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

Bladder Cancer
Bladder Cancer
Non-Muscle-Invasive
of
(Stages Ta, T1 and Tis)
Archived Document—
For Reference Only
Bladder Cancer Clinical Guidelines Panel Members and Consultants
The Bladder Cancer Clinical Guidelines Panel consists of board-certified urologists who are experts in the treatment of blad-
der cancer. This
Report on the Management of Non-Muscle-Invasive Bladder Cancer (stages Ta, T1 and Tis) was extensively
reviewed by over 50 physicians throughout the country in February 1999. The Panel finalized its recommendations for the
American Urological Association (AUA) Practice Parameters, Guidelines and Standards Committee, chaired by Joseph W.
Segura, MD, in July 1999. The AUA Board of Directors approved these practice guidelines in August 1999.
The Summary Report also underwent independent scrutiny by the Editorial Board of the
Journal of Urology, was accepted
for publication in August 1999, and appeared in its November 1999 issue.
A Doctor’s Guide for Patients and Evidence Working
Papers
have also been developed; both are available from the AUA.
The AUA expresses its gratitude for the dedication and leadership demonstrated by the members of the Bladder Cancer
Clinical Guidelines Panel in producing this guideline.
Members Consultants
ISBN 0-9649702-5-2
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
Randall G. Rowland, M.D.
Professor and Director
Division of Urology
University of Kentucky
Chandler Medical Center
Lexington, Kentucky
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
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
Archived Document—
For Reference Only
Page i
Copyright © 1999 American Urological Association, Inc.
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, con-
current with an aging population (Landis, Murray, Bolden, et al., 1999; Parker, Tong, Bolden, et
al., 1996, 1997; Wingo, Tong, Bolden, et al., 1995).
Bladder cancer is largely a disease afflicting the late middle age and old age populations.
Although the disease does occur in young persons—even in children—more than 70 percent of
new cases are diagnosed in persons aged 65 and older (Lynch and Cohen, 1995; Yancik and Ries,
1994). As the baby boom generation ages over the next two decades, the incidence of bladder can-
cer will likely accelerate.
At any age, most bladder cancers, when initially diagnosed, have not invaded the detrusor mus-
cle (Fischer, Waechter, Kraus, et al., 1998; Fleshner, Herr, Stewart, et al. 1996). These 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 po-
tential benefits and possible adverse effects of treatment interventions and to produce practice poli-
cy recommendations accordingly. The three types of outcomes the panel determined to be 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-mus-
cle-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 re-
spects they behave differently from one another and to group them in a single category is mislead-
ing. (See the discussion on page 16.)
A summary of this report has been published in the
Journal of Urology (November 1999). A
Doctor's Guide for Patients
and Evidence Working Papers are available for purchase through the
AUA.
Introduction
Archived Document—
For Reference Only
Archived Document—
For Reference Only
Page iii
Copyright © 1999 American Urological Association, Inc.
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
Contents
Archived Document—
For Reference Only
Managing Editor
Lisa Emmons
Graphic Desgner
Gary Weems
Copy Editor
Lisa Goetz
Copyright © 1999
American Urological Association, Inc.
Archived Document—
For Reference Only
To develop recommendations for treatment of
non-muscle-invasive bladder cancer, the AUA
Bladder Cancer Clinical Guidelines Panel re-
viewed the literature on bladder cancer from
January 1964 to January 1998 and extracted and
meta-analyzed all relevant data to estimate as ac-
curately as possible both desirable and undesir-
able outcomes of alternative treatment modalities.
The panel followed an explicit approach to the de-
velopment of practice policy recommendations
(Eddy, 1992). This approach emphasizes the 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.
More than 90 percent of all bladder cancers
in the United States and Europe, both muscle-
invasive and noninvasive, are transitional cell car-
cinomas originating in the urothelium that 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 configura-
tion); flat patches of carcinoma in situ (CIS);
nodular tumors; sessile growths; and mixed
growths such as high-grade papillary tumors to-
gether 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, fre-
quency 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 exami-
nation; urine analysis; and a cystoscopic examina-
tion of the bladder and urethra. Diagnostic cysto-
scopies today are usually outpatient procedures
done with a flexible or rigid cystoscope under lo-
cal anesthesia. Diagnostic tools available in addi-
tion 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 tak-
en 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 tu-
mors and T1 tumors.
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 devel-
oped 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 prima-
ry tumors, adapted from the American Joint
Committee on Cancer (AJCC) staging manual
(Fleming, 1997).
Page 1 Executive SummaryCopyright © 1999, American Urological Association, Inc.
Executive Summary:
Report on the management of non-muscle-invasive
bladder cancer (stages Ta,T1 and Tis)
Methodology
Background
Archived Document—
For Reference Only
Page 2 Executive Summary Copyright © 1999, American Urological Association, Inc.
Basic characteristics of
stages Ta, T1 and Tis
Stage Ta tumors are confined to the urothelium
(above the basement membrane) and have a papil-
lary configuration described by Johansson 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 configura-
tion and a likelihood of being underdiagnosed
(Epstein, Amin, Reuter, et al., 1998). CIS can be
focal, multifocal or diffuse. On cystoscopic ex-
amination, it usually appears as a slightly raised,
reddened patch of velvety mucosa but often is
endoscopically invisible.
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 character-
istics. In particular, they all tend to group bladder
carcinomas similarly into three principal grades
based mainly on degree of anaplasia (Bergkvist,
Ljungqvist and Moberger, 1965; Epstein, Amin,
Reuter, et al., 1998; Koss, 1975). The three
grades—low (grade 1), intermediate (grade 2) and
high (grade 3)—correspond respectively to well
differentiated, moderately differentiated and poor-
ly differentiated tumors. Grade has been shown
to be a highly predictive indicator of future tumor
behavior with regard to both recurrence and pro-
gression.
In most cases of non-muscle-invasive bladder
cancer, tumors are treated initially with TURBT,
fulguration and/or laser therapy. A careful cysto-
scopic examination of all bladder surfaces, the
urethra and the prostate precedes resection (Koch
and Smith, 1996). Findings with prognostic sig-
nificance 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 tu-
mors; and 2) tissue resection for pathologic evalu-
ation 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 healthy-
appearing muscle fibers should be visible at the
base. Necrotic-appearing tissue implies an inva-
sive 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). 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 tu-
mors (Koch and Smith, 1996).
Intravesical chemotherapy and
immunotherapy
Intravesical chemotherapy or immunotherapy
is most often used as adjuvant treatment to pre-
vent tumor recurrence following the TURBT of
primary non-muscle-invasive bladder tumors, in-
cluding possible recurrence because of iatrogenic
implantation of tumor cells. Intravesical therapy
is also used to treat known existing tumors in cases
Treatment alternatives
Archived Document—
For Reference Only
Page 3 Executive SummaryCopyright © 1999, American Urological Association, Inc.
of CIS, which frequently cannot be treated ade-
quately by resection or fulguration because of dif-
fuse involvement. The chief intravesical agents
currently available are thiotepa, doxorubicin, mit-
omycin C and bacillus Calmette-Guérin (BCG).
Chapter 3 of this report contains an evidence-
based comparative outcomes analysis of 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 cross-
linking nucleic acid. Its low molecular weight of
189 allows partial absorption through the urotheli-
um, 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 cytotox-
ic in the S phase. Its molecular weight of 580 is
high, and absorption and systemic toxicity are ex-
tremely rare.
Mitomycin C is an antibiotic that works by
inhibiting DNA synthesis. Because of its moder-
ately high molecular weight of 329, there are
few problems with transurothelial absorption,
and myelosuppression is rare. However, mito-
mycin 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 tu-
berculosis vaccine. Its now widespread use as in-
travesical 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 under-
stood, but clearly involves a strong inflammatory
immunologic host response with release of inter-
leukins 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.
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 carci-
noma 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 "op-
tion," as used in the panel's recommendations, re-
fer 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 be-
cause patient preferences are divided. In the latter
case particularly, the panel considered it important
to take into account likely preferences of individ-
ual patients when selecting from among alterna-
tive interventions.
Index patients
The specific types of patients to whom the
panel's recommendations apply are termed index
patients. In recognition of the differences in deci-
sion-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 can-
cer;
Index Patient No. 2: A patient with estab-
lished 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)
Treatment recommendations
Archived Document—
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Page 4 Executive Summary Copyright © 1999, American Urological Association, Inc.
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:
If the patient does not have an established histologic diagnosis, a biopsy should be ob-
tained for pathologic analysis.
Recommendations for Index Patient No. 2
A patient with established bladder cancer of any grade, stage Ta or T1, with or with-
out CIS, who has not had prior intravesical therapy.
Standard:
Complete eradication of all visible tumors should be performed if surgically feasible
and if the patient's medical condition permits.
Option:
Surgical eradication can be performed by one of several methods, including electro-
cautery resection, fulguration or laser ablation.
(continued on next page)
Archived Document—
For Reference Only
Page 5 Executive SummaryCopyright © 1999, American Urological Association, Inc.
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 tu-
mors.
Option:
Cystectomy may be considered for initial therapy in some patients with CIS or T1 tu-
mors.
Recommendations for Index Patient No. 3
A patient with CIS or high-grade T1 cancer who has had at least one course of intrav-
esical therapy.
Option:
Cystectomy may be considered as an option for patients with CIS or high-grade 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 treat-
ment.
Archived Document—
For Reference Only
Page 6 Executive Summary Copyright © 1999, American Urological Association, Inc.
Recommendation for all
index patients
This recommendation is based on the panel's
expert opinion. Although all of the adjuvant treat-
ments 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 al-
tered. 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 blad-
der 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 in-
fection or even death from BCG sepsis in rare cir-
cumstances.
In addition, there is little information defining
the optimal dose, number and timing of instilla-
tions or the influence of long-term maintenance
therapy. Randomized studies supporting the use
of maintenance BCG therapy have been conduct-
ed, but the panel excluded them because their re-
sults have been reported only in abstract form.
Other trials would appear to support a role 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.
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.
In a patient with known bladder cancer, endo-
scopic ablation of all visible tumors should be per-
formed. This can be accomplished with electro-
cautery resection, fulguration or application 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 deci-
sion about whether or not to attempt endoscopic
removal of bladder tumors. This recommendation
is based on the panel's expert opinion.
For bladder cancers that do not invade the de-
trusor muscle, several methods for tumor destruc-
tion provide apparently comparable results.
Adequate tissue should be available for determina-
tion of pathologic stage, but endoscopic ablative
Standard: Physicians should discuss with the
patient the treatment options and the benefits
and harms, including side effects, of intravesi-
cal treatment, especially those side effects asso-
ciated with a particular agent.
Standard: If the patient does not have an es-
tablished histologic diagnosis, a biopsy 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.
Option: Surgical eradication can be performed
by one of several methods, including electro-
cautery resection, fulguration or laser ablation.
Archived Document—
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Page 7 Executive SummaryCopyright © 1999, American Urological Association, Inc.
techniques may not permit submission of all ma-
terial for histologic evaluation. This recommen-
dation is based on the panel's expert opinion.
A recommendation stronger than an option for
this group of patients (Index Patient No. 2) cannot
be supported by the evidence in the outcomes ta-
bles (see page 23). Most studies combined pa-
tients who had low-grade stage Ta tumors with
patients who had T1 lesions and higher-grade can-
cers, 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 lit-
tle evidence that adjuvant therapy affects the pro-
gression rate. For rapidly recurring low-grade Ta
tumors, adjuvant therapy may be useful. The out-
comes tables show a decreased recurrence proba-
bility for all the intravesical therapies studied,
compared to TURBT alone.
Based on evidence from the literature and pan-
el opinion, both BCG and mitomycin C are supe-
rior to doxorubicin or thiotepa for reducing recur-
rence of T1 and high-grade Ta tumors. There is
no evidence that any intravesical therapy affects
the ultimate rate of progression to muscle-invasive
disease.
Because there is risk of progression to muscle-
invasive disease even after intravesical therapy,
cystectomy may be considered as an initial treat-
ment option in certain cases. Among factors asso-
ciated with increased risk of progression are 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.
This recommendation is based upon panel
opinion rather than evidence in the outcomes ta-
bles. However, other data in the literature do
show a substantial risk of progression to muscle-
invasive 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 thera-
py alters this risk of progression. Thus, there are
some patients with symptomatic disease or high-
grade 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: 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 endo-
scopic 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.
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.
Archived Document—
For Reference Only
This recommendation is also based on the pan-
el'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 recur-
rence after previous complete response to an in-
travesical agent. Data are insufficient, however, to
allow conclusions about the role of drug combina-
tion regimens or alternating therapies.
Page 8
Copyright © 1999 American Urological Association, Inc.
Archived Document—
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Page 9
Copyright © 1999 American Urological Association, Inc.
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 at-
tempts to arrive at practice policy recommenda-
tions through mechanisms that systematically take
into account relevant factors for making selections
between alternative interventions. Such factors in-
clude estimation of the outcomes from the inter-
ventions, consideration of patient preferences and
assessment of the relative priority of the interven-
tions for a share of limited health care resources
when possible. For estimating the outcomes of in-
terventions, emphasis is placed on the use of sci-
entific evidence. When panel opinion is neces-
sary, the explicit approach calls for 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 esti-
mate outcomes of alternative treatment modalities
as accurately as possible. The panel members
themselves served as proxies for patients in con-
sidering preferences with regard to health and eco-
nomic outcomes.
The review of the evidence began with a litera-
ture search and extraction of data as described 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 out-
comes estimates for the following therapeutic al-
ternatives 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-Guérin (BCG).
The panel utilized the FAST*PRO
®
meta-
analysis 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 recur-
rence 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 in-
tervention 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 appre-
ciable 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 inter-
ventions are not sufficiently well-known to
permit meaningful decisions, 2) preferences
among the outcomes are not known, 3) pa-
tients' preferences are divided among the alter-
native interventions and/or 4) patients are in-
different about the alternative interventions.
A standard has the least flexibility. A guide-
line has significantly more flexibility, and options
are the most flexible. In this report, the terms are
used to indicate the strength of the recommenda-
tions. 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
Chapter 1: Methodology
Archived Document—
For Reference Only
Page 10
Copyright © 1999 American Urological Association, Inc.
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 be-
cause of insufficient evidence or because patient
preferences are divided. In the latter case particu-
larly, 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 searches were performed mostly us-
ing the MEDLINE
®
database. Some articles (in-
cluding some that predate the inception of MED-
LINE
®
in 1966) were added for review based on
panel members' own knowledge. The 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 result-
ing database of search results was used as the ba-
sis 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 extrac-
tion. From a database of 5,712 citations, the panel
selected 227 articles for retrieval and data extrac-
tion. 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 re-
viewers, who extracted the articles and transcribed
the data onto the forms. The panel rejected 46 ar-
ticles at this stage because of reasons such as in-
adequate methods, no relevant data or superses-
sion by a later article from the same source (see
Appendix A, Figure A-5). The result was 181 ar-
ticles to be used as the source of data for this re-
port. All data were entered into a Microsoft
Access 97
®
database (Microsoft, Redmond,
Washington), then double-checked at a later time.
The bar graph in Figure A-1 on page 50 cate-
gorizes by year of publication the number of arti-
cles reviewed and the number accepted for 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.
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 out-
comes evidence from the literature to generate
probability estimates. The methods chosen de-
pend 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 gener-
ate comparative estimates of recurrence and pro-
gression probabilities for the different treatment
alternatives. The small patient size of many of
these studies, however, made them suboptimal for
estimating probabilities of treatment complica-
tions, particularly uncommon complications.
Thus, the panel opted to include data from clinical
series as well as from RCTs for generating com-
plications estimates.
If a number of studies have some degree of rel-
evance to a particular cell or cells in an 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
TM
computer
Literature search,
article selection and
data extraction
Evidence combination
Archived Document—
For Reference Only
Page 11
Copyright © 1999 American Urological Association, Inc.
software (Eddy and Hasselblad, 1992). The
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 progres-
sion, data from multi-armed RCTs were combined
meta-analytically to determine the difference be-
tween two treatment alternatives. All alternatives
were compared in pairs. For estimates of treat-
ment 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 prob-
ability between two treatment interventions. For
example, if 10 percent of patients given interven-
tion 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 out-
come being assessed. It further assumes that this
underlying rate varies from study to study, and
that the variation in the true rate is normally dis-
tributed.
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-per-
cent confidence interval is such that the probabili-
ty (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.
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 "superfi-
cial bladder cancer," without reporting stage-spe-
cific results. In addition, most studies do not seg-
regate 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 recommenda-
tions.
A possible limitation in using RCTs for meta-
analysis is that, by their nature, most RCTs com-
pare two or more different treatments, whereas 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 compar-
isons should line up consistently in relation to one
another, and it should be possible to generate
numbers that show with consistency the differ-
ences among all of a given set of treatments.
For example, assume that a two-way compari-
son based on meta-analysis of RCTs shows the es-
timated probability of patient survival to be 20
percent greater after treatment A than after treat-
ment 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 treat-
ments 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 differ-
ences in study designs, differences in the mea-
sures 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 ulti-
mately decided to combine data from studies that
differ in these areas, because such differences
software (Eddy and Hasselblad, 1992). The
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 progres-
sion, data from multi-armed RCTs were combined
meta-analytically to determine the difference be-
tween two treatment alternatives. All alternatives
were compared in pairs. For estimates of treat-
ment 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 prob-
ability between two treatment interventions. For
example, if 10 percent of patients given interven-
tion 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 out-
come being assessed. It further assumes that this
underlying rate varies from study to study, and
that the variation in the true rate is normally dis-
tributed.
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-per-
cent confidence interval is such that the probabili-
ty (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.
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 "superfi-
cial bladder cancer," without reporting stage-spe-
cific results. In addition, most studies do not seg-
regate 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 recommenda-
tions.
A possible limitation in using RCTs for meta-
analysis is that, by their nature, most RCTs com-
pare two or more different treatments, whereas 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 compar-
isons should line up consistently in relation to one
another, and it should be possible to generate
numbers that show with consistency the differ-
ences among all of a given set of treatments.
For example, assume that a two-way compari-
son based on meta-analysis of RCTs shows the es-
timated probability of patient survival to be 20
percent greater after treatment A than after treat-
ment 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 treat-
ments 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 differ-
ences in study designs, differences in the mea-
sures 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 ulti-
mately decided to combine data from studies that
differ in these areas, because such differences
Limitations
Archived Document—
For Reference Only
Page 12
Copyright © 1999 American Urological Association, Inc.
appear to have little or no effect on rates of recur-
rence and progression. This is demonstrated by
the comparative data from BCG studies shown in
Table C-1 in Appendix C. The panel also com-
bined 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 fol-
low-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 complica-
tion, 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 publi-
cation bias. Studies with poor results are less
likely to be published because either they are nev-
er submitted for publication or they are rejected
later. For example, with regard to articles com-
paring adjuvant therapies to TURBT alone, there
is the possibility that studies demonstrating nega-
tive 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 pa-
tients in their treatment decision making.
Archived Document—
For Reference Only
Page 13
Copyright © 1999 American Urological Association, Inc.
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 de-
scriptions 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 meth-
ods for treating primary tumors and for predicting
likelihood of tumor recurrence and subsequent
progression.
Malignant transformation of a normal bladder
cell begins with alteration of the cell's DNA.
Epidemiologic evidence implicates chemical car-
cinogens as a causative agent in many patients.
Specifically, the evidence points to aromatic
amines, such as 2-naphthylamine and 4-amino-
biphenyl, 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 indus-
trial 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 10-
year period (Piper, Tonascia and Metanoski,
1985). The average latency period is 22 years,
and most patients have renal pelvic tumors as well
(Johansson, Angervall, Bengtsson, et al., 1974).
The drug cylophosphamide, which is used to treat
a variety of conditions including Hodgkin's dis-
ease, can also lead to development of bladder can-
cer; the causative agent is believed to be cy-
clophosphamide's urinary metabolite acrolein.
The latency period is a relatively short 6-13 years,
and most of the tumors are high grade when diag-
nosed (Cohen, Garland, St. John, et al., 1992;
Fernandes, Manivel, Reddy, et al., 1996; O'Keane,
1988; Talar-Williams, Hijazi, Walther, et al.,
1996). Bladder cancer can result from radiothera-
py used to treat uterine or cervical cancer or 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 ge-
netic mechanisms, some of which have been un-
der study for years. Oncogenes are an example.
These are altered forms of alleles called proto-
oncogenes. Proto-oncogenes encode a growth
factor as well as receptor proteins and are neces-
sary for normal cell development. The altered
forms, oncogenes, lead to unregulated cell divi-
sion 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 apop-
tosis before the DNA can replicate, thus suppress-
ing proliferation of cells that have genetic abnor-
malities (Harris and Hollstein, 1993). If p53 itself
is damaged, it may no longer be able to function
(Cordon-Cardo, 1995). Bladder cancers associat-
ed with mutated p53 tend to behave quite aggres-
sively (Cordon-Cardo, 1995; Esrig, Elmajian,
Groshen, et al., 1994), and altered genes like p53
may serve as markers to indicate the relative ag-
gressiveness of individual tumors.
More than 90 percent of all bladder cancers in
the United States and Europe, both muscle inva-
sive and noninvasive, are transitional cell
Etiology
Major types of
bladder cancer
Archived Document—
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Page 14
Copyright © 1999 American Urological Association, Inc.
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 to-
gether 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 blad-
ders (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 irrita-
tion from long-term indwelling catheters and uri-
nary calculi. Spinal-cord injured patients, in par-
ticular, are at risk for squamous cell bladder can-
cer (Navon, Soliman, Khonsari, et al., 1997). 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 (El-
Bolkainy, Mokhtar, Ghoneim, et al., 1981).
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 com-
posed 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.
Beyond the basement membrane is the lamina
propria, extending to the detrusor muscle. As not-
ed, 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 pre-
sent in small, fragmented tumor specimens ob-
tained 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-inva-
sive, but actually limited to the lamina propria.
The detrusor muscle itself consists of interlacing
bundles of smooth muscle with a covering of adi-
pose tissue (or peritoneum).
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, fre-
quency 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 exami-
nation; urine analysis; and a cystoscopic examina-
tion of the bladder and urethra. Diagnostic cysto-
scopies today are usually outpatient procedures
done with a flexible or rigid cystoscope under lo-
cal anesthesia. Diagnostic tools available in addi-
tion 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 dis-
cussed later.
Also, because hematuria can originate else-
where 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.
Histology
Diagnosis
Archived Document—
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Page 15
Copyright © 1999 American Urological Association, Inc.
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 (Grégoire, Fradet, Meyer, et al.,
1997).
Cytologic assessment is least sensitive for de-
tecting low-grade bladder tumors. Because the
cells of these well-differentiated tumors often
closely resemble normal urothelial cells, malig-
nant features may be difficult to recognize. In ad-
dition, 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 sub-
stantial 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
(Grégoire, Fradet, Meyer, et al., 1997; Messing
and Catalona, 1998).
Now being investigated are ways to improve
cytology performance such as through immunos-
taining with either Lewis
x
antigen or cytokeratin
20 (Klein, Zemer, Buchumensky, et al., 1998;
Pode, Golijanin, Sherman, et al., 1998).
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
TM
and BTA TRAK
TM
, 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
rapidly recurring bladder cancer after a transure-
thral 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 lim-
ited (Stampfer, Carpinito, Rodriguez-Villanueva,
et al., 1998).
Another test is based on telomerase activity.
Telomerase is an enzyme responsible for chromo-
some-end (telomere) maintenance and is com-
monly active in cancer. The TRAP test, or telom-
eric repeat amplification protocol assay, is report-
ed to be highly sensitive but may require 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-stick-
type assays) appear promising but need to be test-
ed 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 in-
sufficient specificity to allow treatment decisions
based on a positive test, although they appear to
be more sensitive than cytology for detecting tu-
mors, especially low-grade lesions.
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 tu-
mors 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 evalu-
ate 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 tu-
mors.
Laser coagulation may be used to ablate tu-
mors in some cases, especially recurrent lesions.
If laser therapy is used, cold-cup biopsies may be
taken for pathologic evaluation.
For staging of bladder cancer, the original
Jewett-Strong system (1946), modified by
Staging
Archived Document—
For Reference Only
Marshall (1952, 1956), has generally given way to
the TNM (tumor, node, metastasis) system devel-
oped 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 tu-
mors, 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 pre-
sent 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 Tis––are 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 mus-
cle, but otherwise differ markedly from one an-
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 re-
cur as low-grade Ta tumors. Progression to mus-
cle-invasive disease takes place in less than 10
percent of patients with these tumors (Holmäng,
Hedelin, Anderström, et al., 1997; Kiemeney,
Witjes, Heijbroek, et al., 1993; Prout, Barton,
Griffin, et al., 1992). By contrast, T1 tumors 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 pa-
tients with T1 disease.
Basic characteristics of
stages Ta, T1 and Tis
Stage Ta tumors are confined to the urothelium
(above the basement membrane) and have a papil-
lary configuration described by Johansson 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 pro-
gression when T1 tumors penetrated to the level
of the muscularis mucosa and beyond a two-fold
increase in incidence of recurrence and an eight-
fold increase in incidence of progression. Hasui
and colleagues, as well as other authors, have pro-
posed subdividing the stage T1 classification into
stages T1a and T1b, using the muscularis mucosa
as the dividing line. Unfortunately, the muscu-
laris mucosa makes an unreliable point of refer-
ence, being discontinuous and often difficult to
identify; but there is growing evidence that tumor
penetration to this depth does have important im-
plications, such as a higher risk of later detrusor
muscle invasion (Epstein, Amin, Reuter, et al.,
1998; Holmäng, Hedelin, Anderström, et al.,
Page 16
Copyright © 1999 American Urological Association, Inc.
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
Archived Document—
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Page 17
Copyright © 1999 American Urological Association, Inc.
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 urotheli-
um, but with a flat, disordered, nonpapillary con-
figuration and a likelihood of being underdiag-
nosed (Epstein, Amin, Reuter, et al., 1998). CIS
can be focal, multifocal or diffuse. On cystoscop-
ic examination, it usually appears as a slightly
raised, reddened patch of velvety mucosa—but
often it is endoscopically invisible. Much about
this peculiar cancer is poorly understood, includ-
ing its natural history and the mechanism by
which it spreads. The most ominous characteris-
tic 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 in-
formation in patients with diffuse CIS. If untreat-
ed, CIS is likely to progress to muscle-invasive
disease in a substantial percentage of patients
(Hudson and Herr, 1995).
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 charac-
teristics. In particular, they all tend to group blad-
der carcinomas similarly into three principal
grades based mainly on degree of anaplasia
(Bergkvist, Ljungqvist and Moberger, 1965;
Epstein, Amin, Reuter, et al., 1998; Koss, 1975).
The three grades—low (grade 1), intermediate
(grade 2) and high (grade 3)—correspond respec-
tively to well differentiated, moderately differenti-
ated and poorly differentiated tumors. Grade has
been shown to be a highly predictive indicator of
future tumor behavior with regard to both recur-
rence and progression.
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 tu-
mors and the presence of CIS. Stage is particu-
larly 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; Holmäng, Hedelin,
Anderström, et al., 1997; Kiemeney, Witjes,
Heijbroek, et al., 1993; Prout, Barton, Griffin, et
al., 1992). Moreover, the likelihood of muscle in-
vasion appears to be greater still for T1 tumors
that have penetrated beyond the muscularis mu-
cosa (Epstein, Amin, Reuter, et al., 1998;
Holmäng, Hedelin, Anderström, et al., 1997).
Other possible predictors of recurrence and/or
progression include DNA ploidy, blood group
antigens and various molecular markers. DNA
ploidy is measured by flow cytometry, often per-
formed 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 inde-
pendent 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,
such as ABO antigens and the Lewis
x
antigen, has
been associated with an unfavorable prognosis in
some studies, but other studies have found no cor-
relation with either recurrence or progression
(Newman, Carlton and Johnson, 1980; Richie,
Blute and Waisman, 1980; Yamada, Fukui,
Kobayashi, et al., 1991).
Molecular markers, such as abnormal expres-
sion of the tumor-suppressor genes p53 and pRb
(see page 13), show considerable promise as
prognostic indicators for bladder cancer, especial-
ly 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.
Prognostic indicators
Grade classification
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Page 18
Copyright © 1999 American Urological Association, Inc.
In most cases of non-muscle-invasive bladder
cancer, tumors are treated initially with TURBT,
fulguration and/or laser therapy. A careful cysto-
scopic examination of all bladder surfaces, the
urethra and the prostate precedes resection (Koch
and Smith, 1996). Findings with prognostic sig-
nificance 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
and Catalona, 1998).
Resection and fulguration
of bladder tumors
As stated on page 15, a TURBT has two main
purposes: 1) complete eradication of all visible tu-
mors; and 2) tissue resection for pathologic evalu-
ation 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 move-
ment of tumors away from and toward the resecto-
scope. When a tumor is removed, a separate biop-
sy can be taken at the base with the resecting loop.
After which, healthy-appearing muscle fibers
should be visible at the base. Necrotic-appearing
tissue implies an invasive carcinoma. The pres-
ence 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 can-
cer, 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 de-
termine 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 resec-
tion of primary non-muscle-invasive bladder tu-
mors, including possible recurrence because of ia-
trogenic implantation of tumor cells. Intravesical
therapy is also used to treat known existing tumors
in cases of CIS, which frequently cannot be treat-
ed 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 proper-
ties of the chief intravesical agents currently avail-
able are described later in this chapter. Chapter 3
contains an evidence-based comparative outcomes
analysis of most of these agents.
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 cross-
linking 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 in-
stillations 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.
Treatment alternatives
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Page 19
Copyright © 1999 American Urological Association, Inc.
Mitomycin C
Mitomycin C is an antibiotic that works by in-
hibiting DNA synthesis. Because of its moderate-
ly 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 ad-
ministered 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 cyto-
toxic 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 an-
thracycline 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 in-
visible 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.
Bacillus Calmette-Guérin (BCG)
BCG, a live attenuated strain of
Mycobacterium bovis, was first used as a tubercu-
losis vaccine. Its now widespread use as intraves-
ical immunotherapy for management of noninva-
sive bladder cancer began in the 1970s, heralded
by the 1976 Morales study (Morales, Eidinger
and Bruce, 1976). BCG 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, Blumen-
stein, Crawford, et al., 1995).
Several substrains of BCG have been used, in-
cluding the Pasteur, Armand-Frappier, Tice,
Evans, Tokyo, Dutch (RIVM) and Connaught
strains. Although all of them are derived from
one original strain developed at the Pasteur
Institute, the viability of BCG organisms per mil-
ligram of vaccine may vary with different sub-
strains and from lot to lot within the same sub-
strain (Cummings, Hargreave, Webb, et al., 1989;
Kelley, Ratliff, Catalona, et al., 1985; Messing
and Catalona, 1998).
BCG's mechanism of action is not fully under-
stood, but it clearly involves a strong inflammato-
ry immunologic host response with release of in-
terleukins and other cytokines (Morales, 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 re-
quire that many instillations; other patients re-
quire more than six (Brosman, 1992; Eure,
Cundiff and Shellhammer, 1992; Haaff, Dresner,
Ratliff, et al., 1986). Optimal dosing and instilla-
tion schedules have not yet been established. 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 adminis-
tered too soon after TURBT or traumatic catheter-
ization.
Valrubicin and Interferon
Valrubicin and interferon are two newer agents
for treating bladder cancer. Valrubicin, a semi-
synthetic 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 us-
ing valrubicin, but only about one of five patients
with BCG-refractory CIS was reported to have
had a complete response.
Interferons have antiproliferative, antiangio-
genic and immunostimulatory properties; and re-
combinant interferon alpha-2b has been effective
Archived Document—
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