladder Cancer Clinical Guidelines
Panel generated the recommendations in this
chapter based upon analysis of comparative outcomes data from both randomized controlled trials (RCTs) and clinical series and upon expert
opinion. The recommendations apply to treatment of patients with non-muscle-invasive, transitional cell carcinoma of the bladder, including
CIS (CIS) as well as stages Ta and T1 tumors.
The panel evaluated comparative data for the following treatment methods in particular:
Transurethral resection of bladder tumor
(TURBT);
TURBT plus thiotepa;
TURBT plus doxorubicin;
TURBT plus mitomycin C;
TURBT plus bacillus Calmette-Gurin (BCG).
3. Option: A policy is considered an option if 1)

the health and economic outcomes of the interventions are not sufficiently well-known to
permit meaningful decisions, 2) preferences
among the outcomes are not known, 3) patients' preferences are divided among the alternative interventions and/or 4) patients are indifferent about the alternative interventions.
A standard has the least flexibility. A guideline has significantly more flexibility, and options
are the most flexible. In this report, the terms are
used to indicate the strength of the recommendations. A recommendation was labeled a standard,
for example, if the panel concluded that it should
be followed by virtually all health care providers
for virtually all patients. A guideline generally
denotes a recommendation supported by objective
data but not with sufficient strength to warrant a
designation of standard. An option in this report
would include treatments for which there appears
to be equal support in the literature or ones for
which there is insufficient published information
to support a stronger recommendation. Also, as
noted in the above definition, options can exist because of insufficient evidence or because patient
preferences are divided. In the latter case particularly, the panel considered it important to take into account likely preferences of individual patients with regard to health outcomes when selecting from among alternative interventions.
Archived Document
For Reference Only
Treatment policies:
levels of flexibility
As explained in Chapter 1 (page 9), panel recommendations were graded according to three
levels of flexibility as determined by strength of
evidence and the expected amount of variation in
patient preferences. The definitions of these three
levels of flexibility are repeated as follows from
Chapter 1:
1. Standard: A treatment policy is considered a
standard if the health and economic outcomes
of the alternative interventions are sufficiently
well-known to permit meaningful decisions
and there is virtual unanimity about which intervention is preferred.
2. Guideline: A policy is considered a guideline
if 1) the health and economic outcomes of the
interventions are sufficiently well-known to
permit meaningful decisions and 2) an appreciable but not unanimous majority agree on
which intervention is preferred.
Page 28
Index patients
The specific types of patients to whom the
panel's recommendations apply are termed index
patients. In recognition of the differences in decision making that occur depending upon patient
circumstances, the panel defined three different
index patients:
Index Patient No. 1: A patient who presents
with an abnormal growth on the urothelium, but
who has not yet been diagnosed with bladder cancer;
Index Patient No. 2: A patient with established bladder cancer of any grade, stage Ta or
T1, with or without CIS, who has not had prior

intravesical therapy; and
Index Patient No. 3: A patient with CIS or
high-grade T1 cancer who has had at least one
course of intravesical therapy.
Treatment
recommendations
Recommendation
for all index patients
Standard: Physicians should discuss with the patient the treatment options and the benefits and
harms, including side effects, of intravesical treatment, especially those side effects associated with
a particular agent.
This recommendation is based on the panel's

expert opinion. Although all of the adjuvant treatments studied decrease the recurrence probability
of bladder cancer when they are compared to
TURBT alone, the published literature does not
unequivocally support the conclusion that the rate
of progression to muscle-invasive disease is altered. Patients contemplating intravesical therapy
should consider information about all expected
outcomes, including the possible side effects of
therapy. All of the treatments have in common
some side effects, especially those related to bladder irritation; other side effects are either unique
or peculiar to a particular drug. The incidence of
serious or life-threatening side effects with any of
the treatments is low, as shown in Table 5 (page
24); the panel is aware of reports documenting
systemic infection or even death from BCG sepsis
in rare circumstances.
In addition, there is little information defining
the optimal dose, number and timing of instillations or the influence of long-term maintenance
therapy. Randomized studies supporting the use
of maintenance BCG therapy have been conducted, but the panel excluded them because their results have been reported only in abstract form.
Other trials would appear to support a role for
maintenance therapy.
Recommendation
for Index Patient No. 1
A patient who presents with an abnormal
growth on the urothelium, but who has not yet
been diagnosed with bladder cancer.
.
Standard: If the patient does not have an established histologic diagnosis, a biopsy should be obtained for pathologic analysis
Although urine cytology and other novel tumor markers, as discussed in Chapter 2 (page 15),
can provide suggestive evidence of bladder cancer, the definitive diagnosis is established by
pathologic examination of tissue removed by
TURBT or biopsy. Transitional cell carcinoma of
the bladder often has a characteristic appearance,
but other conditions can mimic the gross appearance of bladder cancer. It is important, therefore,
to prove by microscopic analysis that gross abnormalities are from transitional cell carcinoma.
Intravesical immunotherapy or chemotherapy
should not be used in the absence of a histologic
diagnosis.
Archived Document
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Recommendations for
Index Patient No. 2
A patient with established bladder cancer of

any grade, stage Ta or T1, with or without CIS,
who has not had prior intravesical therapy.
Standard: Complete eradication of all visible tumors should be performed if surgically feasible
and if the patient's medical condition permits.
In a patient with known bladder cancer, endoscopic ablation of all visible tumors should be
performed. This can be accomplished with electrocautery resection, fulguration or application of
laser energy. Sometimes, the extent of disease or
the location of the lesions may preclude complete
eradication. Also, co-morbid conditions must be
considered and may occasionally influence a decision about whether to attempt endoscopic removal
of bladder tumors. This recommendation is based
on the panel's expert opinion.
Page 29
Option: Surgical eradication can be performed by

one of several methods including electrocautery resection, fulguration or laser ablation.
Option: Cystectomy may be considered for initial

therapy in some patients with CIS or T1 tumors.
For bladder cancers that do not invade the detrusor muscle, several methods for tumor destruction provide apparently comparable results.
Adequate tissue should be available for determination of pathologic stage, but endoscopic ablative techniques may not permit submission of all
material for histologic evaluation. This recommendation is based on the panel's expert opinion.
Because there is risk of progression to muscleinvasive disease even after intravesical therapy,
cystectomy may be considered as an initial treatment option in certain cases. Among factors associated with increased risk of progression are large
tumor size, high grade, tumor location in a site
poorly accessible to complete resection, diffuse
disease, infiltration of lymphatic or vascular
spaces and prostatic urethral involvement. This
recommendation is based on the panel's expert
opinion.
Option: Adjuvant intravesical chemotherapy or

immunotherapy is an option for treatment after endoscopic removal of low-grade Ta bladder cancers.
Recommendations for
Index Patient No. 3
A recommendation stronger than an option for
this group of patients (Index Patient No. 2) cannot
be supported by the evidence in the outcomes tables. Most studies combined patients who had
low-grade stage Ta tumors with patients who had
T1 lesions and higher-grade cancers, creating difficulty in extracting information about this subgroup. However, based upon panel opinion, many
patients with low-grade Ta tumors do not require
adjuvant intravesical therapy. There is a low risk
of disease progression (overall less than 10 percent) in this group and little evidence that adjuvant therapy affects the progression rate. For
rapidly recurring low-grade Ta tumors, adjuvant
therapy may be useful. The outcomes tables show
a decreased recurrence probability for all the intravesical therapies studied, compared to TURBT
alone.
A patient with CIS or high-grade T1 cancer

who has had at least one course of intravesical
therapy.
Archived Document
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Guideline: Intravesical instillation of either BCG
or mitomycin C is recommended for treatment of
CIS and for treatment after endoscopic removal of
T1 tumors and high-grade Ta tumors.
Based on evidence from the literature and panel opinion, both BCG and mitomycin C are superior to doxorubicin or thiotepa for reducing recurrence of these tumors. There is no evidence that
any intravesical therapy affects the ultimate rate
of progression to muscle-invasive disease.
Page 30
Option: Cystectomy may be considered as an option for patients with CIS or high-grade T1 cancers
that have persisted or recurred after an initial intravesical treatment.
This recommendation is based upon panel

opinion rather than evidence in the outcomes tables. However, other data in the literature do
show a substantial risk of progression to muscleinvasive cancer in patients with diffuse CIS and
high-grade T1 tumors (Herr, 1997; Hudson and
Herr, 1995; Kiemeney, Witjes, Heijbroek, et al.,
1993). It is not certain whether intravesical therapy alters this risk of progression. Thus, there are
some patients with symptomatic disease or highgrade tumors who may want to move directly to
cystectomy. Physicians should present specific
information about the risks of cystectomy and
methods for urinary reconstruction to patients
who are contemplating bladder removal.
Option: Further intravesical therapy may be considered as an option for patients with CIS or highgrade T1 cancers that have persisted or recurred after an initial intravesical treatment.
This recommendation is also based on the panel's expert opinion. Optimal dosing schemes for
intravesical chemotherapy and immunotherapy
have not been established, but weekly instillations
for at least six weeks are used most often. There
is additional evidence showing that some patients
will respond to second induction regimens, particularly with BCG. Repeat intravesical therapy
may be appropriate in patients who develop a late
recurrence after previous complete response to an
intravesical agent. Data are insufficient, however,
to allow conclusions about the role of drug combination regimens or alternating therapies. Also,
as of this writing, there are preliminary data about
use of valrubicin for this patient. The panel did
not formally review clinical studies for valrubicin.
Areas for future

research
recurrence (such as tumor size, number or a history

of frequent recurrences) may not necessarily predict progression.
Tumor stage at the time of presentation is an
important factor. Only a small percentage of patients with Ta tumors show progression. A T1 lesion, especially when high grade or with associated CIS, places the patient at much greater risk.
Recent efforts to substratify stage T1 cancer based
upon depth of infiltration must be further clarified.
The risk and significance of urothelial carcinoma outside the bladder must be further determined. Especially in patients with CIS, urothelial
cancers within the ureter or intrarenal collecting
system may occur at a frequency far exceeding
the previously accepted predictions of occurrence
(about 5 percent of patients). Periodic monitoring
of the upper urinary tract is necessary, and studies
are needed to better determine the efficacy of administration of chemotherapy or immunotherapy
to the upper urinary tract. Prostatic urethral involvement may occur, especially in patients with
CIS, even in the absence of identifiable disease
within the bladder.
Advances in molecular biology and genetics
have identified a number of markers that may be
useful for both detection and prognosis of bladder
cancer. These may allow identification of patients
at high risk for recurrence or progression and
could alter time-honored regimens for follow-up
of patients with bladder cancer. Historically, cystoscopic bladder surveillance has been performed
every three months for at least a year and with declining frequency after that point in patients with
stage Ta or T1 bladder cancer. Prognostic markers may in the future allow follow-up surveillance
to be customized to individual patient risk.
The role of treatment regimens using alternating or combined drugs must be determined. Early
instillation of drugs, sometimes immediately after
TURBT, may improve results, but randomized
studies are needed to explore this possibility.
Also, as new drugs or treatment strategies emerge,
adequate studies to determine their role must be
performed.
Archived Document
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Large, often multicenter RCTs have helped define the roles of TURBT and intravesical therapy
for the treatment of bladder cancer. Much additional work is needed, however. Many studies
have focused primarily on recurrence, whereas
progression may be an outcome of more significance to the patient. Many of the treatment
schemes, including those for dose and frequency,
have been chosen arbitrarily. Studies have frequently combined patients who have substantially
different tumor parameters, which limits the ability to analyze selected patient groups.
Many patients with CIS or stage Ta/T1 bladder
cancer never develop disease progression or muscle-invasive cancer. Better methods are needed,
however, to identify those more likely to develop
disease progression.
The prognostic significance of tumor grade is
well recognized, as there is a clear increase in risk
of progression with higher-grade tumors. DNA
ploidy status, determined by flow cystometry, has
not provided useful information independent of
tumor grade in most studies. Factors that predict
Page 31
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Page 32
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Table A-1 Articles extracted by Papyrus reference number
Appendix A Data Presentation
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Appendix B Data extraction form
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Appendix C: Data analysis

Table C-1 Comparative data from six BCG studies
Study
Interventions
Patients
Results
Luftenegger, 1996
BCG (Pasteur) 120 mg

for six weeks with and
without intradermal
BCG
78 patients without intradermal, 76 patients with
No difference in recurrence at 5 year follow-up,

p=.61
Martinez-Pineiro, 1995
BCG (Connaught) 81mg

for 6 weeks followed by
biweekly for 12 weeks
vs. 27mg for the same
schedule
204 patients, high dose

210 patients, low dose
followed 18 months
Recurrence:
37 high dose
41 low dose
Progression:
5 high dose
10 low dose
Differences not stat. significant at p=.05
Archived Document
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Kaisary, 1987
BCG (Glaxo) 60 mg for

six weeks followed by
intradermal, vs. BCG
(Pasteur) 120 mg for the
same schedule
11 patients, Glaxo
10 patients, Pasteur
followed 18 months
9 recurrences, Glaxo
10 recurrences, Pasteur
Hudson, 1987
BCG (Pasteur) 120mg

for 6 weeks, vs. same
plus maintenance instillation every 3 months
21 patients, each group

(note that 19 others in
each group were lost to
follow-up or excluded
due to early recurrence)
Mean follow-up 16 mo.
Recurrence:
6 in non-maintenance group
5 in maintenance group
Badalament, 1987
BCG (Pasteur) 120mg

for six weeks vs. same
schedule plus maintenance instillation every
month
47 patients, maintenance
46 patients, non-maintenance, followed a mean
of 22 months
No difference in tumor reduction, p=.77, no difference in disease free interval,

p=.8, no difference in progression, p=.5
Pagano, 1995
BCG (Pasteur) 75mg vs.

BCG (Pasteur) 150mg
for 6 weeks
plus two year maintenance
90 patients, low dose

93 patients, high dose
Higher disease free interval

in low dose group
(p=.0009)-primarily in CIS
patients. Progression rates
the same in the two groups
(9%)
Each of the six studies in this table compared two groups of bladder cancer patients, all of whom were being treated
with BCG. The two groups differed in respective studies with regard to dosages administered, route of administration (with and without intradermal boosters), schedules and types of BCG strains yet outcomes did not differ significantly. Results are summarized for each study in the fourth column on the right.
Page 56
Tables C-2 and C-3: Articles Analyzed for Recurrence and Progression Data
R ec u r ren c e
BCG vs TURBT
BCG vs. Thiotepa
Mitomycin C vs. BCG
Mitomycin C vs. BCG CIS
Lamm et al., 1981

Pagano et al., 1991
Sarosdy and Lamm, 1989
Krege et al., 1996
Lamm, 1985
Melekos et al., 1993
Brosman, 1982
Rodrigues and Lemos, 1983
Martinez-Pineiro et al., 1990
Debruyne et al., 1988

Krege et al., 1996
Lundholm et al., 1996
Vegt et al., 1995
Debruyne et al., 1989
Lamm et al., 1995
Lamm et al., 1995

Vegt et al., 1995
Rintala et al., 1989
BCG vs Doxorubicin
Thiotepa vs. TURBT
Thiotepa vs. Mitomycin C
Thiotepa vs. Doxorubicin

Lamm et al., 1991
Lamm et al., 1989
Schulman et al. 1982

Koontz et al., 1981
Byar and Blackard, 1977
Hirao et al., 1987
Netto et al., 1983
Anonymous, 1985
Prout et al., 1983
Hirao et al., 1992
Zincke et al., 1983
Asahi et al.,1980
Hirao et al., 1987

Flanigan et al., 1986
Horn et al., 1981

Hirao et al., 1987
Bouffioux et al., 1992
Zincke et al., 1983
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Mitomycin C vs. TURBT
Mitomycin C vs. Doxorubicin
Doxorubicin vs. TURBT
Hirao et al., 1987

Huland and Otto, 1983
Kim and Lee, 1989
Nujima et al., 1983
Krege et al., 1996
Tolley et al.,1996
Akaza et al., 1987
Hirao et al., 1987

Akaza et al., 1987
Silberberg and Zarrabi, 1987
Hirao et al., 1987

Nujima et al., 1983
Kurth et al., 1984
Akaza et al., 1987
Rubben et al., 1988
Kurth et al., 1997
P ro g res s io n
BCG vs. TURB
BCG vs. Thiotepa
Mitomycin C vs. BCG
Thiotepa vs. TURBT
Pagano et al., 1991

Melekos et al., 1993
Krege et al., 1996
Brosman, 1982
Martinez-Pineiro, et al.,
1990

Vegt et al., 1995
Lamm et al., 1995
Byar and Blackard, 1977

Hirao et al., 1987
Anonymous, 1985
Prout et al., 1983
Thiotepa vs. Mitomycin C
Mitomycin C vs. TURBT
Mitomycin C vs. Doxorubicin Doxorubicin vs. TURBT
Flanigan et al., 1986
Huland and Otto, 1983

Kim and Lee, 1989
Akaza et al., 1992
Akaza et al., 1992
Hirao et al., 1987

Akaza et al., 1992
Kurth et al., 1997
Page 57
Index
A
ABO antigen, as prognostic indicator, 17
Adenocarcinoma, 14
Adriamycin. See Doxorubicin
Arthralgia, as complication of treatment, 22
B
Bacillus Calmette-Gurin (BCG), as intravesical therapy
and CIS tumors, 5, 7, 19, 30
and recurrence following intravesical therapy, 3, 7, 8,
19, 22, 25-26, 29, 30, 31
and Ta tumors, 5, 7, 30
and T1 tumors, 5, 7, 30
compared to other intravesical therapies, 7, 20, 26, 30
complications from, 3, 6, 19, 26, 27, 29
cost of, 25
description of, 3, 19
dosage of, 8, 19, 31
outcomes of, 3, 7, 9, 12, 22, 23-24, 25
recommendations for use as treatment, 5, 7, 8, 28,
29, 30, 31
Bacterial cystitis, as complication of treatment, 22
BCG sepsis, 3, 6, 19, 27, 29
BCG. See Bacillus Calmette-Gurin
Biopsy of bladder cancer tumors, 2, 4, 6, 14, 29
Bladder contracture, as complication of treatment, 22
Bladder irritability
as complication of bladder cancer, 6, 29
as symptom of bladder cancer, 1, 14
Bladder perforation, as complication of treatment, 22
Blood group antigens, as prognostic indicators, 17
Blood in urine, as complication of treatment, 22
TM
BTA stat test, 15, 20
TM
BTA TRAK test, 15, 20
and treatment with BCG, 7, 19, 30

and treatment with mitomycin C, 7, 30
definition and description of, 1, 2, 13, 17
outcomes of treatment on, 3, 7, 11, 25
recommendations for treatment of, 3, 4, 5, 7, 28, 29,
30, 31
symptoms of, 14
Complications, 1, 3, 6, 11, 12, 26-27.
See also specific complications
Cost of treatment. See specific treatment methods
Cylophosphamide, in etiology of bladder cancer, 13
Cystectomy, 5, 7, 19, 20, 21, 30
Cystitis, as complication of treatment with BCG, 3, 19
Cystoscopy
as diagnostic tool, 1, 2, 14
and recurrence of tumors, 20, 31
Cytokeratin, 15
Cytologic assessment
and tumor grade, 15
as diagnostic tool, 1, 14, 15, 29
and recurrence of tumors, 15, 20
Archived Document
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C
Carcinoma in situ. See CIS tumors
Chemotherapy. See Intravesical therapy
Cigarette smoke, in etiology of bladder cancer, 13
CIS tumors
and cystectomy, 5, 7, 30
and cytologic assessment, 15, 20
and intravesical therapy, 2-3, 18, 19, 20, 28, 30, 31
and staging, 16, 17
Page 58
Death, 21, 22, 27

and BCG sepsis, 6, 29
Diagnostic evaluation, 1, 4, 6, 7, 14-15, 29
recommendations for, 4, 6, 7, 29
DNA ploidy status, as prognostic indicator, 17, 31
Doxorubicin
as intravesical therapy, 3, 7, 19, 22, 26, 28, 30
compared to other intravesical therapies, 7, 26
cost of, 25
dosage of, 19
outcomes of treatment, 3, 7, 9, 22, 23-24, 26, 28
recommendations for use as treatment, 7, 28
Dysuria
as complication of treatment, 21, 22
E
Electrocautery resection, 2, 4, 6, 18, 29, 30
Endoscopic ablation, recommendations for use, 6, 7,
29, 30
Epididymitis, 22, 26
Epirubicin, 19. See also Doxorubicin
F
Fever, as complication of treatment, 22, 26
Flow cystometry, 17, 31
Frequency of urination
as complication of treatment, 21, 22, 26
Fulguration, 2, 3, 4, 6, 18, 29, 30
H
Hematuria
as complication of treatment with BCG, 3, 19
Hepatitis, as complication of treatment, 22
I
Immunostaining techniques, 15
Immunotherapy. See Intravesical therapy
Index patient
definition of and criteria for, 3, 28-29
recommendations for, 4-8, 29-31
Industrial chemicals, in etiology of bladder cancer, 13
Interferon, 19-20
Intravesical drugs. See specific drugs
Intravesical therapy. See also specific intravesical
therapy treatment methods
as treatment after endoscopic ablation, 4, 5, 6, 29,
30-31
as treatment after TURBT, 2-3, 18, 19, 22, 23-24,
25-26, 28, 29
costs of individual therapies, 22, 25
dosage of, 6, 8, 18-19, 29, 31
limitations to outcomes, 11, 25
outcomes of treatment, 9, 11, 25-26
recommendations for use as treatment, 3, 4, 5, 7-8,
28, 29, 30, 31
cost of treatment, 3, 19, 25

outcomes of treatment, 3, 7, 9, 23-24, 26
recommendations for use as treatment, 5, 7, 19, 28, 30
Myelosuppression, as complication of treatment, 3, 18,
19, 22
N
Nausea, as complication of treatment, 22
Nd:YAG laser, 2, 5, 18
NMP-22, 15, 20
Nocturia, as complication of treatment, 22, 26
Nuclear matrix protein test. See NMP-22
O
Outcomes. See outcomes under specific treatment
methods
P
p53 and pRb tumor-suppressor genes, as cause of
bladder cancer, 13, 17
Pain, as complication of treatment, 22
Patient
appropriate for laser therapy, 2
informing about intravesical treatment, 4, 6, 29
spinal-cord injured patients, 14
Phenacetin-related analgesic abuse, as cause of bladder cancer, 13
Pneumonia or pneumonitis, as complication of treatment, 22
Progression of tumors
and cystectomy, 7
and intravesical therapy, 7, 12, 25, 26, 29, 30, 31
and prognostic indicators, 17, 31
and tumor grade, 2, 7, 16, 17, 22, 31
and TURBT followed by intravesical therapy, 6, 7,
25, 29
as outcome, 7, 9, 10, 11-12, 22, 25-26, 29, 30, 31
factors associated with increased risk, 7, 22, 30, 31
Prostatic urethral involvement, 17, 31
Prostatitis, as complication of treatment, 22, 26
Proto-oncogenes, in etiology of bladder cancer, 13
Pulmonary changes, as complication of treatment, 22
Archived Document
For Reference Only
J
Jewett-Strong staging system, 1, 15-16
L
Laser ablation, 4, 30
Laser therapy, 2, 6-7, 15, 18, 29, 30
LewisX antigen, 15, 17
M
Mitomycin C
compared to other intravesical therapies, 7, 26, 30
R
Radiotherapy, in etiology of bladder cancer, 13
Rash, as complication of treatment, 22
Recurrence of tumors
and cystoscopy, 20
and cytology, 15, 20
Page 59
and intravesical therapy, 5, 7-8, 12, 18, 19, 22, 2526, 29, 30, 31
and prognostic indicators, 17, 31
and treatment with BCG, 3, 8, 19, 22, 25, 26, 29, 30,
31
and tumor grade, 2, 7, 16, 17
and TURBT followed by intravesical therapy, 2, 6, 7,
25, 29, 30
and urine assay tests, 15
as outcome, 6, 7, 9, 10, 11-12, 21, 22, 25-26, 29, 30,
31
Risk factors for bladder cancer, 13
S
Schistosoma haematobium, 14
Sepsis. See BCG sepsis
Squamous cell carcinoma, 14
Superficial cancer, i, 10, 11, 16
Systemic toxicity
of doxorubicin, 3, 19
of thiotepa, 3, 18
as intravesical therapy, 3, 18, 25, 26, 28, 30

compared to other intravesical therapies, 7, 26, 30
cost of, 3, 18, 25
dosage of, 18
outcomes of use as treatment, 3, 25, 26, 28
recommendations for treatment of, 7, 30
TIS (stage) tumors. See CIS tumors
TNM staging system, 1, 16
Transitional cell carcinoma, See also T1 (stage) tumors, Ta (stage, tumors, and CIS tumors
definition and description of, 1, 6, 13-14, 29
grading of, 2, 17, 31
Transurethral resection
and intravesical therapy, 2, 7, 21, 28, 30
and treatment with BCG, 3, 7, 9, 22, 28
and treatment with doxorubicin, 3, 7, 9, 22, 28
and treatment with mitomycin C, 3, 7, 9, 28
and treatment with thiotepa, 3, 7, 9, 25, 26, 28
as treatment, 22, 28, 31
definition and description of, 1, 2, 18
diagnosis of, 6, 14, 15, 18, 29
outcomes of use as treatment, 3, 7, 9, 12, 21, 25, 27
without adjuvant therapy, 3, 9, 12, 22, 25, 26, 30
Archived Document
For Reference Only
T
T1 (stage) tumors
and cystectomy, 5, 30
and progression of, 16, 17, 22, 30, 31
and recurrence of, 16, 17, 30, 31
and TURBT, 1, 3, 15
and TURBT followed by intravesical therapy, 7
endoscopic ablation of, 5, 7, 29, 30
outcomes of treatment, 3, 11
recommendations for treatment of, 3, 4, 5, 6, 7-8, 28,
29, 30
staging of, 16
Ta (stage) tumors
and cystoscopy, 20
and grade, 2, 16
and progression, 16, 17, 22, 30, 31
and recurrence, 16, 17, 19, 21, 22, 30
and staging, 16, 21
and TURBT, 1, 7, 15
and TURBT followed by intravesical treatment, 7,
30
endoscopic ablation of, 5, 7, 29
outcomes of treatment, 3, 11, 21, 22
recommendation for treatment of, 3, 4, 5, 6, 7, 28,
29, 30
staging of, 16
Telomeric repeat amplification protocol assay test
(TRAP test), 15
Thiotepa
Page 60
Urethral infection, as complication of treatment, 22, 26

Urgency
as complication of treatment, 22
Urinary incontinence, as complication of treatment, 22
Urinary tract infections, 14
Urine assay tests. See specific tests
Urine cytology. See Cytologic assessment
Urothelial carcinoma, 31
V
Valrubicin, 19, 31
Vomiting, as complication of treatment, 22
Archived Document
For Reference Only
An attempt has been made to recommend a range of generally acceptable modalities of treatment,
taking into account variations in
resources and in patient needs and
preferences. It is recommended that
the practitioner articulate and document the basis for any significant
deviation from these parameters.
Finally, it is recognized that conformance with these guidelines
cannot ensure a successful result.
The parameters should not stifle
innovation, but will, themselves,
be updated and will change with
both scientific knowledge and
technological advances.
This material may not be reproduced in electronic or other format without written permission of the American Urological Association, Inc.
ISBN 0-9649702-S-2
For additional copies, physicians may contact:

American Urological Association, Inc.
Health Policy Department
1000 Corporate Boulevard
Linthicum, MD 21090
October 1999
(Stages Ta, T1 and Tis)
Archived Document
For Reference Only
Management of Non-Muscle-Invasive Bladder Cancer
This report is intended to furnish

to the skilled practitioner a consensus of clear principles and
strategies for quality patient care,
based on current professional literature, clinical experience, and
expert opinion. It does not establish a fixed set of rules or define
the legal standard of care, preempting physician judgment in individual cases.

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American

Bladder Cancer Guidelines Panel

Bladder Cancer Clinical Guidelines Panel Members and Consultants

Hanan S. Bell, Ph.D.

Copyright 1999 American Urological Association, Inc.

Copyright 1999 American Urological Association, Inc.

hematuria. This set of symptoms is associated

Copyright 1999, American Urological Association, Inc.

Page 1 Executive Summary

Resection and fulguration of

Numerous classification systems for grading

Page 2 Executive Summary

The Nd:YAG laser has so far proven to be the

Intravesical chemotherapy and

Copyright 1999, American Urological Association, Inc.

Copyright 1999, American Urological Association, Inc.

Page 3 Executive Summary

Recommendation for Index Patient No. 1

Recommendations for Index Patient No. 2

Complete eradication of all visible tumors should be performed if surgically feasible

(continued on next page)

Page 4 Executive Summary

Copyright 1999, American Urological Association, Inc.

Recommendations for Index Patient No. 3

Cystectomy may be considered as an option for patients with CIS or high-grade T1

Copyright 1999, American Urological Association, Inc.

Page 5 Executive Summary

Recommendation for all

Although urine cytology and other novel tumor

Page 6 Executive Summary

Standard: Complete eradication of all visible

Option: Surgical eradication can be performed

Copyright 1999, American Urological Association, Inc.

Option: Cystectomy may be considered as an

Copyright 1999, American Urological Association, Inc.

This recommendation is based upon panel

Option: Further intravesical therapy may be

Page 7 Executive Summary

larly with BCG. Repeat intravesical therapy may

Copyright 1999 American Urological Association, Inc.

To develop the recommendations in this Report

combine the outcomes evidence from the various

Copyright 1999 American Urological Association, Inc.

denotes a recommendation supported by objective

MEDLINE search was performed in 1989. A

Copyright 1999 American Urological Association, Inc.

Copyright 1999 American Urological Association, Inc.

its frequency. The panel attempted to determine

Copyright 1999 American Urological Association, Inc.

Chapter 2: Non-muscle-invasive bladder cancer

clophosphamide's urinary metabolite acrolein.

Copyright 1999 American Urological Association, Inc.

carcinomas originating in the urothelium that

Beyond the basement membrane is the lamina

Hematuria is the usual first sign of bladder

Copyright 1999 American Urological Association, Inc.

TURBT (described on page 18) is the usual

Copyright 1999 American Urological Association, Inc.

other, particularly with regard to tumor recurrence

Use of the term "superficial"

Stage Ta tumors are confined to the urothelium

Copyright 1999 American Urological Association, Inc.

1997). In addition, tumor infiltration of vascular