1. health and fitness
2. disease
3. cancer

Bladder Cancer
Bladder Cancer Clinical Guideline
Update Panel
Members:
M. Craig Hall, M.D., Chair
Sam S. Chang, M.D., Vice-chair
Guido Dalbagni, M.D.
Raj Som Pruthi, M.D.
Paul F. Schellhammer, M.D.
John Derek Seigne, M.B.
Eila Curlee Skinner, M.D.
J. Stuart Wolf, Jr., M.D.
Consultants:
Hanan S. Bell, Ph.D.
Patrick M. Florer
Diann Glickman, Pharm.D.
Suzanne Pope
AUA Staff:
Heddy Hubbard, Ph.D.
Edith Budd
Michael Folmer
Katherine Moore
Kadiatu Kebe
Guideline for the Management
of Nonmuscle Invasive Bladder
Cancer: (Stages Ta,T1, and Tis):
2007 Update
Chapter 1: The Management of Bladder Cancer: Diagnosis and Treatment
Recommendations
Table of Contents
Introduction..................................................................................................................................... 3
Background ..................................................................................................................................... 4
Epidemiology.............................................................................................................................. 4
Etiology....................................................................................................................................... 4
Molecular Mechanisms of Urothelial Carcinogenesis................................................................ 5
Major Pathologic Subtypes......................................................................................................... 5
Presentation and Diagnosis ............................................................................................................. 6
Urine-based Markers................................................................................................................... 7
Fluorescence Cystoscopy............................................................................................................ 7
Diagnostic Transurethral Resection of Bladder Tumor .............................................................. 8
Tumor Characteristics..................................................................................................................... 8
Staging ........................................................................................................................................ 8
Grading ..................................................................................................................................... 10
Other Prognostic Indicators ...................................................................................................... 11
Risk Stratification ..................................................................................................................... 12
Treatment Alternatives.................................................................................................................. 12
Transurethral Resection of Bladder Tumor .............................................................................. 14
Intravesical Chemotherapy and Immunotherapy...................................................................... 14
Bacillus Calmette-Guérin ..................................................................................................... 15
Interferon .............................................................................................................................. 15
Thiotepa ................................................................................................................................ 15
Mitomycin C.......................................................................................................................... 16
Intercalating Agents (Doxorubicin, Epirubicin, and Valrubicin)......................................... 16
Other Therapies......................................................................................................................... 17
Photodynamic Therapy ......................................................................................................... 17
Laser Ablation Therapy ........................................................................................................ 18
Conservative Management.................................................................................................... 18
Follow-up.................................................................................................................................. 18
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Methodology ................................................................................................................................. 19
Literature Search and Data Extraction...................................................................................... 19
Evidence Combination.............................................................................................................. 19
Results of the Outcomes Analyses................................................................................................ 22
Treatment Guideline Statements................................................................................................... 23
For All Index Patients ............................................................................................................... 24
Future Research Needs ................................................................................................................. 30
Reporting of Bladder Cancer Data............................................................................................ 31
Acknowledgements and Disclaimers............................................................................................ 33
References………………………………………………………………………………………..35
Copyright © 2007 American Urological Association Education and Research, Inc.®
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Introduction
More than 60,000 new cases of bladder cancer are diagnosed each year in the United States
accounting for approximately 13,000 deaths annually.1 In recent decades the overall incidence of
bladder cancer has appeared to be rising2 and this may be due to the latent effects of tobacco
abuse and industrial carcinogens, as well as the overall aging of our population.
When initially diagnosed, most bladder cancers are nonmuscle invasive (also referred to as
“superficial”) – i.e., either noninvasive and confined to the mucosa or invading the lamina
propria but not yet invading the detrusor muscle. In 1999, the American Urological Association
(AUA) published a report by Smith and associates on the Bladder Cancer Clinical Guidelines
Panel Summary Report on the Management of Nonmuscle Invasive Bladder Cancer (Stages Ta,
T1 and Tis) (AUA Guideline) produced by the AUA’s Bladder Cancer Clinical Guideline Panel
(Appendix 1).3 That expert panel developed a practice guideline for three types of patients: (1)
the patient who presents with an abnormal growth on the urothelium but not yet diagnosed with
bladder cancer; (2) the patient with established bladder cancer of any grade, stage Ta or T1, with
or without carcinoma in situ (Tis) who had not had prior intravesical therapies; and (3) the
patient with Tis or high-grade T1 cancer who had at least one course of intravesical therapy. The
report provided an evidence-based guideline for the patient with nonmuscle invasive bladder
cancer and included management standards, guidelines, and options based on the strength of
evidence and expected amount of variation in patient preferences.
Since 1999 the field of nonmuscle invasive bladder cancer has changed substantially with
regard to the understanding of the molecular biology and clinical behavior of this heterogeneous
disease. In addition, the growing body and quality of clinical research methodologies have
improved during this period. The more recent publication of randomized controlled trials, the
gold standard of treatment evaluation, has allowed the evaluation and comparison of various
treatment modalities. For these reasons, the AUA Practice Guidelines Committee has elected to
update the initial report by appointing a panel (Appendix 2) to develop a new guideline for the
management of nonmuscle invasive bladder cancer founded on evidence-based outcomes in the
literature as well as expert opinion. Only topics having sufficient evidence on which to base
conclusions were addressed in this guideline.
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Background
This section will provide a current overview of nonmuscle invasive urothelial carcinoma
including a discussion of epidemiologic features and possible etiologic factors, and a review of
the histology and tumor subtypes of this disease.
Epidemiology
In the United States in 2007 an estimated 67,160 new cases of bladder cancer are expected to be
diagnosed (approximately 50,040 men and 17,120 women), with an overall-lifetime risk of
developing bladder cancer of approximately 1 in 28.1,4 During the last three decades, i.e., since
1975, there has been a gradual rising trend in bladder cancer incidence by approximately 40%
according to the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER)
Registry.2 There will be approximately 13,750 deaths from bladder cancer in the United States
this year.1,4 Despite the increasing incidence of this disease, the death rate from bladder cancer
has been gradually declining. Currently there are approximately 500,000 survivors of bladder
cancer in the United States.5
Bladder cancer is three times more common in men than women and is the fourth most
common cancer (and second most common urologic cancer) found in men in the United States.
Caucasian Americans have approximately a two-fold increase in risk of developing bladder
cancer compared with African Americans. Latin Americans have an even lower risk of bladder
cancer development than African Americans.5 The underlying reasons for differences in gender
and racial incidence are currently not well understood. Bladder cancer is a disease of older
individuals with greater than 90% of diagnoses in patients more than 55 years of age; although
uncommon, bladder cancer can occur in young adults and even in children.5
Etiology
The etiology of bladder cancer appears to be multifactorial with exogenous environmental
factors, as well as endogenous molecular factors, playing possible roles. First postulated by Rehn
in 1895, the link between bladder cancer and environmental carcinogens has long been
observed.6 A large body of epidemiologic evidence linking bladder cancer to certain chemical
agents, occupations, and industries has been generated since that time. As the bladder functions
as a reservoir of urine, it is therefore possible that it is susceptible to the effects of a variety of
potential environmental carcinogens in the process of waste elimination. Rising rates of bladder
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cancer in recent decades, the increased incidences observed in industrial countries, and the
relatively long latency periods observed between exposure and cancer development suggest a
potential cumulative effect of carcinogens on malignant transformation of the urothelial lining of
the bladder.
Molecular Mechanisms of Urothelial Carcinogenesis
Abnormal metabolic pathways and molecular instabilities may likewise play a role in bladder
cancer development and progression. These include: (1) altered metabolism/detoxification of
carcinogens, and (2) inherent or acquired genetic abnormalities that may promote tumor
development (oncogenes), inhibit tumor cell proliferation (tumor suppressor genes), or impair
DNA repair (DNA repair enzymes). Pathways involved in altered chemical metabolism of
exogenous carcinogens have included aberrant cytochrome P450 metabolism (associated genetic
defects), glutathione-s-transferase abnormalities, and N-acetyltransferase genetic and metabolic
derangements.7-10 In addition, DNA abnormalities may be inherent or acquired secondarily to
carcinogenic exposure. Genetic instability may result in abnormal activity of oncogenes (e.g., ras
and myc families) resulting in aberrant protein expression (e.g., GDP/GTP binding proteins),
cellular proliferation, and resistance to apoptosis.10,11 Abnormalities in tumor suppressor genes
associated with bladder cancer have also been well studied and include p53, p21, p16, and Rb
(retinoblastoma) tumor suppressor genes that may be mutated or inactivated, and such defects
may thereby predispose to cell cycle dysregulation and tumor cell development and
progression.12-15 Alterations in DNA repair (e.g., ner genes, ber genes, and dsb repair genes)
have likewise been associated with polymorphisms that may result in bladder urothelial
carcinogenesis.10,16,17 Other potential inherent and acquired pathways have also been identified
and may also be involved including telomere dysfunction, apoptosis, and cellular
inflammation.18,19
Major Pathologic Subtypes
Transitional cell carcinoma, the most common pathologic subtype of bladder cancer, is observed
in over 90% of tumors.20 Less common subtypes include squamous cell carcinoma observed in
approximately 5% of bladder cancers in the United States and adenocarcinomas observed in
approximately 1% of bladder cancers.21,22 Not infrequently, bladder tumors that are
predominantly transitional in histology may have areas of squamous and/or glandular
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differentiation. Recently recognized variants of transitional cell carcinoma (nested and
micropapillary) may have prognostic and therapeutic significance. Squamous cell carcinoma
accounts for up to 75% of bladder cancers in certain regions of the world in which
schistosomiasis (also known as Bilharziasis) infection is endemic.23,24 Other uncommon types of
nonurothelial cancers of the bladder include small cell (neuroendocrine) carcinomas,
mesenchymal tumors, lymphomas, lymphoepithelial variants, and secondary malignancies
(either via direct extension or as a site of distant metastases).
Presentation and Diagnosis
Hematuria, occurring in the majority of patients with bladder cancer, is continuous or
intermittent and either visible (gross) or microscopic. From microscopic hematuria screening
studies, it has been estimated that approximately 1.3% of patients will have an underlying
diagnosis of bladder cancer (range 0.4% to 6.5%), although this is more likely in patients with
gross hematuria.25-27 As such, the 2001 AUA Best Practice Policy on Asymptomatic Microscopic
Hematuria28 recommends that all patients with hematuria, particularly those without evidence of
infections, stones, or other causative factors, should undergo cystoscopy and upper tract
imaging.3 Irritative voiding symptoms including frequency, urgency, and dysuria are particularly
associated with carcinoma in situ. Indeed, the diagnosis of bladder cancer is a consideration in
patients with irritative voiding symptoms in the absence of infection.
The physical exam of patients with bladder cancer is often unremarkable especially in the
case of nonmuscle invasive disease. A bimanual exam at the time of transurethral resection of the
bladder tumor (TURBT) may help with clinical staging, especially for patients with muscle
invasive disease. Cytology, either voided or upon barbotage, is an important adjunct in the
diagnosis and surveillance of patients with urothelial carcinoma. The urinary tract and its unique
epithelium (urothelium) are particularly suitable for cytologic sampling. Urinary cytology can be
used to screen and evaluate patients at high risk for urothelial tumors (e.g., those with hematuria
or irritative voiding symptoms) and to monitor recurrence, progression, or response to treatment
in patients with a known history of transitional cell carcinoma. Sensitivity and positive predictive
value of urinary cytology are particularly high in high-grade urothelial tumors as well as in cases
of carcinoma in situ in which sensitivities can exceed 90%. Cytology is less effective for lowgrade tumors and as a qualitative technique is subject to considerable variation in
interpretation.29-33 Radiologic imaging is often performed in conjunction with cystoscopy and is
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part of the hematuria evaluation in the patient undergoing assessment for urothelial cancer. In
addition, in patients with a known history of bladder cancer, imaging can be useful in evaluating
the presence of upper tract tumors that occur in less than 5% of patients with a known history of
lower tract (i.e., bladder) cancer.31,34 Common imaging techniques include intravenous urogram,
retrograde pyelography, computerized tomography, and magnetic resonance imaging.
Urine-based Markers
Whereas the diagnosis and surveillance of patients with nonmuscle invasive urothelial cancers
rely on cystoscopy, cytology, and biopsy when necessary, in recent years there has been an
intense search for noninvasive adjunctive urine-based markers that could improve or perhaps
replace cytology and cystoscopy. These may aid both in the diagnosis and the surveillance of
patients with nonmuscle invasive urothelial cancers. Currently available Food and Drug
Administration (FDA)-approved tests include the bladder tumor antigen STAT test (Bard
Diagnostics, Redmond, WA, USA), the BTA TRAK test (Poly Med Co, Cortlandt Manor, NY,
USA), the nuclear matrix protein (NMP) 22, and NMP22 BladderChek assays (Matritech,
Newton, MA, USA), ImmunoCyt test (Diagnocure Inc, Quebec City, Quebec, Canada), and
fluorescence in situ hybridization (FISH) analysis (Urovysion Systems Vysis, Abbott
Laboratories, Abbott Park, IL, USA). Other recently investigated tests and identified markers
include Quanticyt (Gentian Scientific, Niawer, The Netherlands), BLCA-4, hyaluronic acid,
telomerase, LewisX blood group antigens, microsatellite polymorphism analysis, cytokeratins,
and survivin.32,35 Despite their present and future potential, the critical evaluation and
comparison of urine-based markers is beyond the scope of the current guideline involving the
management of nonmuscle invasive bladder cancer.
Fluorescence Cystoscopy
In recent years, fluorescence cystoscopy, in contrast to conventional white light cystoscopy, has
been investigated as a tool to enhance detection of occult papillary lesions and carcinoma in situ.
Recent fluorescence photo detection strategies have used 5-aminolevulinic acid (5-ALA) – a
precursor of heme biosynthesis. Intravesical installation of 5-ALA results in selective
enhancement of protoporphyrin IX visualization through uptake by neoplastic cells. Upon
excitation with blue light, protoporphyrin IX becomes readily visible with an appropriate
observation filter on the cystoscope.36 5-Aminolevulinic acid-enhanced cystoscopy does appear
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to have improved sensitivities in detecting nonmuscle invasive bladder tumors such as carcinoma
in situ.36,37 Improved detection may enhance tumor identification and facilitate eradication
thereby lowering recurrence rates.38,39 Unfortunately, the specificity of fluorescence cystoscopy
is limited; false-positive results may occur in patients with inflammatory lesions especially after
use of intravesical therapies. Ongoing studies determining the effect of its use on disease free
survival are accruing patients.
Diagnostic Transurethral Resection of Bladder Tumor
Ultimately, the diagnosis of urothelial carcinoma is made upon excision of the vesical lesion by
TURBT.40 Transurethral resection of bladder tumor provides essential histopathologic
information for bladder tumor diagnosis as well as staging and grading of the cancer. At the time
of TURBT, it is essential not only to resect the tumor itself but to provide a deep enough
resection and biopsy to adequately assess the depth of invasion (i.e., sampling of the muscularis
propria) for adequate staging information.41 As outlined in subsequent text, repeat TURBT
(restaging TURBT) provides additional diagnostic and potentially prognostic information for
patients with high-grade T1 tumors as well as select patients with high-grade Ta tumors.42,43
Tumor Characteristics
Staging
The staging for bladder cancer is divided into clinical and pathological stages. Clinical stage
reflects the histologic findings at TURBT, the clinician’s physical exam (including bimanual
exam under anesthesia), and findings on radiologic imaging. Pathological staging (also known as
surgical staging) is based on the extent of disease following surgical resection of the bladder
(partial versus radical cystectomy) and of the adjacent pelvic lymph nodes. In the past, the Panel
avoided using the term "superficial" in their report when categorizing the three nonmuscle
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
discouraged44 as Ta, T1, and Tis tumors behave differently from one another particularly with
regard to tumor recurrence and progression.44-46
Currently, the staging system of the American Joint Committee on Cancer, also known as the
Tumor-Node-Metastases (TNM) classification, is the most commonly used and universally
accepted staging system for bladder cancer.47 Under this system, nonmuscle invasive tumors
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include: (1) papillary tumors confined to the epithelial mucosa (stage Ta), (2) tumors invading
the subepithelial tissue (i.e., lamina propria; T1), and (3) Tis (Table 1).
Table 1: Staging of primary tumors (T) in bladder cancer47
TX: Primary tumor cannot be assessed
Ta: Noninvasive papillary carcinoma
Tis: Carcinoma in situ
T1: Tumor invades lamina propria
T2: Tumor invades muscularis propria
T2a: Invades superficial muscularis propria (inner half)
T2b: Invades deep muscularis propria (outer half)
T3: Tumor invades perivesical tissue/fat
T3a: Invades perivesical tissue/fat microscopically
T3b: Invades perivesical tissue fat macroscopically (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
Data gathered during the past few decades demonstrate that approximately 70% to 75% of
bladder cancers present as nonmuscle invasive tumors.31,48 Of these tumors, the majority (70% to
75%) are confined to the bladder mucosa (stage Ta).20,31,48 Ta tumors are typically papillary in
appearance and are often solitary lesions. The vast majority of lesions are categorized as low
grade with only 2% to 4% categorized as high grade.20,49,50 Recent studies, however, have
reported a greater prevalence of high-grade tumors.51 Ta tumors, like all bladder tumors, have a
high rate of recurrence after TURBT but the risk of stage progression, particularly for low-grade
papillary Ta tumors, remains low (less than 5%).31,50
Tumors that invade beyond the basement membrane into the subepithelial connective tissue
(i.e., lamina propria) are stage T1 tumors and represent approximately 25% of all nonmuscle
invasive tumors at initial presentation.20,31,50 T1 tumors can be papillary or nodular in
appearance. T1 bladder cancers have a worse prognosis than Ta tumors with a greater risk of
progression to muscle invasive disease.52-54 The lamina propria maintains abundant vascular and
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lymphatic channels that may predispose to tumor dissemination, and contains a variable layer of
smooth muscle fascicles termed the muscularis mucosa.
Carcinoma in situ, a unique subtype of nonmuscle invasive transitional cell carcinoma,
warrants its own unique stage and classification. Tis may appear as flat erythematous or
“velvety” lesions of the mucosa or can be occult lesions not readily visualized on standard
cystoscopy. Histologically, Tis are flat lesions in which surface epithelium-contained cells are
cytologically malignant with severe cytological atypia and nuclear aplasia. The marked
architectural and cytological abnormalities and disorderly appearance represent a process that is
truly high grade. Tis is considered an ominous lesion due to its occult and multicentric nature
that makes it difficult to readily identify and survey.55 Furthermore, its propensity for
progression to invasion in up to 83% of untreated cases is indicative of a potentially aggressive
tumor.56 The majority of Tis cases occur in association with high-grade nodular tumors; only 3%
to 5% occur as isolated Tis disease.57
Grading
Tumor grade has long been recognized as one of the most important prognostic indicators with
regard to the potential for disease recurrence and progression.44,48,58 The most widely used
classification for grading of nonmuscle invasive urothelial neoplasms has been the 1973 World
Health Organization (WHO) classification. This system has designations for papilloma and
Grades 1, 2, and 3 carcinomas. In 2004, members of the WHO and International Society of
Urologic Pathologists published and recommended a revised consensus classification for
papillary neoplasms (Table 2).59 A new category of papillary urothelial neoplasm of low
malignant potential was created to describe lesions with an increased number of urothelial layers
when compared with papilloma but without cytologic features of malignancy.59 The authors also
categorized nonmuscle invasive papillary carcinomas as either low or high grade. This
classification attempts to avoid the classification of intermediate grade (1973 WHO Grade 2), the
grade that often represented the default grade diagnosis.59,60 Indeed some reports have shown that
Grade 2 tumors represent up to 65% of urothelial carcinoma diagnosed.60,61 Under the new
system, some Grade 2 lesions will be classified as low grade and others will now be categorized
as high-grade tumors. This new system will potentially allow for enhanced prognostic
significance but certainly will be greatly dependent on the pathologist for making these
distinctions.
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Table 2: 2004 World Health Organization/ International Society of Urologic Pathologists:
Classification of Nonmuscle Invasive Urothelial Neoplasia59
Hyperplasia (flat and papillary)
Reactive atypia
Atypia of unknown significance
Urothelial dysplasia
Urothelial carcinoma in situ
Urothelial papilloma
Papillary urothelial neoplasm of low malignant potential
Nonmuscle invasive low-grade papillary urothelial carcinoma
Nonmuscle invasive high-grade papillary urothelial carcinoma
Other Prognostic Indicators
Although stage and grade represent perhaps the most important features of nonmuscle invasive
urothelial neoplasm with regard to prognosis, other important clinical, histologic, and molecular
features may also help predict prognosis and therapeutic response (Millan-Rodriquez European
meta-analysis). Tumor multiplicity and tumor size represent two often used clinical features with
prognostic significance in regard to disease recurrence.62-66 Some authors have evaluated the
potential prognostic value of substaging T1 tumors histologically to portend disease recurrence,
response to therapy, and ultimately progression.67-71
A variety of other molecular markers in bladder cancer have been studied with regard to their
ability to predict disease recurrence, response to therapy, and progression. These include flow
cytometry, blood group antigens (e.g., LewisX), tumor suppressor genes (e.g., p53 and Rb),
proliferative indices (Ki-67), urinary growth factors (e.g., epidermal growth factor, basic
fibroblast growth factor, and CD44), matrix metalloproteinses (e.g., MMP-9), and urinary
plasminogen activator (uPA).35,72,73 In the future such indicators may prove to be valuable
adjuncts to stage and grade in the management of nonmuscle invasive urothelial cancers.
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Risk Stratification
Nonmuscle invasive bladder cancer represents a wide range of tumor biology and behavior. It is
this heterogeneity that complicates the ability to compare therapeutic efficacy of different
treatment modalities and thereby establish a common treatment guideline. For example, patients
with the micropapillary variant of bladder cancer uniformly do poorly with bladder
conservation.74 This difficulty highlights the need to group or classify patients according to
tumor behavior and prognosis. Such risk stratification could help classify patients with similar
risk of stage progression and like prognoses. Index patients defined by the Panel below will
assist in determining appropriate therapy for different risk categories. The European Association
of Urology (EAU) has supported recent efforts in the development of risk stratification schemes
and has included them in guidelines for nonmuscle invasive bladder cancer.75
Treatment Alternatives
In most cases of nonmuscle invasive bladder cancer, tumors are treated initially with TURBT. A
careful cystoscopic examination of the entire urethra and all bladder surfaces precedes
resection.55 The position of tumors with reference to the bladder neck and ureteral orifices, the
tumor configuration, whether tumors are papillary or sessile, and estimates of the number of
tumors and their sizes should be noted to assist in future evaluation and follow-up. After
resection of all visible tumors, adjuvant intravesical immunotherapy or chemotherapy can be
used (Table 3).31 Photodynamic therapy and laser ablation have been evaluated as secondary
treatments in specific settings.
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Table 3. Current Treatment Alternatives
Treatment
Indication(s)
Transurethral resection of •
bladder tumor (TURBT)
Intravesical
chemotherapy and
immunotherapy
•
•
•
Laser ablation therapy
•
•
•
Conservative
management (office
fulguration or
cystoscopic surveillance)
•
•
Any suspected urothelial carcinoma; can be the sole
treatment but only in nonmuscle invasive urothelial
carcinoma40
Perioperatively or postoperatively in an adjuvant fashion
To prevent recurrence following TURBT 76-84
Adjunctive therapy in carcinoma in situ where diffuse
tumor prevents complete resection 31,56,85
Treatment of select lower- and upper-tract cancer55,86
Treatment of low-grade papillary tumors
Not appropriate for new lesions prior to tumor
staging/grading
Low risk and recurrent nonmuscle invasive papillary
bladder tumors
Well-documented history of low-grade Ta tumors87-89
Depending on patient and tumor characteristics, a number of patients may benefit from some
form of intravesical therapy. The focus of this Panel’s analyses was largely on the most
commonly employed agents in the United States, bacillus Calmette-Guérin (BCG) and
mitomycin C; however, interferon and other chemotherapeutic agents have been used as well
(Table 4).
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Table 4. Intravesical Immunotherapy and Chemotherapy
Agent
Mechanism of Action
Immunomodulatory Agents
Bacillus Calmette-Guérin •
(BCG)
•
Inflammatory host response; release of cytokines
May be combined with interferons90-94
•
•
•
Lymphocyte activation; cytokine release; phagocyte stimulation
Antiproliferative actions
Antiangiogenic31,90
Chemotherapeutic Agents
Thiotepa
•
Alkylating agent; cross-links nucleic acids95
Mitomycin C
•
Antibiotic; inhibits DNA synthesis76-78
Doxorubicin, epirubicin,
valrubicin
Gemcitabine
•
Intercalating agents; inhibits DNA synthesis75,96-98
•
Deoxycytidine analog; inhibits DNA synthesis99-103
Interferons
Transurethral Resection of Bladder Tumor
Transitional resection of bladder tumor provides histologic assessment as to tumor type, grade,
and depth of invasion (stage). In addition to potentially improving staging accuracy, repeat
TURBT may also improve local control of disease.42,43 Complete eradication of all visible
tumors is accomplished by either resection or fulguration.
Intravesical Chemotherapy and Immunotherapy
Intravesical therapy can be administered in an adjuvant fashion, or as part of a maintenance
regimen to prevent recurrence. Perioperative installation of chemotherapy immediately after
TURBT has been advocated since the 1970s, and is becoming an increasingly common practice
today.76-78 The rationale for perioperative instillation includes the destruction of residual
microscopic tumor at the site of TURBT and of circulating cells, thereby preventing
reimplantation at the time of TURBT. Intravesical therapy can also be employed in a
maintenance fashion as opposed to an induction course alone to provide long-term
immunostimulation or chemotoxicity and thereby prevent disease recurrence.79,80
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Bacillus Calmette-Guérin
Bacillus Calmette-Guérin, a live attenuated strain of Mycobacterium bovis, first indicated as a
tuberculosis vaccine, has had widespread use in intravesical immunotherapy since the 1970s.104
It has since become a first-line treatment for carcinoma in situ and has been shown to be
effective as prophylaxis to prevent bladder cancer recurrences following TURBT.85,105-108
Several products containing different substrains of BCG are available; the viability of BCG
organisms per milligram of vaccine may vary with different substrains and from lot to lot within
the same substrain.31,109,110
Initiation of intravesical BCG therapy is usually delayed for two to three weeks following
TURBT to allow for healing of the urothelium and thereby decrease the risk of systemic side
effects. Most patients develop an inflammatory immunologic response to BCG during a typical
induction course of six weekly instillations. Optimal dosing and instillation schedules have not
yet been established but some recent trials have demonstrated that a reduced dosing regimen
(one-third dose) may be as effective as standard dosing but with fewer side effects.111-113 Metaanalyses (including our own) suggest that maintenance BCG be administered,84,114 although the
optimal schedule and duration of therapy is unknown.
Interferon
Recombinant interferon alpha-2b has been the most commonly utilized interferon to treat
nonmuscle invasive urothelial carcinoma. Intravesical interferon alpha-2b has been shown to
have activity in nonmuscle invasive urothelial carcinoma both as monotherapy and most recently
in combination with low-dose BCG therapy.90-94 These phase II trials have suggested durable
responses in both BCG-naïve and BCG-refractory patients but long-term randomized trials have
yet to be conducted to validate these results.
Thiotepa
Introduced in 1961, thiotepa is the oldest and one of the least expensive of the intravesical drugs.
Doses range from 30 mg in 30 mL of sterile water or saline to 60 mg in 60 mL of water or saline.
The lower dose appeared to be as effective as the higher one in a comparative study when the
concentrations were the same.95 The Medical Research Council Working Party on Urological
Cancer Thiotepa, reported that the lower concentration of 30 mg in 50 mL was not effective.115
The usual regimen consists of six to eight weekly instillations followed by monthly instillations
for one year. A low molecular weight of 189 kd allows partial absorption through the urothelium
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with possible systemic toxicity. Myelosuppression is a risk, especially with the 60 mg dose.
Leukocyte and platelet counts are obtained before each instillation and treatment is delayed if
necessary.
Mitomycin C
Because of its moderately high molecular weight of 329 kd, there are few problems with
transurothelial absorption, and myelosuppression is therefore rare with mitomycin C. Dosage
varies from 20 to 60 mg per instillation; the most 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. Although the optimal method of mitomycin C administration is uncertain, Au et al116
have demonstrated improved recurrence free survival and a prolonged median time to recurrence
using methods to enhance the concentration and activity of mitomycin C in the urine. In this
phase III trial, a six-week intravesical course of 20 mL of mitomycin C at a concentration of 20
mg/mL was found to be inferior to an “optimized” six-week course of mitomycin C which
consisted of a period of dehydration (no fluids for eight hours prior to treatment), urinary
alkalinization (1.3 g NaHC03 by mouth, the night prior, the morning of, and 30 minutes prior to
the intravesical therapy), confirmed complete bladder drainage prior to intravesical instillation of
mitomycin C (postvoid residual <10 mL by ultrasound bladder scanner) and a higher mitomycin
C concentration (40 mg in 20 mL of sterile water).116
Recently, mitomycin C has been commonly used in a perioperative fashion delivered
intravesically immediately after TURBT (or in some studies within 24 hours postoperatively).
Optimal timing post-TURBT has not yet been determined. Several randomized trials and recent
meta-analyses (including our own) have demonstrated a relative-risk reduction with a single
perioperative dose of mitomycin C in patients with nonmuscle invasive urothelial carcinoma
with both low- and high-risk features.76-78 Perioperative mitomycin C should not be administered
to patients with a known or suspected bladder perforation following TURBT as a small number
of serious complications related to mitomycin C extravasation have been reported.117-119
Intercalating Agents (Doxorubicin, Epirubicin, and Valrubicin)
Because its molecular weight of 580 kd is high, absorption and systemic toxicity of the
anthracycline derivative doxorubicin 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. At this time,
epirubicin is not currently available in the United States for the treatment of bladder cancer.
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Valrubicin, a semisynthetic analog of doxorubicin, was approved by the U. S. FDA in 1998 for
the treatment of BCG refractory carcinoma in situ of the bladder in patients who are medically
unfit or refuse a cystectomy, with modest efficacy observed in this setting.98 Although valrubicin
has not been commercially available in the United States over the last few years, it is anticipated
to again become an available chemotherapeutic agent for this disease.
Gemcitabine
Gemcitabine has a broad spectrum of antitumor activity and was first approved in the United
States for the treatment of pancreatic cancer. In recent phase III trials of patients with metastatic
bladder cancer, systemic gemcitabine in combination with cisplatin has been shown to result in
similar survival rates compared to traditional systemic chemotherapeutic regimens, but with
overall better patient tolerability and a better safety profile.99 Recently, intravesical gemcitabine
has been shown to have activity in nonmuscle invasive bladder cancer in intermediate risk and
high risk patients.100-103 Although early results are promising, the limited patient population
evaluated supports the need for additional phase II and randomized phase III trials. Typical
intravesical doses employed include 2 g in 50 to 100 mL of saline given weekly for six weeks
with two-hour dwell times.
Other Therapies
Photodynamic Therapy
Several investigators have evaluated the efficacy of photodynamic therapy in the management of
nonmuscle invasive urothelial carcinoma. The antitumor effects of photodynamic therapy
primarily are due to the creation of reactive oxygen species that result from activation of a
photosensitizing agent within the tissue. The agent is activated by absorbance of wavelengths of
light specific for the spectrum of the agent.120,121 The clinical trials of photodynamic therapy in
the last 30 years have most commonly employed porfimer sodium as its sensitizing agent, but
more recent studies have evaluated the therapeutic effects of 5-ALA. There are very few reports
of the success of photodynamic therapy for bladder carcinoma with long-term follow-up.122,123
Enthusiasm for its use is tempered by its side effects including skin photosensitivity similar to
that in patients with porphyria. In addition, local symptoms including irritating voiding
symptoms, notable tissue sloughing, bladder contracture, and reflux have also been
reported.124,125 Photodynamic therapy is not readily available in the United States.
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Laser Ablation Therapy
The neodymium-doped: yttrium aluminum garnet laser has so far proven to provide the most
versatile wavelength for treating bladder cancer but other wavelengths also have been used.55,86
Lasers are not optimal for the treatment of new bladder lesions as tissue samples are requisite to
determine depth of invasion (stage) and tumor grade. Appropriate patients for this therapy have
papillary, low-grade tumors and a history of low-grade, low-stage tumors.55
Conservative Management
Certain patients with low risk and recurrent nonmuscle invasive bladder tumors may be managed
conservatively with office fulguration of the lesions or even cystoscopic
surveillance.87-89 Only those patients with a well-documented history of low-grade Ta tumors
have been considered for such an approach, in that the surgical and anesthetic risks of multiple
repeated TURBTs in these patients may exceed the low risk of disease progression. Certainly,
larger experiences and confirmatory trials are indicated to validate and support a conservative
approach.
Follow-up
The high frequency of local recurrence and the potential for stage progression especially for
high-risk disease highlights the importance of vigilant surveillance with cystoscopy for patients
with nonmuscle invasive bladder cancer. Furthermore the potential for disease recurrence and
progression even in the long term typically requires and necessitates lifelong follow-up.31,88,126,127
Although a variety of different follow-up strategies have been advocated, the most common
approach has included patient assessment every three months in the first two years after initial
diagnosis followed by every six months for the subsequent two to three years, and then annually
thereafter.31,128 Clinical follow-up involves an appropriate patient history including voiding
symptoms and hematuria, urinalysis, cystoscopy, and urine cytology. Some studies have
suggested that three-month post-TURBT clinical response as determined by follow-up
cystoscopy is an important predictor of recurrence and progression.64,129 At the present time, the
use and utility of urine-based molecular markers in the follow-up of patients remains uncertain.
Surveillance often includes periodic upper tract imaging, especially for high-risk patients.31,34
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Methodology
The methodology of this guideline update was similar to that used in the previous guideline. The
intention was to determine the impact of the various available treatments on the outcomes of
importance to patients. The efficacy outcomes examined were recurrence of bladder tumors and
progression in stage or to cystectomy. The Panel also attempted to estimate the occurrence of
side effects and complications of treatments and focused on post-TURBT treatments. It was
assumed that all patients had TURBT eradication of all visible tumors. The Panel examined the
efficacy of alternative follow-up treatments including repeat TURBT, intravesical immuno- and
chemotherapies and photodynamic therapy. The impact of tumor stage, grade, multiplicity, and
recurrence status on outcomes was also considered. Excluded were treatments that were not
generally available in the United States and were not expected to be approved for general use by
the time the guideline was published. The Panel also decided not to update outcomes for thiotepa
and doxorubicin, treatments included in the previous guideline but deemed less effective than
other agents by the previous panel, and as a result were not included in their analysis.
Literature Search and Data Extraction
The review of the evidence began with a literature search and data extraction. Articles included
were identified on four MEDLINE searches beginning in October 2004 and concluding in
February 2006, and supplemented with existing meta-analyses. Articles published between
January 1, 1998 and December 31, 2005 were included in the analysis. The searches were limited
to human subjects, English language, publication date from 1998 (the cutoff from the previous
guideline) and contained the MeSH heading “bladder neoplasms.” A total of 5,020 citations and
abstracts were reviewed for relevance by the Panel chair and vice chair. In total, data from 322
articles were extracted by the Panel members. Inconsistencies in data recording were reconciled,
extraction errors were corrected, and some articles were excluded by the Panel. A total of 158
articles were accepted for data analysis.
Evidence Combination
The analytic goals were expanded from the previous guideline. In addition to meta-analyzing the
randomized controlled trials to determine if there were significant differences among the
treatments, the Panel also decided to develop outcomes tables which actually provided estimates
of outcomes for the different treatment modalities. For this guideline, the Panel elected to use the
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confidence profile method,130,131 which provides methods for analyzing data from studies that are
not randomized controlled trials. Three different meta-analyses of the efficacy data were
performed.
1. Meta-analysis of the comparable randomized controlled trials to determine the differences
between pairs of available treatments. This analysis provides estimates of the absolute
differences.
2. Meta-analysis of the individual arms of the randomized controlled trials to combine all the
data from such trials for each treatment. This “single-arm” analysis provides an estimate of the
actual rate of occurrence of each outcome.
3. Meta-analysis of the individual arms from all studies regardless of study design. For
complications and side effects, only this method was used.
Hierarchical meta-analysis was used throughout due to the lack of homogeneity among the
studies.
The outcomes analyzed for efficacy included recurrence and progression. For recurrence,
only probability of recurrence (percentage of patients with recurrence) provided sufficient data
for analysis. Time between recurrences, frequency of recurrences, and number of individual
tumor recurrences could not be meta-analyzed. Similarly, the Panel decided that only probability
of overall progression could be analyzed. Overall progression included progression in stage or to
cystectomy. Grade progression could not be analyzed.
The way in which complications were grouped varied from study to study. Different names
were also used for similar complications. The Panel attempted to group complications by
including similar complications in a single group. Only studies that specifically reported data
concerning occurrences of complications were included in the analysis.
The Panel attempted to evaluate outcomes based on a variety of patient characteristics
including stage, grade, tumor multiplicity, and recurrence. However, in most cases, the outcomes
data were not fully or consistently stratified by these conditions. Ultimately, the Panel elected to
include all studies and analyze the data based on high and low risk as well as an analysis
including all studies. Low risk was defined as Grade 1 or low grade. High risk included groups
that had no Grade 1 (low grade) patients or were entirely Tis and/or T1.
Although the Panel originally considered a wide variety of treatments, limited data were
available for many of those of interest. The Panel decided that it could not distinguish between
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the different types of TURBT, including repeat TURBT, so all forms of TURBT were considered
the same. The Panel also considered maintenance therapy versus induction only. A wide variety
of induction and maintenance schedules have been used and reported in the literature. Because
the issues concerning the comparison of BCG with mitomycin C and of maintenance with
induction were so important, the Panel elected to incorporate all randomized controlled trials of
these agents in the analyses including those from the original guideline.
After the evidence was combined and outcome tables were produced, the Panel met to review
the results and identify anomalies. From the evidence in the outcome tables and expert opinion,
the Panel drafted the treatment guideline. As in the previous guideline, the guideline statements
were graded with respect to the degree of flexibility in their application. Although the
terminology has changed slightly, the current three levels are essentially the same as in the
previous guideline. A "standard" has the least flexibility as a treatment policy; a
"recommendation" has significantly more flexibility; and an "option" is even more flexible.
These three levels of flexibility are defined as follows:
1.
Standard: A guideline statement is a standard if: (1) the health outcomes of the
alternative interventions are sufficiently well known to permit meaningful decisions and
(2) there is virtual unanimity about which intervention is preferred.
2.
Recommendation: A guideline statement is a recommendation if: (1) the health
outcomes of the alternative intervention are sufficiently well known to permit
meaningful decisions, and (2) an appreciable but not unanimous majority agrees on
which intervention is preferred.
3.
Option: A guideline statement is an option if: (1) the health outcomes of the
interventions are not sufficiently well known to permit meaningful decisions, or (2)
preferences are unknown or equivocal. Options can exist because of insufficient
evidence or because patient preferences are divided and may/should influence choices
made.
The draft was sent to 88 peer reviewers; the Panel revised the document based on the
comments received from 38. The guideline was submitted for approval to the Practice Guidelines
Committee of the AUA and then to the Board of Directors for final approval.
The guideline is published on the AUA website (http://www.auanet.org). A summary will be
published in The Journal of Urology.
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Results of the Outcomes Analyses
Detailed findings of the efficacy and complications outcomes analyses are found in Chapter 3 of
the guideline while a summary of the results of the complications analysis also is provided in this
section. As mentioned previously, although the Panel considered a wide variety of treatments,
data on the use of TURBT, BCG, and mitomycin C induction and maintenance regimens only
were sufficient for analysis.
The Panel reviewed and analyzed treatment complications from both randomized controlled
and nonrandomized trials. However, a number of limitations precluded meaningful combination
and comparison among treatments, such as various undefined descriptors used among studies for
the same complication. The degree of overlap between different complications was also
impossible to glean from many reports. For example, within the category of lower urinary tract
symptoms (LUTS), if “frequency” was noted in 20% of patients and “urgency” in 18%, it is
likely that a large number of patients had both symptoms, but the exact number is unknown. In
addition, few studies listed the total number of patients who experienced complications or how
many had more than one complication.
Complications were combined into several large categories of bladder contracture,
epididymitis/prostatitis/urethral infections, hematuria, LUTS, fever/chills/flu symptoms, and
systemic infection (See Chapter 3). Lower urinary tract symptoms (including frequency,
urgency, dysuria, etc.) were the most common side effects reported with all of the treatment
options. Such symptoms were reported in 2% of patients treated with TURBT alone, or TURBT
combined with single-dose post-TURBT mitomycin C. This is compared to a rate of 22% to 24%
with multiple-dose mitomycin C with or without maintenance treatment, 38% with induction
BCG, and 57% with induction plus maintenance BCG. Other local symptoms such as hematuria,
bladder pain and prostatitis were also common, and were similar across all intravesical
treatments. Bladder contracture is a rare event for all intravesical therapies, including both
immunotherapy and chemotherapy. Systemic complications including immunologic reactions
(arthralgia, skin rash, and fever/chills/flu symptoms) and other systemic side effects
(malaise/fatigue, nausea/vomiting, altered liver function tests, neurologic symptoms,
cardiovascular or pulmonary problems, and sepsis) were also reported, and were more common
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with regimens containing BCG and/or interferon than those using intravesical chemotherapy or
TURBT alone.
Only a few studies identified the number of patients who were unable to complete the initial
course of therapy due to the side effects, a phenomenon that appeared to be relatively
uncommon.132 Additionally, no significant difference in complications has been reported
between maintenance therapy versus an induction course. This contradicts the experience of the
Panelists and other reports noting side effects do occur fairly frequently during maintenance
regimens especially with immunotherapy regimens. In the Southwest Oncology Group (SWOG)
trial, for example, only 17% of patients in the maintenance arm completed the treatment as
planned largely because of side effects.80 In general, Panel members felt that in patients with
tumors that carry considerable risk of progression and ultimate death from bladder cancer, the
potential benefits of intravesical treatments such as BCG seem to outweigh the risk of serious
complications. On the other hand, the risk of possible serious side effects from intravesical
immunotherapy may outweigh the potential benefit of therapy for those with low-risk lesions.
Consequently, intravesical chemotherapy, especially single-dose chemotherapy, is an important
alternative for low-risk patients.
Treatment Guideline Statements
The Panel based the majority of the following guideline statements on a careful analysis of
comparative outcomes from randomized controlled trials. Included were data published after the
previous guideline was completed as well as results from previous studies involving TURBT and
intravesical therapies. These statements apply to the treatment of patients with nonmuscle
invasive transitional cell carcinoma of the bladder including Tis as well as stages Ta and T1
tumors. Inherent in these guideline statements is the importance of individualizing patient
diagnostic evaluation and therapy. Some of the treatment paradigms addressed below were not
based on data but on Panel experience alone.
In an attempt to recognize commonly encountered clinical variations, the Panel has
designated certain example settings as “index patients.” In establishing these index patients, the
Panel closely examined pressing questions involving the use of intravesical chemotherapy versus
immunotherapy and the role of maintenance therapy. Each guideline statement addresses a
specific index patient.
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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.
[Based on Panel consensus.]
Although a variety of the adjuvant intravesical treatments studied decrease the probability of
bladder cancer recurrence when compared with TURBT alone, published data do not support the
conclusion that the rate of progression to muscle invasive disease is necessarily significantly
altered, especially with low-risk tumors. Physicians should discuss these potential benefits as
well as the possible complications with the patient. Currently, there is little evidence defining
and/or verifying the optimal dose, number of doses, and timing of instillations for either
induction or maintenance intravesical therapy. This lack of uniformity renders the establishment
of a guideline statement regarding specific regimens impossible and increases the difficulty of
comparing therapy types.
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.
[Based on Panel consensus.]
Although laboratory diagnoses can indicate the likelihood 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.
Standard: Under most circumstances, complete eradication of all visible tumors
should be performed.
[Based on Panel consensus.]
When feasible, surgeons should attempt to resect all tumors. The size and/or multiplicity of
tumors or obvious deep muscle invasion may prevent complete resection. Also, comorbid
conditions must be considered and may occasionally influence a decision about whether or not to
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attempt entire endoscopic removal of bladder tumors. Tumor resection can be accomplished with
electrocautery resection, fulguration, or application of laser energy.
Adequate tissue should be available for determination of clinical stage, but in some cases
endoscopic ablative techniques may not permit submission of all material for histologic
evaluation.
Standard: If bladder cancer is confirmed, periodic surveillance cystoscopy should
be performed.
[Based on Panel consensus.]
Neither the ideal interval nor the duration of follow-up cystoscopy has been defined. Given
the variable risk of recurrence and progression, a risk-adapted approach should be considered.
Patients with high-risk disease should undergo more intensive followup.
Option: An initial single dose of intravesical chemotherapy may be administered
immediately postoperatively.
[Based on Panel consensus.]
The immediate use of intravesical chemotherapy was considered an option and not a standard
by the Panel because of potential cost issues, uncertainty of pathology, side effects, and patient
preference. In addition, the use of immediate intravesical chemotherapy would not be beneficial
for bladder tumors that are most likely muscle invasive. In cases where the tumor appears to be
papillary (Ta) by visual inspection and there are no contraindications to therapy, such as bladder
perforation, immediate intravesical chemotherapy should be considered.
For Index Patient No. 2: A patient with small volume, low-grade Ta bladder cancer.
Recommendation: An initial single dose of intravesical chemotherapy may be
administered immediately postoperatively.
[Based on review of the data.]
Although outcomes data pertaining specifically to patients with low-grade, Ta bladder cancer
are limited, the risk of recurrence and more importantly progression is relatively low. Metaanalyses including our own, do confirm, however, for nonmuscle invasive cancer, single
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postoperative instillation does decrease recurrence. In our comparison, the combination of
TURBT and single-dose mitomycin C resulted in 17% (95% confidence interval [CI]: 8, 28)
fewer recurrences than TURBT alone when all patient risk groups were considered. There is no
evidence that multiple adjuvant instillations of either BCG or chemotherapy have additional
benefit in patients at initial diagnosis of Ta Grade 1 bladder cancer.
For Index Patient No. 3: A patient with multifocal and/or large volume, histologically
confirmed, low-grade Ta or a patient with recurrent low-grade Ta bladder cancer.
Recommendation: An induction course of intravesical therapy with bacillus
Calmette-Guérin or mitomycin C is recommended for the treatment of these
patients with the goal of preventing or delaying recurrence.
[Based on review of the data.]
Adjuvant intravesical therapy is useful for nonmuscle invasive tumors. The Panel identified
BCG and mitomycin C because they are the most widely available of the intravesical therapies
and are used in the United States. The results of the analysis demonstrated a decreased
probability of recurrence with either BCG or mitomycin C when compared to TURBT alone. In
our meta-analysis of randomized controlled trials, regardless of patient risk, recurrences were
reduced by 24% (95% CI: 3, 47) with the combination of TURBT and BGG induction only and
by 3% (95% CI: -10, 16) with TURBT and mitomycin C induction only compared with TURBT
alone. While it may appear from these data that BCG is superior to mitomycin C, the wide
confidence intervals do not permit this conclusion.
Option: Maintenance bacillus Calmette-Guérin or mitomycin C may be considered.
[Based on review of the data.]
Maintenance therapy with BCG or mitomycin C is more effective in decreasing recurrences,
when compared to induction alone. However, when considering cost, possible side effects, lack
of a uniform and accepted dosing schedule and, importantly, the low risk of progression in this
index patient, the Panel believes that routine maintenance therapy is an option. The Panel’s metaanalysis of randomized controlled trials published between 1990 and 2006 demonstrated that
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compared to TURBT alone, recurrences are decreased by 31% (95% CI: 18, 42) with TURBT
and BGG maintenance and by 18% (95% CI: 6, 30) with TURBT and mitomycin C maintenance.
It is unclear whether any intravesical therapy affects the ultimate rate of progression to muscle
invasive disease in these low-risk patients. The progression rate estimate in all patient risk
groups was 8% (95% CI: 0, 15) with TURBT and BCG maintenance and 4% (95% CI: -26, 32)
with TURBT and mitomycin C maintenance. Although maintenance therapy reduces recurrence
and may reduce progression, the side effects and discomfort of the treatment and possibly the
costs of the treatment may outweigh the benefits for some patients. Thus, discussion of the
tradeoffs and consideration of patient preferences are important before beginning or continuing
maintenance therapy. The optimal maintenance schedule and duration has yet to be determined.
However, the best available evidence supports the use of the SWOG regimen 80,133 a six-week
induction course of BCG followed by a three-week maintenance course at 3, 6, 12, 18, 24, 30,
and 36 months (if tolerated by the patient). This regimen was used in, by far, the largest trial that
demonstrated the benefit of maintenance BCG therapy.
For Index Patient No. 4: A patient with initial histologically confirmed high-grade Ta, T1,
and/or carcinoma in situ bladder cancer.
Standard: For patients with lamina propria invasion (T1) but without muscularis
propria in the specimen, repeat resection should be performed prior to additional
intravesical therapy.
[Based on review of the data and Panel consensus.]
Disease-appropriate therapy is predicated on accurate staging. Despite continued attempts to
improve clinical staging, however, a significant percentage of patients are understaged. In the
absence of muscularis propria in the specimen, data suggests that 20% to 40% of patients will
have either residual tumor and/or unrecognized muscle invasive disease.134-136 With the lack of
accurate noninvasive clinical staging modalities, efforts should be focused on acquiring a
definitive tissue diagnosis. Repeat resection may also be appropriate for patients with high-grade
Ta tumors as well as patients with T1 tumors and muscularis propria in the specimen to increase
the accuracy of clinical staging.
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Recommendation: An induction course of bacillus Calmette-Guérin followed by
maintenance therapy is recommended for treatment of these patients.
[Based on review of the data.]
As with Index Patient No. 3, both BCG and mitomycin C are intravesical therapies that can
favorably prolong recurrence-free rates. However, in this high-risk group, maintenance BCG is
superior to mitomycin C with or without maintenance. In our single-arm meta-analysis of
randomized controlled trials of high-risk patients, the estimated five-year recurrence rate was
34% in patients receiving TURBT and BCG maintenance and 62% with mitomycin C
maintenance. The meta-analysis of all risk groups found that, compared with TURBT and
mitomycin C maintenance, TURBT and BCG maintenance therapy reduced recurrence by 17%
(95% CI: 7, 26). In addition, there are limited data suggesting a trend to preventing progression
with maintenance BCG. The progression in one study of 380 patients was reduced by 5% (95%
CI: -1, 11) with TURBT plus BCG maintenance when compared with TURBT plus mitomycin C
maintenance.84 Although maintenance therapy reduces recurrence and may reduce progression,
the side effects and discomfort of the treatment and possibly the costs of the treatment may
outweigh the benefits for some patients. Thus, discussion of the tradeoffs and consideration of
patient preferences is important before beginning or continuing maintenance therapy.
Option: Cystectomy should be considered for initial therapy in select patients.
[Based on review of the data and Panel consensus.]
Because there is risk of initially understaged muscle invasive disease or progression to
muscle invasive disease even after intravesical therapy, cystectomy may be considered as an
initial treatment option in certain cases.137,138 It is not certain whether intravesical therapy alters
this risk of progression. In addition, the high cure rate associated with patients undergoing
cystectomy further justifies this decision choice.139-141 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, the presence of carcinoma in situ, infiltration of lymphatic or
vascular spaces, and prostatic urethral involvement.64,66,129,142 Cystectomy, however, is not
without its possible complications and morbidity. Physicians should present specific information
about the risks of cystectomy and methods for urinary reconstruction to patients who are
contemplating bladder removal.
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For Index Patient No. 5: A patient with high- grade Ta, T1, and/or carcinoma in situ bladder
cancer which has recurred after prior intravesical therapy.
Standard: For patients with lamina propria invasion (T1) but without muscularis
propria in the specimen, repeat resection should be performed prior to additional
intravesical therapy.
[Based on review of the data and Panel consensus.]
This guideline statement is the same for Index Patient 4. In this setting, accurate clinical
staging is crucial for appropriate therapy.
Recommendation: Cystectomy should be considered as a therapeutic alternative for
these patients.
[Based on review of the data.]
Even more so than patients who initially present with high-risk disease, those who fail initial
intravesical therapy should be considered for cystectomy.137 There is a substantial risk of
progression to muscle invasive cancer in these patients. The high likelihood of intravesical
treatment failure and adverse consequences of delaying cystectomy make cystectomy the
preferred treatment for these patients.
Option: Further intravesical therapy may be considered for these patients.
[Based on review of the data and Panel consensus.]
There is some evidence that select patients will respond to second induction regimens,
particularly with BCG.80,143,144 Repeat intravesical therapy may be appropriate in patients who
develop a late recurrence after previous complete response to an intravesical agent. However, in
patients at high risk for progression, further intravesical therapy puts the patient at risk for
muscle invasion and/or metastasis.137 Data are insufficient, however, to support conclusions
about the role of drug combination regimens or the beneficial effect of alternating therapies.
.
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Future Research Needs
As illustrated in this evidence-based review, large, often multicenter, randomized, controlled
trials have helped define the role of TURBT and the added benefits and risks of intravesical
immunotherapy and chemotherapy for the treatment of bladder cancer. To date, most studies
have focused primarily on the risk of recurrence and if recurrence can be decreased with
intravesical therapy. However, progression is a more important outcome with lethal implications,
and yet, the reduction of progression to muscle invasion remains definitively unproven and the
endpoint of disease-specific survival is often unexamined.
Although many published studies have tested a variety of drugs and delivery regimens, they
have failed to separate outcomes based on initial patient tumor characteristics such as number,
size, stage, and grade. This lack of uniformity makes it very difficult to compare results between
different observational or randomized trials. Although meta-analyses have been performed, it is
difficult not to include discordant groups and thus compare groups of patients with inherently
different risks of recurrence and progression or who receive different treatments. Many newer
treatments and combinations of treatments have not yet been tested in large phase III trials. The
clinician who today is faced with a patient who presents with a specific clinical picture is still
often uncertain as to which treatment to recommend. This guideline attempts to provide a
rational approach to these complex patients.
While tumor grade and the stage of nonmuscle invasive tumors can stratify risk for
progression to muscle invasion, clinical understaging remains a difficult treatment situation and
only contributes to the importance of better determining a patient’s real prognosis. Profiling of
tissue and urine promise to provide better risk assignment and optimally to direct targeted
treatment so as to increase efficacy and minimize toxicity.
The risk and significance of urothelial carcinoma outside the bladder must be further
determined. Especially in patients with carcinoma in situ, urothelial cancers within the ureter or
intrarenal collecting system may also occur at a frequency far exceeding the 5% previously
accepted incidence. Periodic monitoring of the upper urinary tract is of value, 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
carcinoma in situ, even in the absence of identifiable disease within the bladder.
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Historically, cystoscopic bladder surveillance for patients with nonmuscle invasive bladder
cancer has been performed every three months for at least a year and with a progressively
declining frequency after that point. Advances in molecular biology hold the promise of some
day accurately predicting in advance which therapy is most likely to succeed and which tumors
will not respond to intravesical therapy. With that knowledge, cystectomy can be offered early to
those most likely to benefit.
Reporting of Bladder Cancer Data
The discoveries that will improve diagnosis and predict the biologic activity of urothelial cancer
and response to various therapies are forthcoming. One strategy that is immediately available to
improve the database of information and therefore the validity of conclusions regarding
diagnosis, therapy, and outcomes is the construction of and adherence to a uniform system of
reporting. The extraordinary individual variability of both observational and randomized
controlled trials makes it very difficult to consolidate data in a meaningful fashion to permit
robust conclusions despite the large number of patients that might be involved in the trial. The
Panel suggests that authors refer to the CONSORT guidelines145 and also proposes the following
suggestions for authors to follow in their reporting of randomized controlled trials or
observational cohort studies. This template does not in any way attempt to compromise or
marginalize current data but provides an organization that will allow future guidelines to be more
informative.
To allow optimal comparison between treatment outcomes, the Panel proposes that future
research in Ta and T1 bladder cancer include the following standard parameters for either
observational studies or prospective clinical trials:
1. A table delineating outcomes stratified by stage (Ta, T1, Tis, or Ta, T1 with or without
Tis) and grade, as the risk associated with these tumor categories is different.
2. A table delineating outcomes stratified by whether tumors are primary or recurrent and
solitary or multiple. This would allow comparison of individual patient situations.
3. Reporting of endpoints, including recurrence and/or progression, using Kaplan-Meier
methodology for graphic and tabular data at defined 12-month intervals and specifying
the number of patients followed at each interval.
4. Separate reporting of grade or stage of progression with emphasis on progression from
nonmuscle involvement to muscle invasion.
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5. The specific total number of complications that occurred and the number of patients
reporting each complication.
Similarly, it has been almost impossible to compare complications associated with various
treatments because of the tremendous variability in reporting methods. Ideally, we would
develop a standardized system of reporting similar to that of the National Institutes of Health
Common Toxicity Assessment system which would allow us to compare the type and severity of
complications experienced by patients treated in different studies. However, until that is
available and accepted, we would propose that the following minimum reporting information on
complications be included with each study report:
1. The number of patients for whom complications either resulted in a delay in therapy or
withdrawal from therapy. In addition, it is important to report when this occurred (i.e., at
what point during therapy).
2. The total number of patients who experienced local or systemic side effects or both.
3. Combination of specific lower urinary tract symptoms (frequency, urgency, dysuria) into
a “LUTS” category.
4. The number of patients who developed severe side effects such as debilitating bladder
contracture or complications requiring surgery or hospitalization.
If clinical studies of new treatments follow these reporting criteria, we will have powerful
tools to compare treatment outcomes in the future.
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32
Acknowledgements and Disclaimers
AUA Guideline for the Management of Nonmuscle Invasive Bladder Cancer: (Stages Ta, T1,
and Tis): 2007 Update
The supporting systematic literature review and data analysis, and the drafting of this document
were conducted by the Bladder Cancer Guideline Update Panel (the Panel) created in 2005 by
the American Urological Association Education and Research, Inc. (AUA). The Practice
Guidelines Committee (PGC) of the AUA selected the Panel chair and vice chair who in turn
appointed the Panel members, urologists with specific expertise in this disease.
The mission of the Panel was to develop either analysis- or consensus-based recommendations, depending on the type of evidence available and Panel processes to support optimal
clinical practices in the management of nonmuscle invasive bladder cancer. This document was
submitted to 88 urologists and other health care professionals for peer review. After revision of
the document based upon the peer review comments, the guideline was submitted to and
approved by the PGC and the Board of Directors of the AUA. Funding of the Panel and of the
PGC was provided by the AUA, although Panel members received no remuneration for their
work. Each member of the PGC and of the Panel furnished a current conflict of interest
disclosure to the AUA.
The final report is intended to provide medical practitioners with a current understanding
of the principles and strategies for the management of nonmuscle invasive bladder cancer. The
report is based on an extensive review of available professional literature, as well as clinical
experience and expert opinion. Some of the medical therapies currently employed in the
management of bladder cancer have not been approved by the U. S. Food and Drug
Administration (FDA) for this specific indication. Thus, doses and dosing regimens may deviate
from that employed for FDA-approved indications, and this difference should be considered in
the risk-versus-benefit assessment.
This document provides guidance only, and does not establish a fixed set of rules or
define the legal standard of care. As medical knowledge expands and technology advances, the
guideline will change. Today the guideline statements represent not absolute mandates but
provisional proposals or recommendations for treatment under the specific conditions described.
For all these reasons, the guideline does not preempt physician judgment in individual cases.
Also, treating physicians must take into account variations in resources, and in patient tolerances,
needs, and preferences. Conformance with the guideline reflected in this document cannot
guarantee a successful outcome.
Copyright © 2007 American Urological Association Education and Research, Inc.®
33
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113. Mugiya S, Ozono S, Nagata M, Takayama T, Ito T, Maruyama S et al: Long-term outcome
of a low-dose intravesical bacillus Calmette-Guerin therapy for carcinoma in situ of
the bladder: results after six successive instillations of 40 mg BCG. Jpn J Clin Oncol
2005; 35: 395.
114. Han RF and Pan JG: Can intravesical bacillus Calmette-Guerin reduce recurrence in
patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology
2006; 67: 1216.
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115. The effect of intravesical thiotepa on tumour recurrence after endoscopic treatment of newly
diagnosed superficial bladder cancer. A further report with long-term follow-up of a
Medical Research Council randomized trial. Medical Research Council Working Party
on Urological Cancer, Subgroup on Superficial Bladder Cancer. Br J Urol 1994; 73: 632.
116. Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL et al: Methods
to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.
J Natl Cancer Inst 2001; 18: 597.
117. Nieuwenhuijzen JA, Bex A and Horenblas S: Unusual complication after immediate
postoperative intravesical mitomycin C instillation. Eur Urol 2003; 43: 711.
118. Racioppi M, Porreca A, Foschi N, Delicato G, Destito A and D’Addessi A: Bladder
performance: a potential risk of early endovesical chemotherapy with mitomycin C.
Urol Int 2005; 75: 373.
119. Cliff AM, Romaniuk CS and Parr NJ: Perivesical inflammation after early mitomycin C
instillation. BJU Int 2000; 85: 556.
120. Nseyo UO: Photodynamic therapy. Urol Clin North Am 1992; 19: 591.
121. Manyak MJ: Photodynamic therapy: principles and urologic applications. Semin Urol 1991;
9: 192.
122. Hisazumi H, Misaki T and Miyoshi N: Photoradiation therapy of bladder tumors. J Urol
1983; 130: 685.
123. Prout GR Jr, Lin CW, Benson R Jr, Nseyo UO, Daly JJ, Griffin PP et al: Photodynamic
therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell
carcinoma of the bladder. N Engl J Med 1987; 317: 1251.
124. Harty JI, Amin M, Wieman TJ, Tseng MT, Ackerman D and Broghamer W:
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Complications of whole bladder dihematoporphyrin ether photodynamic therapy. J Urol
1989; 141: 1341.
125. Manyak MJ: Practical aspects of photodynamic therapy for superficial bladder carcinoma.
Tech Urol 1995; 1: 84.
126. Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC and Fair WR: The untreated
natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997;
158: 62.
127. Leblanc B, Duclos AJ, Bénard F, Côté J, Valiquette L, Paquin JM et al: Long-term
followup of initial Ta grade 1 transitional cell carcinoma of the bladder. J Urol 1999;
162: 1946.
128. Sengupta S and Blute ML: The management of superficial transitional cell carcinoma of the
bladder. Urology 2006; 67: 48.
129. Solsona E, Iborra I, Dumon R, Rubio-Briones J, Casanova J and Almenar S: The 3-month
clinical response to intravesical therapy as a predictive factor for progression in patients
with high risk superficial bladder cancer. J Urol 2000; 164: 685.
130. Eddy DM: The confidence profile method: a Bayesian method for assessing health
technologies. Oper Res 1989; 37: 210.
131. Eddy DM, Hasselblad V and Shachter A: A Bayesian method for synthesizing evidence.
The Confidence Profile Method. Int J Technol Assess Health Care 1990; 6: 31.
132. van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV and EORTC
Genito-Urinary Tract Cancer Group: Maintenance Bacillus Calmette-Guerin for Ta
T1 bladder tumors is not associated with increased toxicity: results from a European
Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III
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Trial. Eur Urol 2003; 44: 429.
133. Böhle A and Bock PR: Intravesical bacille Calmette-Guerin versus mitomycin C in
superficial bladder cancer: formal meta-analysis of comparative studies on tumor
progression. Urology 2004; 63: 682.
134. Dutta SC, Smith JA Jr, Shappell SB, Coffey CS, Chang SS and Cookson MS: Clinical
under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical
cystectomy. J Urol 2001; 166: 490.
135. Schwaibold HE, Sivalingam S, May F and Hartung R: The value of second transurethral
resection for T1 bladder cancer. BJU Int 2006; 97: 1199.
136. Brauers A, Buettner R and Jakse G: Second resection and prognosis of primary high risk
superficial bladder cancer: is cystectomy of ten too early? J Urol 2001; 165: 808.
137. Herr HW and Sogani PC: Does early cystectomy improve the survival of patients with high
risk superficial bladder tumors? J Urol 2001; 166: 1296.
138. May M, Nitzke T, Helke C, Vogler H and Hoschke B: Significance of the time period
between diagnosis of muscle invasion and radical cystectomy with regard to the
prognosis of transitional cell carcinoma of the urothelium in the bladder. Scand J Urol
Nephrol 2004; 38: 231.
139. Bianco FJ Jr, Justa D, Grignon DJ, Sakr WA, Pontes JE and Wood DP Jr: Management of
clinical T1 bladder transitional cell carcinoma by radical cystectomy. Urol Oncol 2004;
22: 290.
140. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S et al: Radical cystectomy
in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin
Oncol 2001; 19: 666.
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141. Hassan JM, Cookson MS, Smith JA Jr, Johnson DL and Chang SS: Outcomes in patients
with pathological carcinoma in situ only disease at radical cystectomy. J Urol 2004;
172: 882.
142. Kurth KH, Denis L, Bouffioux C, Sylvester R, Debruyne FM, Pavone-Macaluso M et al:
Factors affecting recurrence and progression in superficial bladder tumours. Eur J Cancer
1995; 31A: 1840.
143. de Reijke TM, Kurth KH, Sylvester RJ, Hall RR, Brausi M, van de Beek K et al: Bacillus
Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ
of the bladder: results of a European Organization for the Research and Treatment of
Cancer – Genito-Urinary Group Phase III Trial (30906). J Urol 2005; 173: 405.
144. Catalona WJ, Hudson MA, Gillen DP, Andriole GL and Ratliff TL: Risks and benefits of
repeated courses of intravesical bacillus Calmettte-Guerin therapy for superficial bladder
cancer. J Urol 1987; 137: 220.
145. CONSORT guidelines. http://www.consort-statement.org. Accessed September 4, 2007.
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Chapter 2: Methodology
Table of Contents
Introduction..................................................................................................................................... 2
Problem Definition.......................................................................................................................... 2
Literature Search and Data Extraction............................................................................................ 2
Evidence Combination.................................................................................................................... 3
Efficacy Analysis........................................................................................................................ 5
Complications ............................................................................................................................. 6
Patient Groups................................................................................................................................. 7
Treatments....................................................................................................................................... 7
Guideline Generation and Approvals.............................................................................................. 8
Dissemination ................................................................................................................................. 8
References....................................................................................................................................... 9
Copyright © 2007 American Urological Association Education and Research, Inc.®
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Introduction
This guideline used an explicit approach to address the relevant factors for choosing among
alternative interventions.1 These factors included outcomes of the interventions, patient
preferences, and the relative priorities of interventions given limited health care resources. In
developing the guideline, the Panel used scientific evidence to estimate outcomes of treatment
modalities as accurately as possible. Panel members themselves served as proxies for patients in
considering preferences with regard to health and economic outcomes.
The steps taken to develop this guideline are summarized in Chapter 1 and described in detail
in the present Chapter. Steps included problem definition, literature search, data extraction,
systematic evidence combination, guideline generation, approval, and dissemination.
Problem Definition
This guideline update was based on the original American Urological Association (AUA)
guideline, Report on The Management of Non-Muscle-Invasive Bladder Cancer (Stages Ta, T1
and Tis) published in 1999.2 The methodology was similar to that used in the previous guideline.
The intention was to determine the impact of the various available treatments on outcomes of
importance to patients. The efficacy outcomes examined were recurrence of bladder tumors and
progression in stage or to cystectomy. The Panel also attempted to estimate the occurrence of
side effects and complications of treatments. The Panel focused on treatments given to patients
after transurethral resection of bladder tumor (TURBT). It was assumed that all patients had
TURBT eradication of all visible tumors. The Panel examined the efficacy of alternative followon treatments including repeat TURBT, phototherapy, intravesical chemotherapy, and
intravesical immunotherapy. The Panel also considered the impact of tumor stage, grade,
multiplicity, and recurrence status on outcomes. Treatments that were not generally available in
the United States and were not expected to be approved for general use by the time of the release
of the guideline were excluded from the analysis. The Panel also decided not to update outcomes
for treatments that were deemed less effective in the previous guideline, namely thiotepa and
doxorubicin.
Literature Search and Data Extraction
The review of the evidence began with a literature search and data extraction. Articles were
selected from a database, based on a series of four MEDLINE searches beginning in October
Copyright © 2007 American Urological Association Education and Research, Inc.®
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2004 and concluding in February 2006. Articles published between January 1, 1998 (the closing
date of the search for the previous guideline) and December 31, 2005 were included in the
analysis. The searches were limited to human subjects, English language, and contained the
MeSH heading “bladder neoplasms.” Additional searches were conducted using various
treatment options and the term “bladder cancer,” but no additional records were detected.
Finally, a review of existing meta-analyses revealed two articles published during the time period
captured in the previous guideline that had been missed and were thus included in the dataset for
the update. A total of 5,020 citations and abstracts were reviewed for relevance (Appendix 3).
The abstracts were reviewed by the Panel chair and vice chair, and an article was selected for
data extraction if either chair felt it might have useful data. In total, 322 articles entered the
extraction process. A data extraction form was developed, tested, and revised (see Appendix 4).
The Panel was trained in data extraction. After double review and quality control of the initial
extractions, single Panel members extracted data from the articles. The final versions of the
extracted data were entered into a Microsoft Access® (Microsoft, Redmond, WA) database. The
Panel met in person and via conference calls to review the extracted data. Inconsistencies in data
recording were reconciled, extraction errors were corrected, and some articles were excluded.
Reasons for excluding articles from further analysis were as follows:
1. The article was included in the previous guideline.
2. The article did not provide usable data on the outcomes of interest.
3. Results for patients with muscle invasive tumors could not be separated from those
without muscle invasion.
4. Either the treatments used were not current or they were not the focus of this analysis.
5. The article was a review article or only provided data reported elsewhere.
A total of 158 articles were accepted although some were later rejected for specific uses. A
complete list of these citations ordered by primary author is provided in Appendix 5. Note that
articles excluded from evidence combination remained candidates for discussion in the text of
the guideline.
Evidence Combination
The analytic goals were expanded from the previous guideline. In addition to meta-analyzing the
randomized controlled trials to determine if there were significant differences among the
treatments, the Panel also decided to develop outcomes tables and to actually provide estimates
Copyright © 2007 American Urological Association Education and Research, Inc.®
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of outcomes for the different treatment modalities. To generate an outcome table, estimates of
the probabilities and/or magnitudes of the outcomes are required for each intervention. Ideally,
these come from a synthesis or combination of the evidence. Such a combination can be
performed in a variety of ways depending on the nature and quality of the evidence. For
example, if there is one good randomized controlled trial, the results of that trial alone may be
used in the outcome table while findings of other studies of lesser quality are ignored.
Alternatively, if there are no studies of satisfactory quality for certain outcome table cells or if
available studies are not commensurable, expert opinion may be used to complete those cells.
Finally, if a number of studies have some degree of relevance to a particular cell or cells, then
meta-analytic mathematical methods may be used.
A variety of specific meta-analytic methods are available, and selection of a particular
method depends on the nature of the evidence. For this guideline, the Panel elected to use the
confidence profile method,3,4 which provides methods for analyzing data from studies that are
not randomized controlled trials.
Three different meta-analyses of the efficacy data were performed:
1.
Meta-analysis of the comparable randomized controlled trials to determine the
differences between pairs of available treatments. This analysis provides estimates of
the absolute differences.
2.
Meta-analysis of the individual arms of the randomized controlled trials to combine all
the data from such trials for each treatment. This “single-arm” analysis provides an
estimate of the actual rate of occurrence of each outcome.
3.
Meta-analysis of the individual arms from all studies regardless of study design. For
complications and side effects, only this method was used.
The Fast*Pro software was used to perform the meta-analyses.5 Many of the studies included
in the meta-analysis had varying results. The variation in outcomes from study to study may have
resulted from differences in patient populations, in how the intervention was performed, or in the
skill of those performing the intervention. Given these differences, a random effects or
hierarchical model was used to combine the studies.
A random-effects model assumes that there is an underlying true rate for the outcome being
assessed for each study. It further assumes that this underlying rate varies from site to site. This
Copyright © 2007 American Urological Association Education and Research, Inc.®
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site-to-site variation in the true rate is assumed to be normally distributed. The method of metaanalysis used in analyzing the data attempts to determine this underlying distribution.
The results of the Confidence Profile Method are probability distributions that are described
using the median of the distribution with a confidence interval.4 In this case, the 95% confidence
interval indicates that the probability (Bayesian) of the true value being outside the interval is
5%. These Bayesian confidence intervals are sometimes called credible intervals.
The Bayesian method of computation assumes a “prior” distribution that reflects knowledge
about the probability of the outcome before the results of any experiments are known. The prior
distributions selected for this analysis are among a class of “noninformative” prior distributions,
which means that they correspond to little or no prior knowledge. The existence of such a prior
distribution can cause small changes in results, particularly for small studies. The prior
distribution for all probability parameters is Jefferey’s prior (beta distribution with both
parameters set to 0.5). The prior for the variance for the underlying normal distribution is gamma
distributed with both parameters set to 0.5.
In addition to the outcomes tables, graphs (Appendices 6 to 8) were developed to visually
show selected treatment differences.
It is important to note that, for certain outcomes, more data were reported for one or another
treatment modality. While resulting confidence intervals reflect available data, the probabilities
for certain outcomes can vary widely from study to study within one treatment modality. In
addition, the fact that data from only one randomized controlled trial were evaluable may have
somewhat biased results. For example, differences in patient selection may have had more
weight in analyses than differing treatment effects. Nevertheless, the results obtained reflect the
best outcome estimates presently available.
Efficacy Analysis
The outcomes analyzed for efficacy included recurrence and progression. A variety of methods
of measuring recurrence were extracted, including probability of recurrence (percentage of
patients with recurrence), time to recurrence, and time between recurrences. However, only
probability of recurrence provided sufficient data for analysis. Similar measures also existed for
progression, including time to progression and probability of progression. Moreover, there were
different types of progression recorded including stage, grade, metastasis, and cystectomy.
Copyright © 2007 American Urological Association Education and Research, Inc.®
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Ultimately, the Panel decided that only probability of progression could be analyzed.
Progression was defined as progression in stage or to cystectomy.
The meta-analyses were conducted in three ways:
1.
Meta-analysis of comparable randomized controlled trials—this method used
controlled trial data as reported to determine the difference between two treatments.
The meta-analytic result gives an estimate of the absolute magnitude of the difference
and whether it reaches statistical significance (p<0.05).
2.
Meta-analysis of comparable arms of randomized controlled trials—this method
combines the individual arms reflecting the same treatment from controlled trials. For
example, if one randomized controlled trial compared TURBT alone to mitomycin C
and another compared mitomycin C to bacillus Calmette-Guérin (BCG), the two
mitomycin C arms would both be included in creating the mitomycin C estimate.
3.
Meta-analysis of comparable arms from all studies—this method combines arms as in
method two but includes data from clinical series as well as randomized controlled
trials.
Thus three outcomes tables exist for the efficacy data. The outcomes tables for methods two and
three are formatted the same. Because the first method produces pair-wise results, the table is
necessarily formatted differently.
Data from randomized controlled trials dealing with mitomycin C and/or BCG from the data
extracted for the previous guideline were included in all three analyses. Other data from the
previous guideline were not included.
One issue that is problematic when meta-analyzing data about time points is how to deal with
losses to follow-up. Although most studies reported Kaplan-Meier data for recurrence (fewer for
progression), not all studies provided the number of patients at risk. In order to avoid penalizing
those studies which included numbers at risk, the initial study size was used as the denominator
in all meta-analyses at all time points.
Complications
Different studies grouped complications into varying categories. They also used different terms
for similar complications. The Panel grouped complications in an attempt to include all similar
complications. Complications were variably reported. Only studies that specifically reported data
concerning occurrences of complications were included in complication analyses. The Panel did
Copyright © 2007 American Urological Association Education and Research, Inc.®
6
not assume that the lack of reporting implied the lack of occurrence of any specific complication.
Also, some investigators may only have reported complications that had occurred and did not
report that a complication did not occur. Combining complications into categories reduced the
possibility of an overestimation of the complication rate. The probability that a patient would
have a complication was still most likely slightly overstated because some patients experienced
multiple complications. Thus, the result of the meta-analysis was best interpreted as the mean
number of complications the patient may experience rather than as the probability of having a
complication. There were insufficient data to permit meaningful meta-analyses of patient deaths.
The estimates of death rates provided in the guideline result from the Panel's expert opinion and
the limited available data.
Patient Groups
The Panel attempted to evaluate outcomes based on a variety of patient characteristics including
stage, grade, tumor multiplicity, and recurrence. However, in most cases, the outcomes data were
not fully or consistently stratified by these conditions. Ultimately, the Panel elected to analyze
the combined data from all studies and also the individual data sets for high- and low- risk
patients. Low risk was defined as Grade 1. High risk included groups that had no Grade 1
patients or were entirely carcinoma in situ and/or T1.
Treatments
The Panel considered a wide variety of treatments. However, limited data were available for
many of the treatments of interest. Ultimately, the Panel decided that it could not distinguish
between the different types of TURBT, including repeat TURBT. All forms of TURBT were
considered the same. The Panel also considered maintenance therapy versus induction only. A
wide variety of induction and maintenance schedules have been used and reported in the
literature. The Panel ultimately decided that any treatment administered for a longer time period
than an initial induction regimen would be considered as maintenance therapy. Finally, a single
postoperative dose of mitomycin C was examined as a third alternative dosing regimen.
Because the issues surrounding the comparison of BCG and mitomycin C maintenance
therapy and induction alone were so important, the Panel elected to combine data from the
randomized controlled trials included in the original guideline with the data from the current
Copyright © 2007 American Urological Association Education and Research, Inc.®
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analyses. Nonrandomized studies or studies of other regimens from the earlier guideline were
not included.
Guideline Generation and Approvals
After the evidence was combined and outcome tables were produced, the Panel met to review the
results and identify anomalies. Additional teleconferences were held to review updates to the
outcomes tables based on the problems identified. From the evidence in the outcome tables and
expert opinion, the Panel drafted the treatment guideline. The draft was sent to 88 peer reviewers
of whom 38 provided comments; the Panel revised the document based on the comments
received. The guideline was submitted for approval first to the Practice Guidelines Committee of
the AUA. It was then forwarded to the Board of Directors for final approval.
Dissemination
The guideline is published on the AUA website http://www.auanet.org/. A summary will be
published in The Journal of Urology.
Copyright © 2007 American Urological Association Education and Research, Inc.®
8
References
1. Eddy DM: Manual for Assessing Health Practices & Designing Practice Policies: The
Explicit Approach. Philadelphia: American College of Physicians – American
Society of Guternal Medicine 1992; p 126.
2. Smith JA Jr, Labasky RF, Montie JE, Rowland RG, Cockett ATK and Fracchia JA: Report
on the management of non-muscle-invasive bladder cancer (stages Ta, T1 and
Tis). http://www.auanet.org/guidelines/. Accessed September 4, 2007.
3. Eddy DM: The confidence profile method: a Bayesian method for assessing health
technologies. Oper Res 1989; 37: 210.
4. Eddy DM, Hasselblad V and Shachter R: A Bayesian method for synthesizing evidence:
The Confidence Profile Method. Int J Technol Assess Health Care 1990; 6: 31.
5. Eddy DM and Hasselblad V: Fast*Pro. Software for Meta-analysis by the Confidence
Profile Method. Boston: Academic Press 1992; p 196.
Copyright © 2007 American Urological Association Education and Research, Inc.®
9
Chapter 3: Outcomes Analysis for the Treatment of Nonmuscle Invasive
Bladder Cancer
Table of Contents
Introduction..................................................................................................................................... 2
Efficacy Outcomes: Recurrence and Progression........................................................................... 2
Types of Treatment Interventions................................................................................................... 3
Efficacy Outcomes - Results of the Analysis ................................................................................. 3
Primary Therapy ......................................................................................................................... 9
Maintenance Therapy ............................................................................................................... 13
Previously Published Meta-analyses............................................................................................. 19
Complications of Treatment ......................................................................................................... 22
References..................................................................................................................................... 32
Copyright © 2007 American Urological Association Education and Research, Inc.®
1
Introduction
The patient with nonmuscle invasive bladder cancer is concerned with the prevention of tumor
recurrence and progression in addition to the discomfort, inconvenience, cost, and side- effect
profile of the available treatment alternatives. Since publication of the initial report of the
American Urological Association (AUA) Bladder Cancer Guideline Panel in 1999,1 much has
been learned about the efficacy of various intravesical agents and of other potential treatment
strategies such as the efficacy of immediate postoperative intravesical chemotherapy and the use
of intravesical maintenance therapy. However, considerable uncertainty still exists regarding the
relative value of the different intravesical agents as well as the efficacy of the newer treatment
strategies.
The report reflects the current Panel’s careful meta-analysis of published studies and attempts
to address the outcomes of importance to the patient and treating physician. Our meta-analysis
combined with published data is the basis for the treatment guidelines presented in Chapter 1.
Efficacy Outcomes: Recurrence and Progression
The primary treatment for nonmuscle invasive transitional cell cancer is transurethral resection
(TURBT). Although TURBT is an essential diagnostic tool and an effective therapy, 45%
(confidence interval [CI]: 37 to 54) of patients will have tumor recurrence within 12 months of
TURBT alone. Tumor recurrence is hypothesized to be due to a combination of missed tumors,
an incomplete initial resection, implantation of tumor cells shed at the time of the resection,
and/or a de novo tumor occurrence from “at-risk” urothelium. A second, less frequent, but more
consequential outcome is the 3% to 15% risk of tumor progression to muscle invasive and/or
metastatic bladder cancer. Progression can also include the chance of cancer-related death.
In this analysis, we have examined both the early and late risk of recurrence as well as the
risk of progression following intravesical chemo- or immunotherapy. Every attempt was made to
report outcomes stratified by risk of recurrence based on known clinicopathological parameters
(e.g., grade, stage, size of tumor, and multiplicity). Assessing the effect of intravesical therapy on
overall and bladder cancer-specific survival was hindered and limited by the small number of
events reported in the literature. Every attempt was made to distinguish outcomes between
different types of nonmuscle invasive cancer (e.g., Ta versus T1, or versus carcinoma in situ).
Despite these efforts, our ability to do so was limited because many of the studies analyzed did
Copyright © 2007 American Urological Association Education and Research, Inc.®
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not provide outcomes data stratified by various risk factors such as stage and grade.
Furthermore, we were limited in assessing progression and survival because of a paucity of data
for these endpoints, which was most likely a consequence of the comparatively short length of
follow-up provided in most randomized controlled trials compared to the long, natural history of
nonmuscle invasive bladder cancer.
Types of Treatment Interventions
The literature is replete with a variety of novel interventions to prevent recurrence and possibly
progression of nonmuscle invasive bladder cancer. The breadth of the variety reflects the
ingenuity of urologists and physicians worldwide, however, the consequence of testing many
hypotheses in small, often inadequately powered trials is the paucity of useful data to generate
guidelines that can be applied in general urological practice to patients with Ta, T1, and
carcinoma in situ bladder cancer.
To formulate a useful guideline, the Panel first excluded therapies that are not readily
available in the United States. Second, for the purposes of the new meta-analysis, the Panel
chose to focus on data and outcomes reported in randomized controlled trials. The use of less
rigorous selection criteria makes comparisons of outcome data difficult because of the wide
variations in both the nature of the disease and the types of treatments. The use of strict criteria
provides the most direct and accurate information for the purpose of developing treatment
guidelines. Finally, in an attempt to provide specified therapy based on clinical risk, the Panel
did accumulate data on patients defined as low risk (Ta, low-grade tumors) versus those defined
as high risk (T1, high grade, and/or carcinoma in situ tumors), however the number of studies
reporting stratified data were few and stratification by stage and grade was rare.
Efficacy Outcomes - Results of the Analysis
For the purpose of the Guideline, the Panel chose to focus the analysis on a series of clinically
relevant questions concerning specific primary therapies and maintenance therapies. Summary
data relevant to these questions are presented in Tables 1 and 2a to 2c and are discussed in the
text that follows. The full set of outcomes tables are presented in Appendix 6.
As discussed in Chapter 2, the efficacy outcomes were analyzed in three ways: meta-analysis of
comparable randomized controlled trials (Table 1 and Appendix 6), analysis of comparable arms
Copyright © 2007 American Urological Association Education and Research, Inc.®
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from randomized controlled trials (Table 2 and Appendix 7), and analysis of comparable arms
from all studies (Appendix 8).
The result of the meta-analysis of comparable studies is the central result (best estimate) of
the absolute difference between the two treatments. This number is the median of the posterior
distribution. Negative numbers indicate that the first treatment has fewer occurrences of the
outcome compared to the second treatment in the comparison. For example, the first line of
Table 1 shows that the absolute difference in the rate of recurrence with single-dose mitomycin
C is 17% less than with TURBT alone. If the recurrence rate with TURBT alone were 50%, the
rate with single-dose mitomycin C is expected to be 33%. The CI columns show the credible
intervals (Bayesian CI) for that estimate. If the CI does not include 0 (zero), the estimate is
statistically significantly different from zero at p<0.05 (two-tailed). Note that all presented
numbers are rounded to the nearest whole percent. The number negative zero (-0) denotes a
number less than zero that has been rounded up to zero. Similarly, zero usually denotes a positive
number that has been rounded down to zero. These rounded numbers only become an issue when
determining whether a CI with a zero boundary is statistically significant. The column labeled
S/P shows the total number of studies included in the meta-analysis and the total number of
patients in all study arms included in the analysis.
From Table 1, it is clear that both mitomycin C and bacillus Calmette-Guérin (BCG) therapy
in combination with TURBT reduce the probability of disease recurrence in the time frame of the
studies. All the results are statistically significant except for the two studies examining an
induction course of mitomycin C versus no mitomycin C. The results of this pair-wise metaanalysis are detailed in the discussions of specific therapeutic questions below. No treatment
appears to reduce progression or mortality. Bacillus Calmette-Guérin with maintenance therapy
combined with TURBT, however, just misses reaching a statistically significant improvement in
overall progression in our meta-analysis.
No studies comparing an induction series of mitomycin C with an induction series of BCG
were found on review of the literature. Thus, the Panel attempted to estimate this difference by
using studies that compared induction mitomcyin C with TURBT alone and studies comparing
induction BCG with TURBT alone. Mathematical techniques were used to estimate the
difference between mitomycin C and BCG by creating a distribution for the difference of the two
previous results. This cross-comparison approach did not appear to add useful information.
Copyright © 2007 American Urological Association Education and Research, Inc.®
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Table 1. Pairwise Meta-analysis of all Randomized Controlled Trials Comparing Different Treatments - Recurrence, Progression,
Disease-free Survival and Overall Survival in all Risk Levels*
Recurrence
Difference
S/P
Progression
Difference
Treatment 1
Treatment 2
TURBT + MMC
Single Dose
TURBT + MMC
Induction
TURBT + MMC +
Maintenance
TURBT Alone
2/427
-17
(-28, -8)
TURBT Alone
2/321
-3
TURBT Alone
6/559
TURBT+ BCG
Induction
TURBT + BCG +
Maintenance
TURBT + BCG +
Maintenance
TURBT Alone
TURBT + MMC +
Maintenance
TURBT + BCG +
Maintenance
CI
Est
Rate % (2.5, 97.5)%
S/P
Disease-Specific Survival
Difference
CI
(2.5, 97.5)%
1/306
Est
Rate
%
3
(-16, 10)
1/43
8
(-12, 28)
-18
(-30, -6)
2/126
4
(-26, 32)
1/47
-24
(-47, -3)
TURBT Alone
5/629
-31
(-42, -18)
3/1,680
8
(0, 15)
TURBT + BCG
Induction
4/645
-14
(-26, -1)
2/510
-14
(-37, 10)
TURBT + BCG
Induction
TURBT + MMC
+ Maintenance
3/1,066
-7
(-15, -0)
1/387
0
(-5, 5)
2/594
-17
(-26, -7)
1/380
-5
(-11, 1)
S/P
Est Rate
%
1/126
-1
2/494
3
CI
(2.5, 97.5)%
Overall Survival
Difference
S/P
Est Rate
%
CI
(2.5, 97.5)%
(-9, 6)
2/510
1
(-7, 8)
(-3, 8)
1/244
-3
(-11, 7)
(-4, 10)
Cross study comparison analysis combined with randomized controlled trials
Difference
Treatment 1
Treatment 2
TURBT + BCG
Induction
TURBT + BCG +
Maintenance
TURBT + MMC
Induction
TURBT + MMC
+ Maintenance
S/P
CI
(2.5, 97.5)%
3/368
Est
Rate
%
-21
9/1,554
-4
(-31, 24)
(-48, 9)
*Shading indicates a statistically significant difference between treatments. Negative value indicates benefit favoring treatment in column 1 (treatment 1). Blank cells indicate absence of
data.
BCG, bacillus Calmette-Guérin; CI, confidence interval; Est Rate, estimated occurrence rate; MMC, mitomycin C; S/P, Number of studies/Number of patients; TURBT, transurethral
resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
5
Table 2a. Recurrence by Treatment – Randomized Controlled Trials: All Risk Groups*
Treatment
TURBT alone
TURBT + MMC Single
dose
TURBT + MMC
Induction
TURBT + MMC +
Maintenance
TURBT + BCG Induction
TURBT + BCG +
Maintenance
18/1,057
1 Year
Est
Rate
%
45
CI
(2.5,
97.5) %
(37, 54)
2/206
13
3/310
21/802
2 Year
Est
Rate
%
56
CI
(2.5,
97.5)%
(50, 63)
(1, 40)
2/206
28
40
(30, 52)
3/310
8/890
32
(23, 41)
9/787
26
11/1,426
25
G/P
12/586
3 Year
Est
Rate
%
56
CI
(2.5,
97.5)%
(47, 65)
4/299
(11, 50)
2/206
31
(14, 53)
2/206
53
(41, 63)
3/310
59
(47, 70)
8/890
42
(35, 51)
7/853
44
(33, 56)
6/728
43
(17, 36)
9/787
38
(30, 47)
6/627
37
(28, 46)
5/520
(17, 36)
11/1,426
33
(25, 41)
10/1,398
37
(30, 45)
7/694
G/P
G/P
G/P
4 Year
Est
Rate
%
44
5 Year
Est
Rate
%
41
CI
(2.5,
97.5)%
(30, 59)
5/413
(28, 54)
2/206
46
(37, 55)
3/310
66
(56, 74)
(31, 56)
4/574
49
(39, 59)
39
(29, 51)
6/581
38
(27, 50)
39
(31, 47)
7/1,169
42
(33, 51)
40
G/P
CI
(2.5,
97.5)%
(29, 55)
Overall/Unspecified
CI
Est
G/P
(2.5,
Rate
97.5)%
%
TURBT alone
TURBT + MMC Single
dose
TURBT + MMC
Induction
TURBT + MMC +
Maintenance
TURBT + BCG Induction
TURBT + BCG +
Maintenance
19/1,019
55
(49, 61)
1/92
46
(36, 56)
11/1,086
32
(25, 39)
10/816
36
(27, 45)
19/1,427
29
(23, 36)
* Please see text for data qualification.
BCG, bacillus Calmette-Guérin; CI, confidence interval; Est Rate, estimated occurrence rate; G/P, Number of groups/Number of patients; MMC, mitomycin C;
TURBT, transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
6
Table 2b. Recurrence by Treatment – Randomized Controlled Trials: High-Risk Groups*
Treatment
TURBT alone
TURBT + MMC Induction
TURBT + MMC +
Maintenance
TURBT + BCG induction
TURBT + BCG +
maintenance
G/P
2/132
1 Year
Est
Rate
%
60
CI
(2.5,
97.5)%
(50, 70)
2/132
G/P
2 Year
Est
Rate
%
76
CI
(2.5,
97.5)%
(66, 84)
2/124
G/P
3 Year
Est
Rate
%
77
CI
(2.5,
97.5)%
(56, 91)
G/P
4 Year
Est
Rate
%
CI
(2.5,
97.5)%
G/P
5 Year
Est
Rate
%
CI
(2.5,
97.5)%
2/79
26
(16, 39)
2/79
54
(29, 78)
2/79
64
(40, 83)
2/79
70
(50, 85)
1/16
62
(38, 83)
4/197
15
(8, 23)
4/197
25
(18, 34)
4/197
29
(21, 37)
3/136
33
(24, 43)
3/170
32
(21, 44)
4/322
16
(6, 32)
4/322
24
(15, 35)
3/294
28
(15, 43)
2/229
40
(29, 52)
3/294
34
(18, 54)
Overall/Unspecified
TURBT alone
TURBT + MMC Induction
TURBT + MMC +
Maintenance
TURBT + BCG Induction
TURBT + BCG +
Maintenance
G/P
Est
Rate
%
CI
(2.5,
97.5)%
11/441
60
(51, 68)
3/91
44
(32, 57)
4/186
34
(24, 45)
5/573
27
(16, 40)
* High risk included groups that had no Grade 1 patients or were entirely carcinoma in situ and/or T1. Please see text for data qualification.
BCG, bacillus Calmette-Guérin; CI, confidence interval; Est Rate, estimated occurrence rate; G/P, Number of groups/Number of patients; MMC, mitomycin C;
TURBT, transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
7
Table 2c. Progression, Disease-Specific Survival, Overall Survival by Treatment: Randomized Controlled Trials*
Treatment
Progression Overall
Progression High Risk†
Disease-Specific Survival
Overall Survival
Overall/Unspecified
Overall/Unspecified
Overall/Unspecified
Overall/Unspecified
G/P
Est
Rate
%
CI
(2.5,
97.5)%
G/P
CI
Est
Rate (2.5, 97.5)%
%
G/P
Est
Rate
%
CI
(2.5, 97.5)%
G/P
CI
Est
Rat (2.5, 97.5)%
e
%
TURBT alone
17/917
12
(9, 17)
2/48
17
(3, 46)
4/383
94
(89, 97)
5/505
84
(73, 92)
TURBT + MMC Single dose
TURBT + MMC Induction
TURBT + MMC +
Maintenance
1/57
3/343
9/928
2
6
11
(0, 8)
(2, 12)
(8, 16)
1/63
10
(4, 19)
1/92
7/740
91
93
(84, 96)
(91, 95)
7/914
81
(71, 89)
8/546
17/1,701
10
9
(7, 13)
(7, 12)
4/260
5/341
14
14
(9, 19)
(8, 22)
3/325
10/1,442
89
95
(79, 96)
(92, 97)
3/335
13/1,557
73
84
(56, 87)
(78, 89)
TURBT + BCG Induction
TURBT + BCG + Maintenance
* Please see text for data qualification.
†
A subgroup of the first column. High risk included groups that had no Grade 1 patients or were entirely carcinoma in situ and/or T1.
BCG, bacillus Calmette-Guérin; CI, confidence interval; Est Rate, estimated occurrence rate; G/P, Number of groups/Number of patients; MMC, mitomycin C;
TURBT, transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
8
In addition to the randomized controlled trial comparisons, the Panel developed tables
presenting the actual probability of recurrence, progression, and survival for each of the
treatments. The tables that include the results of the analysis of all randomized controlled trial
arms are shown in Tables 2a to 2c. These tables present the central estimate or median from the
posterior distribution resulting from the meta-analysis and the credible CI for that estimate. The
number of patient groups and total number of patients included in each analysis is shown in the
G/P column. Usually the number of groups is the same as the number of articles, but in a few
cases it may be larger if the patient groups within an article were very different from each other.
Keeping the data separate allows the hierarchical meta-analysis techniques to more accurately
estimate the credible CI.
Where possible, estimates were made by yearly time point. Some articles only reported
overall data and did not provide Kaplan-Meier or other estimates of results by time. These
articles are included in the “overall/unspecified” column. The studies providing these
“overall/unspecified” results are usually different from the studies providing the yearly results.
Thus the resulting estimates are not always consistent. Moreover, not all studies that offered
yearly results reported them for all five years. Most commonly, both year four and/or year five
data were not reported. For example, in Table 2a, for TURBT, the year four recurrence total is
higher than that for year five. Four studies were used for the year four total while five were used
for the year five totals. Only three studies reported data for both years and thus were used in both
estimates.
Since the estimates presented in Table 2 are based on a greater number of studies and a
greater variety of studies than the estimates in Table 1, the results are not always consistent. The
comparative results in Table 1 are probably the most meaningful when choosing between
treatments. The results in Table 2 are most useful when direct comparative randomized
controlled trials are not available, or to provide estimates by time point.
The Panel examined certain key clinical questions to provide guidance for common
clinical case scenarios. These questions and scenarios are presented herein.
Primary Therapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
9
1. What is the effect on recurrence of TURBT combined with a single, postoperative
intravesical instillation of mitomycin C versus TURBT alone?
In the initial randomized studies of thiotepa as an adjuvant treatment, the greatest decrease in
tumor recurrence was noted in the studies using a single, early postoperative instillation.2, 3 This
finding suggested that a single, immediate postoperative treatment was a viable alternative to
multiple instillations. Subsequently, several randomized studies comparing different
chemotherapeutic agents with TURBT alone confirmed the efficacy of a single, prophylactic
postoperative instillation.4-7 A European Organization for Research and Treatment of Cancer
(EORTC) study comparing epirubicin to water immediately following TURBT demonstrated that
patients with primary and solitary Ta tumors had a 50% decrease in recurrence with epirubicin.4
These favorable results were confirmed by a randomized controlled trial using mitomycin C for
patients with a single, primary or recurrent, nonmuscle invasive tumor.6 The beneficial effects of
a single instillation in the prevention of tumor cell implantation were mainly noted during the
first 12 months.6 Two prospective, randomized studies demonstrated a positive effect with a
single, postoperative dose of epirubicin among patients with multiple as well as solitary papillary
tumors.6, 7
In a recent meta-analysis of seven randomized trials of 1,476 patients with 3.4 years median
follow-up, Sylvester et al demonstrated a 39% reduction in the odds of recurrence (36.7%
recurrence versus 48.4% recurrence) when a single dose of cytotoxic chemotherapy (epirubicin
in three trials, mitomycin C in two trials, thiotepa in one trial and pirarubicin in one trial) was
delivered postoperatively after TURBT.8 Patients with either single or multiple tumors benefited;
however, 65% of patients with multiple tumors eventually had a recurrence compared to 36%
with single tumors. This analysis was not designed to determine the superiority of one agent
versus another.
The Panel focused its analysis on a single postoperative instillation of mitomycin C as it is
the most commonly used agent in the United States. Two trials were identified as suitable for
meta-analysis 6, 9 and included a combined 427 patients. In the larger trial by Tolley et al,9 60%
of the subjects treated with TURBT alone had recurrences at five years compared to 45% of
those receiving a single, postoperative instillation of 40 mg of mitomycin in 40 mL of water.
Solsona et al6 found a statistically significant decrease in early recurrence of up to two years in
patients who received the single dose of mitomycin C. However, a significant difference in
Copyright © 2007 American Urological Association Education and Research, Inc.®
10
recurrence was not maintained at the final follow-up of nearly eight years. When these trials
were combined for meta-analysis by the Panel, a statistically significant 17% decrease (95% CI:
-28%, -8%) in median recurrence rate was found. Neither of the trials of a single, postoperative
dose of mitomycin C nor our meta-analysis demonstrated an effect on progression. This was
primarily due to the inclusion of relatively low-risk subjects with a consequent small number of
progression events.
In summary, the literature and the current meta-analysis support the use of a single
postoperative instillation of a chemotherapeutic agent (e.g., mitomycin C) in the immediate
postoperative period to decrease the risk of recurrence in patients following an uncomplicated
TURBT of a nonmuscle invasive bladder tumor.
2. What is the effect on recurrence and progression of combining TURBT with an
induction course of intravesical chemotherapy versus TURBT combined with an induction
course of intravesical BCG?
Intravesical therapy of bladder cancer has evolved considerably over the last 30 years. Early
trials demonstrated the effectiveness of intravesical instillation of thiotepa and doxorubicin to
decrease the risk of recurrence of nonmuscle invasive bladder cancer. Follow-up randomized
trials and a subsequent meta-analysis performed by the 1999 AUA Bladder Guideline Panel
clearly demonstrated the superiority of BCG compared to thiotepa and doxorubicin for
nonmuscle invasive cancer. Subsequently, BCG intravesical immunotherapy has been compared
to several different chemotherapeutic agents in terms of recurrence efficacy. The results have
been nonuniform. Possible reasons for the inconsistent findings include varied patient
populations, differing treatment schedules, different types and intrinsic variability of tumors
being treated, and/or actual efficacy differences between the treatments or individual institutions.
Several studies have shown a greater efficacy of BCG, particularly with maintenance therapy
in patients with Tis, while others could not demonstrate this difference.10 For example, in a threearm, prospective, randomized trial of 469 patients, the Dutch Southeast Cooperative Urological
Group compared the efficacy of an induction course of mitomycin C chemotherapy combined
with maintenance to an induction course of BCG-RIVM strain and BCG-Tice strain, in patients
with stages Ta, T1, or carcinoma in situ bladder cancer.11 Mitomycin C was given in a 30-mg
dose once a week for four weeks, followed by a monthly dose for a total of six months. Both
Copyright © 2007 American Urological Association Education and Research, Inc.®
11
strains of BCG were given once a week for six consecutive weeks. Time to recurrence was the
primary endpoint with a mean follow-up of 36 months (range, 2 to 81 months). For stages Ta
and/or T1 without Tis, recurrence was observed in 58 of 136 (43%) evaluable patients treated
with mitomycin C, 75 of 117 (64%) treated with BCG-Tice, and 62 of 134 (46%) treated with
BCG-RIVM. Mitomycin C and BCG-RIVM were equally effective, while mitomycin C was
more effective than BCG-Tice. For patients with Tis the complete response rate was 67% for
mitomycin C, 74% for BCG-Tice, and 60% for BCG-RIVM. Progression in tumor stage was
noted in eight (6%) of the mitomycin C group, seven (5%) of the BCG-Tice group, and eight
(6%) of the BCG-RIVM group.11
Due to varying reported results from single trials, several groups have attempted to
synthesize the data with the use of meta-analyses. Unfortunately, even the meta-analyses did not
support a consensus result. In one meta-analysis, Huncharek and Kupelnick reported that BCG
does not offer a recurrence advantage over intravesical chemotherapy.12 However, in a pooling
of nine randomized trials comparing BCG (induction plus maintenance therapy in six trials and
induction only in three trials) to either mitomycin C, epirubicin, doxorubicin or sequential
mitomycin C, and doxorubicin (in an induction plus maintenance regimen in eight trials and
induction only in one), Sylvester et al were able to demonstrate that the intravesical BCG
induction plus maintenance regimen significantly reduced treatment failure in patients with Tis.13
The long-term benefit of BCG was smaller in comparison with mitomycin C and appeared
superior to mitomycin C only in the trials where maintenance BCG was given.13
In our meta-analysis we are unable to answer the question: Which intravesical chemotherapy
is the most effective to reduce recurrence and progression of bladder cancer? The meta-analysis
performed by the 1999 AUA Bladder Guideline Panel clearly demonstrated the superiority of the
immunotherapy (BCG) compared to thiotepa and doxorubicin. However, there are few
randomized trials that directly compare different intravesical chemotherapies. Specifically, there
are few trials that compare mitomycin C to other intravesical chemotherapy agents. Our current
meta-analysis confirms that epirubicin, mitomcycin C, mitoxantrone, and interferon all have
activity in preventing bladder cancer recurrence. We were unable to identify any trials that
demonstrated that these agents were superior to BCG. In contrast, however, we identified three
trials with a total of 1,066 patients (Table 1) which when combined for meta-analysis showed
that mitomycin C with maintenance was superior to BCG induction without maintenance.
Copyright © 2007 American Urological Association Education and Research, Inc.®
12
Therefore, by inference, it appears that mitomycin C may be the most active of currently
available intravesical chemotherapies. However, this perceived superiority of mitomycin C
remains to be proven by direct clinical trials. At this point, no single chemotherapy agent can be
considered superior, nor can an induction course of BCG without maintenance be considered
superior to an induction course of mitomycin C without maintenance.
Similarly, the results are not definitive with regard to cancer progression. Sylvester et al
could not demonstrate a statistically significant advantage for BCG versus mitomycin C for
progression in Tis (overall 14% difference favoring BCG).13 Using a larger database including
non-English studies, Böhle et al did find a statistically significant reduction in risk of progression
in trials comparing BCG immunotherapy versus mitomycin C (odds ratio [OR]=0.66).14
However , two caveats that may have biased the results toward BCG need to be kept in mind.
First, the analysis included studies involving BCG maintenance, not a single induction course.15
Second, the studies with mitomycin C did not routinely incorporate more recent modifications in
mitomycin C administration that have been shown in a randomized trial to optimize efficacy.15
In summary, the literature and the current meta-analysis do not demonstrate clear
superiority of an induction course of any particular intravesical chemotherapy or of BCG over
other therapies. Based on multiple studies, an induction course of either intravesical
chemotherapy or BCG should be administered for the treatment of nonmuscle invasive bladder
cancers that have an increased risk of recurrence but a low risk of progression.
Maintenance Therapy
1. What is the effect on recurrence and progression of TURBT combined with an induction
course of intravesical mitomycin C versus TURBT combined with an induction course of
mitomycin C and maintenance mitomycin C?
We did not identify any trials that directly compared an initial induction course of mitomycin
C to mitomycin C induction with maintenance therapy. Huncharek et al16 performed a metaanalysis examining only primary tumors without carcinoma in situ that were treated with a
variety of agents including thiotepa, epirubicin, doxorubicin, mitomycin C, peplomycin,
neocarzinost, and mitoxantrone.16 When the authors compared a short postoperative course
(single dose or a less than two-month postoperative course) to either one or two years of
maintenance therapy, they reported a significant reduction in recurrence rates in patients who
received maintenance therapy. Combining studies that utilized short-term therapy yielded a total
Copyright © 2007 American Urological Association Education and Research, Inc.®
13
of 1,258 subjects and a decrease in recurrence rate at two years of 32% compared to TURBT
alone. Combining studies that used one year of maintenance therapy yielded a total of 1,721
subjects and a decrease in recurrence rate at two years of 31% compared to TURBT alone.
Combining studies that used two years of maintenance therapy yielded a total of 575 subjects
and a decrease in recurrence rate at two years of 73% compared to TURBT alone. Importantly, at
least two years of maintenance therapy was necessary before a substantial difference in
recurrence was noted. In a follow-up meta-analysis of patients with recurrent Ta and/or T1
bladder tumors, Huncharek et al demonstrated a similar result in favor of maintenance therapy.17
We identified six trials (Table 1) containing a total of 559 subjects that compared the
recurrence rates following mitomycin C plus maintenance therapy with or without an induction
course to that of TURBT alone. A variety of different treatment schedules (Table 3) were used
and patients were followed for two through seven years.5,18-22 In our meta-analysis, mitomycin
C with maintenance therapy significantly reduced the recurrence rate by 18% (95% CI: -30%,
-6%) compared to TURBT alone. Although none of the trials reported a direct comparison
between maintenance and a single postoperative intravesical instillation of mitomycin C, the
decrease in recurrence rate was substantially greater in the subjects undergoing maintenance
therapy than with the single postoperative instillation (18% versus 3%). When interpreting these
results one should remember that these studies did not routinely incorporate more recent
modifications in mitomycin C administration that have been shown in a randomized trial to
optimize mitomycin C efficacy than with induction alone (18% versus 3%).15
Copyright © 2007 American Urological Association Education and Research, Inc.®
14
Table 3. Mitomycin C Maintenance Schedules
Reference
Concentration*
Induction
Tsushima
et al18
30 mg in 100 mL
Once a week
x6
Maintenance
Total Duration
2 Consecutive
2 Years
days every 4
weeks for 2 years
20 mg in 40 mL
Once a week
Every other week
2 Years
Hirao
x2
for 14 weeks
et al19
Every month for
8 months
Every 3 months
for 1 year
Huland and
20 mg in 20 mL
Every other week
2 Years
Otto20
for 12 months
Every 4 weeks for
1 year
Tolley et
40 mg in 40 mL
Single dose
Every 3 months
1 Year
al5
after TURBT
for 1 year
Akaza et
40 mg in 20 mL
Once a week
Every other week
2 Years
al21
x2
for 14 week
Every month for
8 months
Every 3 months
for 1 year
40 mg in 50 mL
Every other week
2 Years
Krege et
for 12 months
al22
Every 4 weeks for
1 year
* All mitomycin C was diluted in normal saline except in Tolley’s study where the diluent was
water.
TURBT, transurethral resection of bladder tumors.
We were unable to identify published studies suitable for meta-analysis that examined the
effect of mitomycin C induction with maintenance therapy on the risk of progression of bladder
cancer. Thus, the impact on progression is still unclear.
In summary, although the Panel did not identify any randomized trials that directly
compared an induction course of mitomycin C to an induction course of mitomycin C plus
maintenance therapy, the literature and the current meta-analysis suggest that maintenance
therapy enhances the effectiveness of mitomycin C induction in preventing tumor recurrence.
Copyright © 2007 American Urological Association Education and Research, Inc.®
15
For the practicing physician, however, a critical problem exists in that the optimal maintenance
dose, schedule, and duration have yet to be determined.
2. What is the effect on recurrence and progression of TURBT combined with an induction
course of intravesical BCG versus TURBT combined with an induction course of
intravesical BCG and maintenance BCG therapy?
Using strict criteria, the Panel identified only four trials comparing the recurrence rates following
an induction course of intravesical BCG to BCG combined with maintenance therapy that were
suitable for meta-analysis.10,23-25 These trials contained a total of 645 subjects. A variety of
different treatment schedules were used as outlined in Table 4 and duration of patient follow-up
ranged from 16 and 90 months. In our meta-analysis, BCG induction with maintenance BCG
therapy significantly reduced the recurrence rate by 14% (95% CI: -26%, -1%) when compared
to a single induction course of BCG.
Han and Pan performed a similar meta-analysis evaluating the efficacy of BCG in reducing
recurrence rates in patients with Ta, T1, and/or Tis bladder cancer.26 Separate analyses examined
the effects of maintenance therapy administered by a variety of different protocols. Induction
BCG administered to 2,072 patients in 10 separate studies was compared to some form of
maintenance therapy administered for at least 1 year in 1,070 patients in eight separate studies.
Maintenance BCG significantly decreased the risk of recurrence with a combined random effect
OR of 0.47 (95% CI: 0.28, 0.78; p=0.004). The effect of BCG maintenance on progression was
not examined in this study.26
Table 4. Bacillus Calmette-Guérin (BCG) Maintenance Schedules
Reference
Strain/Concentration* Induction
Maintenance
Total Duration
Badalament
et al23
Hudson
et al24
Palou
et al25
Lamm
et al10
Pasteur 120 mg in 50
mL
Pasteur 120 mg in 50
mL
Connaught 81 mg
Monthly for 2 years
2 Years
Every 3 months
Not defined
Every week for 6
weeks every 6 months
Every week for 3
weeks at
3,6,12,18,24,30, & 36
months
2 Years
Connaught 81 mg in
50.5 mL
Every week
for 6 weeks
Every week
for 6 weeks
Every week
for 6 weeks
Every week
for 6 weeks
3 Years
* All BCG was diluted in normal saline.
Copyright © 2007 American Urological Association Education and Research, Inc.®
16
Sylvester et al13 drew a similar conclusion to Han and Pan26 regarding recurrence in patients
with Tis. However, they did not directly compare the efficacy of induction BCG to induction
BCG plus maintenance BCG, but rather compared each arm to mitomycin C. In two small trials
containing a total of 90 patients, there was no suggestion of superiority of an induction course of
BCG compared to induction and maintenance mitomycin C. However, in three trials containing a
total of 257 patients, there was a 43% reduction in the odds of treatment failure in the induction
BCG plus maintenance BCG group (OR 0.57; 95% CI: 0.34, 0.97; p=0.04) compared to those
who received mitomycin C induction and maintenance therapy.
In a separate meta-analysis of 24 trials including 4,863 patients, Sylvester et al examined the
ability of a course of intravesical BCG (with or without maintenance) to decrease the rate of
progression of Ta and T1 bladder cancer compared to TURBT alone or TURBT plus another
intravesical chemotherapy.27 BCG therapy decreased the rate of progression from 13.8% to 9.8%
(OR 0.73; 95% CI: 0.06, 0.89; p=0.001) compared to TURBT alone with or without intravesical
chemotherapy. The BCG group had a nonsignificant decrease in the odds of death from bladder
cancer (OR 0.81; 95% CI: 0.58, 1.13; p=0.20). Of interest, only the group receiving maintenance
BCG benefited. However, in the Panel’s meta-analysis of comparable studies, although
approaching statistical significance, progression was not reduced with maintenance BCG (95%
CI: -15, -0).
In summary, the literature and the current meta-analysis support the use of an induction
course of intravesical BCG combined with maintenance BCG therapy as compared to an
induction course of BCG alone to decrease recurrence and possibly progression in patients with
higher risk nonmuscle invasive bladder tumors. The optimal maintenance schedule and duration
have yet to be determined. However, randomized, controlled trials have been conducted using
the Southwest Oncology Group regimen10 of a six-week induction course of BCG followed by
three-week maintenance therapy at 3, 6, 12, 18, 24, 30, and 36 months (if tolerated by the
patient).
3. What is the effect on recurrence and progression of TURBT combined with induction
and maintenance intravesical mitomycin C versus TURBT combined with induction and
maintenance BCG?
Copyright © 2007 American Urological Association Education and Research, Inc.®
17
We identified two trials with a total of 594 subjects that compared the recurrence rates following
an induction course of mitomycin C combined with maintenance mitomycin C to an induction
course of BCG combined with maintenance therapy.22,28 When these two trials are combined for
meta-analysis, BCG with maintenance therapy significantly reduced the recurrence rate by 17%
(95% CI: -26%, -7%) when compared to mitomycin C induction plus maintenance.
Previously published meta-analyses do not directly compare mitomycin C with maintenance
to BCG with maintenance (Table 5). However, the mitomycin C group in these published
analyses do include several trials in which maintenance therapy was administered. One of these
by Böhle et al14 identified 11 trials of TURBT followed by BCG versus TURBT followed by
mitomycin C for the prevention of recurrence of Ta and T1 bladder cancer that were suitable for
meta-analysis. The analysis included six randomized, controlled trials as well as four
observational studies, and one study published in abstract form. Recurrence information was
available on 2,749 patients. In the subgroup of six studies assessing maintenance BCG, uniform
superiority of BCG induction with BCG maintenance was noted (OR 0.43; 95% CI: 0.35, 0.53;
p<0.001).
Sylvester et al13 examined the efficacy of BCG compared to mitomycin C in patients with
carcinoma in situ. BCG was superior to mitomycin C only in the subgroup that received
maintenance BCG therapy. In three trials containing a total of 257 patients, there was a 43%
reduction in the odds of treatment failure in the BCG plus maintenance group (OR 0.57; 95% CI:
0.34, 0.97; p=0.04). There was no difference in the rates of tumor progression and diseasespecific survival between the groups.
In addition, one trial focused on higher risk patients. Lundholm et al29 reported the results of
the Swedish-Norwegian Bladder Cancer Study Group, which enrolled 261 patients with
carcinoma in situ, T1 Grade 3 disease, or multiple recurrent Ta and/or T1 Grade 1 or 2 disease.
Patients were randomized to receive mitomycin C 40 mg or BCG Pasteur strain instilled weekly
for six weeks, followed by monthly instillations for one year and every three months for another
year. The median duration of follow-up was 39 months and the disease-free rates were 49% for
BCG and 33% for mitomycin C. The disease-free rates for BCG and mitomycin among patients
with Ta and/or T1 were 48% and 35%, respectively; among patients with carcinoma in situ, rates
were 54% and 33%. Although BCG was superior to mitomycin C in preventing recurrence, no
significant difference in progression was observed. Patients receiving BCG had more frequent
Copyright © 2007 American Urological Association Education and Research, Inc.®
18
side effects. We only identified one study28 that addressed the issue of progression. No difference
between two therapies was detected.
In summary, the literature and the current meta-analysis of the use of an induction course of
intravesical BCG combined with maintenance BCG therapy when compared to an induction
course of intravesical mitomycin C plus maintenance mitomycin C indicate decreased
recurrence and possibly decreased progression of Ta, T1, and/or carcinoma in situ bladder
tumors in high-risk patients. The optimal maintenance schedule and duration have yet to be
determined. However, high quality randomized controlled trials have been conducted using the
Southwest Oncology Group regimen10 of a six-week induction course of BCG followed by three
weeks of maintenance therapy at 3, 6, 12, 18, 24, 30, and 36 months (if tolerated by the patient).
Previously Published Meta-analyses
Since 1998, the results of several meta-analyses of studies comparing immuno- and
chemotherapies with and without maintenance, or with TURBT, have been published. As
discussed previously, the design of these analyses differs from the Panel’s design in study
inclusion criteria, treatments, analytical methods, and outcomes. A summary of these differences
is presented in Table 5. The Panel applauds such efforts, and its conclusions were similar to
these reported although not identical.
Copyright © 2007 American Urological Association Education and Research, Inc.®
19
Table 5. Results of Previously Published Meta-analyses of Studies Comparing Intravesical Therapies and Differences From
the Panel’s Report
Reference
Comparisons
Results
Differences from the Present MetaAnalysis
BCG vs. No BCG
Han and Pan26
Treatments: BCG vs. no BCG, maintenance and
no maintenance
Outcome: recurrence
BCG vs. Chemotherapy
Treatments: BCG vs. MMC, maintenance and no
Böhle and
maintenance
Bock30
Outcome: progression
Shelley et al31
Treatments: BCG vs. MMC
Outcome: recurrence and progression for highrisk patients
Huncharek and
Kupelnick12
Treatments: BCG vs. chemotherapy
Outcome: progression
ƒ
BCG maintenance superior to no
BCG (p<0.05)
ƒ
BCG no maintenance better but
not reaching statistical
significance
ƒ
BCG superior to MMC (p<0.05)
with BCG maintenance
ƒ
ƒ
No significant difference for all
groups
BCG superior to MMC in high
risk group
ƒ
No significant differences
ƒ
Included
- non-English language studies
- studies rejected from the
present analysis for various
reasons,
- nonrandomized studies
ƒ
Both control arms may have received other
intravesical therapies
ƒ
Included
- non-English language studies
- nonrandomized studies
Included
- studies rejected from the present
analysis for various reasons
- studies using maintenance
therapy only
- studies of high-risk patients
only
Combined studies that use different
chemotherapies with different durations
(initial instillation and maintenance)
ƒ
Copyright © 2007 American Urological Association Education and Research, Inc.®
ƒ
ƒ
Included agents (thiotepa, doxorubicin,
epirubicin, etc.) not included in the present
analysis
ƒ
Restricted to reports with a minimum of
two-year follow-up and excludes Tis
20
1
Sylvester et al13
Treatments: BCG vs. chemotherapy for Tis,
maintenance and no maintenance
Outcome: complete response, recurrence, and
progression
Chemotherapy vs. TURBT alone
Huncharek et al16 Treatments: Chemotherapy vs. no chemotherapy
Outcome: recurrence
Sylvester et al8
2
3
4
Treatments: Single postoperative dose of
chemotherapy vs. TURBT alone
Outcome: recurrence
ƒ
BCG superior to chemotherapy
(p<0.05) for complete response
and lack of recurrence in
complete responders
ƒ
In a sub-analysis, BCG
maintenance superior to MMC
only
ƒ
Progression differences did not
reach statistical significance
ƒ
Chemotherapy superior to no
chemotherapy (p<0.05)
ƒ
ƒ
Single-dose chemotherapy
superior to TURBT alone
(p<0.05), particularly in patients
with single tumors
ƒ
Combined studies that use different
chemotherapies and maintenance with
studies using no maintenance
ƒ
Results for patients with a complete
response to initial therapy only
ƒ
Combined studies that use different
chemotherapies with different durations
(single dose, initial instillation and
maintenance)
ƒ
ƒ
Included agents (thiotepa, doxorubicin,
peplomycin, etc.) not included in the
present analysis
Included and combined multiple
chemotherapies not included in the present
analysis (i.e., pirarubicin, thiotepa, and
epirubicin)
ƒ
Included studies of single-dose MMC only
BCG, bacillus Calmette-Guérin; MMC, mitomycin C; Tis, carcinoma in situ; TURBT, transurethral resection of bladder tumor; vs., versus.
Copyright © 2007 American Urological Association Education and Research, Inc.®
21
Complications of Treatment
A review and evaluation of the complications reported with the treatment of nonmuscle invasive
bladder cancer was undertaken using both randomized controlled trials and nonrandomized trials.
As opposed to treatment efficacy comparisons, the inclusion of data from nonrandomized trials
was thought important and necessary to capture as accurately as possible the side effects that
may occur with therapy.
The Panel noted a number of limitations in the reporting of complications in the publications
available:
1) Complications were reported with a wide variety of descriptors, most of which are not
specifically defined. Many reports made only passing mention of complications or listed
only the most serious complications such as BCG sepsis. Because of this variation,
comparing complications rates from different studies was problematic.
2) It was unclear in most instances whether the lack of reporting of a particular side effect
indicated that none of the patients had that particular symptom or it simply was not
recorded.
3) In addition to the variability of terms used for reporting complications, some studies
used categorizations and combined complications into related groups but these categories
varied among studies further limiting comparative analyses as the degree of overlap
between different categories was impossible to glean. Moreover, few studies listed the
total number of patients who experienced complications or how many patients had more
than one complication.
4) Some of the complications reported seemed highly unlikely to be related to the
treatment (e.g., impotence) or were reported in very few studies.
To address these limitations, the Panel combined the reported complications into several
larger categories: bladder contracture, epididymitis/prostatitis/urethral infections, hematuria,
lower urinary tract symptoms (LUTS), fever/chills/flu symptoms, and systemic infection.
Complications that were highly unlikely to be related to treatment were eliminated. From these
categories, a maximum and minimal overlap could be assumed for each complication in the
category. For example, within the category of LUTS, if “frequency” were noted in 20% of
patients and “urgency” in 18%, it was likely that a large number of patients had both symptoms,
but the exact number is unknown (i.e., in this example the total number of patients with LUTS
Copyright © 2007 American Urological Association Education and Research, Inc.®
22
could be anywhere between 18%, if each patient has both frequency and urgency (maximal
overlap), and 38% if each patient had only one symptom (minimal overlap). The incidence of
each category of complication is listed by treatment in Table 6. For the categories of LUTS and
fever/chills/flu symptoms, assumptions of maximum and minimal overlap between the
complications included within that category are indicated on separate lines. The median and CIs
of the most common complications are also shown graphically in the forest plots in Figures 1a
to1f.
Lower urinary tract symptoms (including frequency, urgency, dysuria, etc.) were the most
common side effects reported with each treatment option. Such symptoms were reported in 2%
of patients treated with TURBT alone, or TURBT combined with single-dose post-TURBT
mitomycin C. In comparison, a rate of 22% to 24% (assuming maximal overlap) was reported
with multiple-dose mitomycin C with or without maintenance treatment, 38% with induction
BCG, and 57% with induction plus maintenance BCG. Other local symptoms such as hematuria,
bladder pain, and prostatitis were also common, and were similar across all intravesical
treatments. Bladder contracture is a rare event for all intravesical therapies including both
immunotherapy and chemotherapy. Systemic complications including immunologic reactions
(arthralgia, skin rash, and fever/chills/flu symptoms) and other systemic side effects
(malaise/fatigue, nausea/vomiting, altered liver function tests, neurologic symptoms,
cardiovascular or pulmonary problems, and sepsis) were also reported, and were more common
with regimens containing BCG and/or interferon than those using intravesical chemotherapy or
TURBT alone.
One of the most important clinical outcomes related to complications was the percentage of
patients who are unable to complete the course of treatment. Unfortunately, only a few studies
identified the number of patients who were unable to complete the initial course of therapy due
to side effects. From these data, patient discontinuation appeared to be relatively uncommon. In
the Panelists’ experience, however, discontinuation of therapy occurs fairly frequently,
especially with immunotherapy regimens.
In general, Panel members felt that in patients with tumors that carry substantial risk of
progression and ultimate death from bladder cancer the potential benefits of intravesical
treatments such as BCG seem to outweigh the risk of serious complications. On the other hand,
the risk of possible serious side effects from intravesical immunotherapy may outweigh the
Copyright © 2007 American Urological Association Education and Research, Inc.®
23
potential benefit of therapy for those with low-risk lesions. These risks and benefits should be
discussed with the patient. Consequently, intravesical chemotherapy, especially a single dose, is
a primary option for low-risk patients.
Copyright © 2007 American Urological Association Education and Research, Inc.®
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Table 6. Complications Incidence by Category and Treatment
Treatment
Bladder
Contracture
Est
Rate
G/P
CI*
%
TURBT alone
1/27
Minimal overlap ( or none)
Epid/Prost/
Urethral
Infections
Est
Rate
G/P
CI*
%
Hematuria
Est
Rate
G/P
CI*
%
G/P
LUTS
Est
Rate
%
CI*
2
(0, 5)
Fever/Chills/Flu
Symptoms
Est
Rate
G/P
CI*
%
Systemic
Infection
Est
Rate
G/P %
CI*
3/3,043
1
(0, 9)
Maximal overlap (if minimal)
TURBT + BCG Induct
1/21
Minimal overlap ( or none)
2/168
1
(0, 11)
11/527
4
(0, 16)
17/1,584
29
(21, 38)
Maximal overlap (if minimal)
TURBT + BCG Induct+ BCG Maint
8/949
Minimal overlap ( or none)
6/443
3
(2, 6)
17/1,523
4
(2, 6)
14/1,233
59
(42, 74)
26
(16, 39)
38
(28, 49)
19
(13, 28)
22/1,753
20
(13, 30)
Maximal overlap (if minimal)
TURBT + MMC: Single dose postop
1/23
20/1,667
1
(0, 10)
7
(2, 17)
4/255
71
(56, 83)
30
(22, 41)
57
(44, 69)
22
(16, 30)
2
(0, 8)
2/209
Minimal overlap ( or none)
Maximal overlap (if minimal)
TURBT + MMC Induct
5/418
Minimal overlap ( or none)
7/657
16
(9, 25)
Maximal overlap (if minimal)
TURBT + MMC Induct + MMC Maint
Minimal overlap ( or none)
2/234
1/26
5
(2, 11)
4/544
8
(2, 22)
Maximal overlap (if minimal)
3/309
58
(32, 81)
30
(17, 47)
24
(16, 24)
26
(13, 43)
16
(11, 23)
9/843
19
(10, 31)
2/220
31
(19, 44)
22
(15, 30)
*Confidence interval (2.5, 97.5)%
BCG, bacillus Calmette-Guérin; CI, confidence interval; Est Rate, estimated occurrence rate; Epid, epididymitis; G/P, Number of group/Number of patients; Induct,
induction; LUTS, lower urinary tract symptoms; Maint, maintenance; MMC, mitomycin C; Prost, prostatitis; TURBT, transurethral resection of bladder tumor
Copyright © 2007 American Urological Association Education and Research, Inc.®
25
Figure 1a. Estimated Occurrence Rates: Bladder Contracture
TURBT alone
TURBT + BCG Induction
TURBT + BCG Induction + BCG Maint
TURBT + MMC Induction + MMC Maint
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
BCG, bacillus Calmette-Guérin; CI, confidence interval; Maint, maintenance; MMC, mitomycin C; TURBT,
transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
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Figure 1b. Estimated Occurrence Rates: Epididymitis/Prostatitis/Urethral Infections
TURBT + BCG Induction
TURBT + BCG Induction + BCG Maint
TURBT + MMC Induction + MMC Maint
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
BCG, bacillus Calmette-Guérin; CI, confidence interval; Epid, epididymitis; Maint, maintenance; MMC,
mitomycin C; TURBT, transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
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Figure 1c. Estimated Occurrence Rates: Hematuria
TURBT + BCG Induction
TURBT + BCG Induction + BCG Maint
TURBT + MMC Induction
TURBT + MMC Induction + MMC Maint
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
BCG, bacillus Calmette-Guérin; CI, confidence interval; Maint, maintenance; MMC, mitomycin C; TURBT,
transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
28
Figure 1d. Estimated Rates: Lower Urinary Tract Symptoms
TURBT alone
TURBT + BCG Induction - Minimal overlap
Maximal overlap
TURBT + BCG Induction + BCG Maint - Minimal overlap
Maximal overlap
TURBT + MMC Single postop dose
TURBT + MMC Induction - Minimal overlap
Maximal overlap
TURBT + MMC Induction + MMC Maint- Minimal overlap
Maximal overlap
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
BCG, bacillus Calmette-Guérin; CI, confidence interval; Maint, maintenance; MMC, mitomycin C; TURBT,
transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
29
Figure 1e. Estimated Occurrence Rates: Fever/Chills/Flu Symptoms
TURBT + BCG Induction - Minimal overlap
Maximal overlap
TURBT + BCG Induction + BCG Maint - Minimal overlap
Maximal overlap
TURBT + MMC Induction - Minimal overlap
Maximal overlap
TURBT + MMC Induction + MMC Maint - Minimal overlap
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
BCG, bacillus Calmette-Guérin; CI, confidence interval; Maint, maintenance; MMC, mitomycin C; TURBT,
transurethral resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
30
Figure 1f. Estimated Occurrence Rates: Systemic Infection
TURBT + BCG Induction
TURBT + BCG Induction + BCG Maint
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
BCG, bacillus Calmette-Guérin; CI, confidence interval; Maint, maintenance; TURBT, transurethral
resection of bladder tumor.
Copyright © 2007 American Urological Association Education and Research, Inc.®
31
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36
Guideline for the Management of
Nonmuscle Invasive Bladder Cancer:
2007 Update
Appendices
American Urological Association Education and
Research, Inc.
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 1
Table of Contents
Appendix 1: Bladder Cancer Clinical Guidelines Panel Members
and Consultants (1999)
3
Appendix 2: Bladder Cancer Clinical Guidelines Panel Members
and Consultants (2007)
4
Appendix 3: Details of the Article Selection Process
5
Appendix 4: Article Extraction Form
6
Appendix 5: Bibliography of Extracted Articles Listed by Primary Author
(includes Procite number and citation)
15
Appendix 6: Efficacy Outcomes Balance Sheets: Dual Arm Analysis
27
Appendix 7: Efficacy Outcomes Balance Sheets and Forest Plots:
Single Arm Analysis, RCTs only
29
Appendix 8: Efficacy Outcomes Balance Sheets: All Single Arm Analyses
61
Appendix 9: Complications and Adverse Events Categories
85
Appendix 10: Complications Balance Sheets
90
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 2
Appendix 1: Bladder Cancer Clinical Guidelines Panel Members
and Consultants (1999)
Panel Members
Joseph A. Smith, Jr., M.D., Chair
Richard F. Labasky, M.D., Facilitator
James E. Montie, M.D.
Randall G. Rowland, M.D.
Abraham T. K. Cockett, M.D.
John A. Fracchia, M.D.
Consultants
Hanan S. Bell, Ph.D.
Patrick M. Florer
Curtis Colby
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 3
Appendix 2: Bladder Cancer Clinical Guidelines Panel Members
and Consultants (2007)
Panel Members
M. Craig Hall, M.D., Chair
Piedmont Urological Associates
High Point, NC
Sam S. Chang, M.D., Vice Chair
Vanderbilt University Medical Center
Department of Urologic Surgery
Nashville, TN
Guido Dalbagni, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY
Raj S. Pruthi, M.D.
Division of Urologic Surgery
University of North Carolina
Chapel Hill, NC
Paul F. Schellhammer, M.D.
Eastern Virginia Medical School
Norfolk, VA
John D. Seigne, M.B.
Division of Urology
Dartmouth Hitchcock Medical Center
Lebanon, NH
Eila C. Skinner, M.D.
USC Department of Urology
Norris Cancer Center
Los Angeles, CA
J. Stuart Wolf, Jr., M.D., Panel Facilitator
University of Michigan
Ann Arbor, MI
Consultants
Hanan S. Bell, Ph.D.
Patrick M. Florer
Diann Glickman, Pharm.D.
Suzanne Boland Pope
Staff
Heddy Hubbard, Ph.D.
Edith Budd
Michael Folmer
Kadiatu Kebe
Katherine Moore
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October 2007
Appendix
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Appendix 3: Details of the Article Selection Process
Identified on PubMed Searches *
Initial Search 1998 - 2004 = 4,422
Aug 2005 Search 12/2004 - 8/2005 = 362
Feb 2006 Search 08/2005 - 12/2005 = 236
Total = 5,020
Met Initial Screening Criteria †
Initial Search 1998 - 2004 = 484
Aug 2005 Search 12/2004 - 8/2005 = 22
Feb 2006 Search 08/2005 - 12/2005 = 6
Total = 512
Met Criteria for Extraction ‡
Initial Search 1998 - 2004 = 285
Aug 2005 Search 12/2004 - 8/2005 = 22
Feb 2006 Search 08/2005 - 12/2005 = 6
Feb 2006 Review of RCTs = 9
Total = 322
Rejected
n = 164
Accepted
n = 158
Case Series/Report
Case-control Study
Cohort study
Controlled trial
Review policy
95
1
7
54
1
No outcomes data
Cannot Separate stages
Cannot interpret data to fit form
Not about treatment
Other Exclusion
Duplicate article
Unidentified
86
8
18
17
31
2
2
* Search Terms were the MeSH Major Topics of bladder cancer and bladder neoplasms.
† Abstracts were screened for articles reporting outcomes (efficacy and safety) of bladder cancer
treatment in patients with clinical stage T1 or T2 disease.
‡ Articles were rejected if outcomes were not reported or stratified for early-stage patients.
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Appendix 4: Article Extraction Form (continued on next page)
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Appendix 5: Bibliography of Extracted Articles Listed by Primary Author
(includes Procite number and citation)
10601
Akaza, H., Koiso, K., Ozono, S., Kuroda, M., Kameyama, S., Okajima, E., Kotake, T., Kakizoe, T.,
Kawabe, K. A clinical study of PMCJ-9 (Bacillus Calmette-Guerin Connaught strain) treatment of
superficial bladder cancer and carcinoma in situ of the bladder. Jpn J Clin Oncol. 2003 Aug; 33: 382-90
13407
Al Khalifa, M., Elfving, P., Mansson, W., Colleen, S., Hellsten, S., Duchek, M., Nyberg, G., Callaghan,
P., Rademark, C., Eriksson, R., Olsson, R., Hagberg, G., Nelson, C. E. The effect of isoniazid on BCGinduced toxicity in patients with superficial bladder cancer. Eur Urol. 2000; 37 Suppl 1: 26-30
13636
Ali-El-Dein, B., Nabeeh, A., Ismail, E. H., Ghoneim, M. A. Sequential bacillus Calmette-Guerin and
epirubicin versus bacillus Calmette-Guerin alone for superficial bladder tumors: a randomized
prospective study. J Urol. 1999 Aug; 162: 339-42
12763
Altay, B., Girgin, C., Kefi, A., Cikili, N. The best management of superficial bladder tumours: comparing
TUR alone versus TUR combined with intravesical chemotherapy modalities?. Int Urol Nephrol. 2000;
32: 53-8
10171
Andius, P., Holmang, S. Bacillus Calmette-Guerin therapy in stage Ta/T1 bladder cancer: prognostic
factors for time to recurrence and progression. BJU Int. 2004 May; 93: 980-4
12397
Au, J. L., Badalament, R. A., Wientjes, M. G., Young, D. C., Warner, J. A., Venema, P. L., Pollifrone, D.
L., Harbrecht, J. D., Chin, J. L., Lerner, S. P., Miles, B. J. Methods to improve efficacy of intravesical
mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst. 2001 Apr 18; 93: 597-604
17590
Babjuk, M., Soukup, V., Petrik, R., Jirsa, M., Dvoracek, J. 5-aminolaevulinic acid-induced fluorescence
cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer.
BJU Int. 2005 Oct; 96: 798-802
1277
Badalament, R.A., Herr, H.W., Wong, G.Y., Gnecco, C., Pinsky, C.M., Whitmore, W.F., Fair, W.R., and
Oettgen, H.F. A prospective randomized trial of maintenance versus nonmaintenance intravesical
bacillus Calmette-Guerin therapy of superficial bladder cancer. Journal of Clinical Oncology. 1987; 5:
441-449
14046
Baniel, J., Grauss, D., Engelstein, D., Sella, A. Intravesical bacillus Calmette-Guerin treatment for Stage
T1 grade 3 transitional cell carcinoma of the bladder. Urology. 1998 Nov; 52: 785-9
17130
Bartoletti, R., Cai, T., Gacci, M., Giubilei, G., Viggiani, F., Santelli, G., Repetti, F., Nerozzi, S., Ghezzi,
P., Sisani, M. Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a
Phase II prospective multicenter study. Urology. 2005 Oct; 66: 726-31
11608
Bassi, P., Spinadin, R., Longo, F., Saraeb, S., Pappagallo, G. L., Zattoni, F., Pagano, F. Delayed highdose intravesical epirubicin therapy of superficial bladder cancer. A way to reduce the side effects and
increase the efficacy--a phase 2 trial. Urol Int. 2002; 68: 216-9
12882
Bazarbashi, S., Raja, M. A., El Sayed, A., Ezzat, A., Ibrahim, E., Kattan, S., Kardar, A., Peracha, A.,
Lindstedt, E., Hanash, K. Prospective phase II trial of alternating intravesical Bacillus Calmette-Guerin
(BCG) and interferon alpha IIB in the treatment and prevention of superficial transitional cell carcinoma
of the urinary bladder: preliminary results. J Surg Oncol. 2000 Jul; 74: 181-4
11065
Berger, A. P., Steiner, H., Stenzl, A., Akkad, T., Bartsch, G., Holtl, L. Photodynamic therapy with
intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a
single-center study. Urology. 2003 Feb; 61: 338-41
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12671
Bernardini, S., Billerey, C., Martin, M., Adessi, G. L., Wallerand, H., Bittard, H. The predictive value of
muscularis mucosae invasion and p53 over expression on progression of stage T1 bladder carcinoma. J
Urol. 2001 Jan; 165: 42-6; discussion 46
10951
Bilen, C. Y., Inci, K., Erkan, I., Ozen, H. The predictive value of purified protein derivative results on
complications and prognosis in patients with bladder cancer treated with bacillus Calmette-Guerin. J
Urol. 2003 May; 169: 1702-5
13024
Bilen, C. Y., Ozen, H., Aki, F. T., Aygun, C., Ekici, S., Kendi, S. Clinical experience with BCG alone
versus BCG plus epirubicin. Int J Urol. 2000 Jun; 7: 206-9
11252
Bogdanovic, J., Marusic, G., Djozic, J., Sekulic, V., Budakov, P., Dejanovic, N., Stojkov, J. The
management of T1G3 bladder cancer. Urol Int. 2002; 69: 263-5
13148
Bono, A. V., Lovisolo, J. A., Saredi, G. Transurethral resection and sequential chemoimmunoprophylaxis in primary T1G3 bladder cancer. Eur Urol. 2000 Apr; 37: 478-83
13118
Brake, M., Loertzer, H., Horsch, R., Keller, H. Long-term results of intravesical bacillus CalmetteGuerin therapy for stage T1 superficial bladder cancer. Urology. 2000 May; 55: 673-8
13098
Brake, M., Loertzer, H., Horsch, R., Keller, H. Recurrence and progression of stage T1, grade 3
transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus CalmetteGuerin. J Urol. 2000 Jun; 163: 1697-701
10132
Campbell, P. A., Conrad, R. J., Campbell, C. M., Nicol, D. L., MacTaggart, P. Papillary urothelial
neoplasm of low malignant potential: reliability of diagnosis and outcome. BJU Int. 2004 Jun; 93: 122831
10257
Canda, A. E., Tuzel, E., Mungan, M. U., Yorukoglu, K., Kirkali, Z. Conservative management of
mucosal prostatic urethral involvement in patients with superficial transitional cell carcinoma of the
bladder. Eur Urol. 2004 Apr; 45: 465-9; discussion 469-70
13701
Cheng, L., Cheville, J. C., Neumann, R. M., Leibovich, B. C., Egan, K. S., Spotts, B. E., Bostwick, D. G.
Survival of patients with carcinoma in situ of the urinary bladder. Cancer. 1999 Jun 1; 85: 2469-74
13416
Cheng, L., Darson, M., Cheville, J. C., Neumann, R. M., Zincke, H., Nehra, A., Bostwick, D. G.
Urothelial papilloma of the bladder. Clinical and biologic implications. Cancer. 1999 Nov 15; 86: 2098101
13167
Cheng, L., Neumann, R. M., Nehra, A., Spotts, B. E., Weaver, A. L., Bostwick, D. G. Cancer
heterogeneity and its biologic implications in the grading of urothelial carcinoma. Cancer. 2000 Apr 1; 88:
1663-70
12793
Collado, A., Chechile, G. E., Salvador, J., Vicente, J. Early complications of endoscopic treatment for
superficial bladder tumors. J Urol. 2000 Nov; 164: 1529-32
12581
Colombo, R., Brausi, M., Da Pozzo, L., Salonia, A., Montorsi, F., Scattoni, V., Roscigno, M., Rigatti, P.
Thermo-chemotherapy and electromotive drug administration of mitomycin C in superficial bladder
cancer eradication. a pilot study on marker lesion. Eur Urol. 2001 Jan; 39: 95-100
14390
Colombo, R., Da Pozzo, L. F., Lev, A., Salonia, A., Rigatti, P., Leib, Z., Servadio, C., Caldarera, E.,
Pavone-Macaluso, M. Local microwave hyperthermia and intravesical chemotherapy as bladder sparing
treatment for select multifocal and unresectable superficial bladder tumors. J Urol. 1998 Mar; 159: 783-7
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10553
Colombo, R., Da Pozzo, L. F., Salonia, A., Rigatti, P., Leib, Z., Baniel, J., Caldarera, E., PavoneMacaluso, M. Multicentric study comparing intravesical chemotherapy alone and with local microwave
hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol. 2003
Dec 1; 21: 4270-6
13565
Dalbagni, G., Rechtschaffen, T., Herr, H. W. Is transurethral biopsy of the bladder necessary after 3
months to evaluate response to bacillus Calmette-Guerin therapy?. J Urol. 1999 Sep; 162: 708-9
11905
Davis, J. W., Sheth, S. I., Doviak, M. J., Schellhammer, P. F. Superficial bladder carcinoma treated with
bacillus Calmette-Guerin: progression-free and disease specific survival with minimum 10-year
followup. J Urol. 2002 Feb; 167: 494-500; discussion 501
10297
De Berardinis, E., Antonini, G., Peters, G. J., Loves, W. J., Van der Born, K., Codacci-Pisanelli, G., Di
Silverio, F. Intravesical administration of gemcitabine in superficial bladder cancer: a phase I study with
pharmacodynamic evaluation. BJU Int. 2004 Mar; 93: 491-4
15920
de Reijke, T. M., Kurth, K. H., Sylvester, R. J., Hall, R. R., Brausi, M., van de Beek, K., Landsoght, K.
E., Carpentier, P. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent
carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of
Cancer--Genito-Urinary Group Phase III Trial (30906). J Urol. 2005 Feb; 173: 405-9
12217
Dutta, S. C., Smith, J. A., Jr., Shappell, S. B., Coffey, C. S., Chang, S. S., Cookson, M. S. Clinical under
staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol.
2001 Aug; 166: 490-3
13384
Fleshner, N., Garland, J., Moadel, A., Herr, H., Ostroff, J., Trambert, R., O'Sullivan, M., Russo, P.
Influence of smoking status on the disease-related outcomes of patients with tobacco-associated
superficial transitional cell carcinoma of the bladder. Cancer. 1999 Dec 1; 86: 2337-45
13523
Fujii, Y., Fukui, I., Kihara, K., Tsujii, T., Kageyama, Y., Oshima, H. Late recurrence and progression
after a long tumor-free period in primary Ta and T1 bladder cancer. Eur Urol. 1999 Oct; 36: 309-13
10619
Fujii, Y., Kawakami, S., Koga, F., Nemoto, T., Kihara, K. Long-term outcome of bladder papillary
urothelial neoplasms of low malignant potential. BJU Int. 2003 Oct; 92: 559-62
11040
Fujikawa, K., Matsui, Y., Kobayashi, T., Miura, K., Oka, H., Fukuzawa, S., Sasaki, M., Takeuchi, H.,
Okabe, T. Predicting disease outcome of non-invasive transitional cell carcinoma of the urinary bladder
using an artificial neural network model: results of patient follow-up for 15 years or longer. Int J Urol.
2003 Mar; 10: 149-52
13947
Giannakopoulos, S., Gekas, A., Alivizatos, G., Sofras, F., Becopoulos, T., Dimopoulos, C. Efficacy of
escalating doses of intravesical interferon alpha-2b in reducing recurrence rate and progression in
superficial transitional cell carcinoma. Br J Urol. 1998 Dec; 82: 829-34
10484
Giannopoulos, A., Constantinides, C., Fokaeas, E., Stravodimos, C., Giannopoulou, M., Kyroudi, A.,
Gounaris, A. The immunomodulating effect of interferon-gamma intravesical instillations in preventing
bladder cancer recurrence. Clin Cancer Res. 2003 Nov 15; 9: 5550-8
10276
Gofrit, O. N., Shapiro, A., Pode, D., Sidi, A., Nativ, O., Leib, Z., Witjes, J. A., van der Heijden, A. G.,
Naspro, R., Colombo, R. Combined local bladder hyperthermia and intravesical chemotherapy for the
treatment of high-grade superficial bladder cancer. Urology. 2004 Mar; 63: 466-71
13911
Gohji, K., Nomi, M., Okamoto, M., Takenaka, A., Hara, I., Okada, H., Arakawa, S., Fujii, A.,
Kamidono, S. Conservative therapy for stage T1b, grade 3 transitional cell carcinoma of the bladder.
Urology. 1999 Feb; 53: 308-13
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11676
Griffiths, T. R., Charlton, M., Neal, D. E., Powell, P. H. Treatment of carcinoma in situ with intravesical
bacillus Calmette-Guerin without maintenance. J Urol. 2002 Jun; 167: 2408-12
10780
Grimm, M. O., Steinhoff, C., Simon, X., Spiegelhalder, P., Ackermann, R., Vogeli, T. A. Effect of
routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J
Urol. 2003 Aug; 170: 433-7
11149
Hara, I., Miyake, H., Takechi, Y., Eto, H., Gotoh, A., Fujisawa, M., Okada, H., Arakawa, S., Kamidono,
S. Clinical outcome of conservative therapy for stage T1, grade 3 transitional cell carcinoma of the
bladder. Int J Urol. 2003 Jan; 10: 19-24
11517
Harris, N. M., Crook, T. J., Dyer, J. P., Solomon, L. Z., Bass, P., Cooper, A. J., Birch, B. R. Intravesical
meglumine gamma-linolenic acid in superficial bladder cancer: an efficacy study. Eur Urol. 2002 Jul; 42:
39-42
10026
Hassan, J. M., Cookson, M. S., Smith, J. A., Jr., Johnson, D. L., Chang, S. S. Outcomes in patients
with pathological carcinoma in situ only disease at radical cystectomy. J Urol. 2004 Sep; 172: 882-4
14351
Herr, H. W. Extravesical tumor relapse in patients with superficial bladder tumors. J Clin Oncol. 1998
Mar; 16: 1099-102
13360
Herr, H. W. Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3)
bladder tumors: 15-year outcome. J Urol. 2000 Jan; 163: 60-1; discussion 61-2
12111
Herr, H. W., Sogani, P. C. Does early cystectomy improve the survival of patients with high risk
superficial bladder tumors?. J Urol. 2001 Oct; 166: 1296-9
13566
Holmang, S., Hedelin, H., Anderstrom, C., Holmberg, E., Busch, C., Johansson, S. L. Recurrence and
progression in low grade papillary urothelial tumors. J Urol. 1999 Sep; 162: 702-7
15685
Hossain, M. Z., Khan, S. A., Salam, M. A., Hossain, S., Islam, R. Holmium YAG laser treatment of
superficial bladder carcinoma. Mymensingh Med J. 2005 Jan; 14: 13-5
10919
Huang, J. S., Chen, W. H., Lin, C. C., Liaw, C. C., Wang, C. H., Lan, Y. J., Lai, C. H., Liu, J. P. A
randomized trial comparing intravesical instillations of mitoxantrone and doxorubicin in patients with
superficial bladder cancer. Chang Gung Med J. 2003 Feb; 26: 91-7
1329
Hudson, M.A., Ratliff, T.L., Gillen, D.P., Haaff, E.O., Dresner, S.M., and Catalona, W.J. Single course
versus maintenance bacillus Calmette-Guerin therapy for superficial bladder tumors: a prospective,
randomized trial. Journal of Urology. 1987; 138: 295-298
13588
Hurle, R., Losa, A., Manzetti, A., Lembo, A. Intravesical bacille Calmette-Guerin in Stage T1 grade 3
bladder cancer therapy: a 7-year follow-up. Urology. 1999 Aug; 54: 258-63
13695
Hurle, R., Manzetti, A., Losa, A., Micheli, E., Ranieri, A., Chinaglia, D., Lembo, A. Intravesical
instillation of mitomycin-C in 242 patients with superficial bladder cancer at high risk of recurrence:
long-term results. Urol Int. 1998; 61: 220-6
11813
Imamoglu, M. A., Bakirtas, H., Yigitbasi, O., Ersoy, H., Sertcelik, A. N. Intravesical epirubicin
treatment following TUR in superficial bladder tumours. Arch Esp Urol. 2001 Dec; 54: 1147-53
11792
Iori, F., Di Seri, M., De Nunzio, C., Leonardo, C., Franco, G., Spalletta, B., Laurenti, C. Long-term
maintenance bacille Calmette-Guerin therapy in high-grade superficial bladder cancer. Urology. 2002
Mar; 59: 414-8
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Irie, A., Uchida, T., Yamashita, H., Matsumoto, K., Satoh, T., Koh, H., Shimura, S., Iwamura, M., Baba,
S. Sufficient prophylactic efficacy with minor adverse effects by intravesical instillation of low-dose
bacillus Calmette-Guerin for superficial bladder cancer recurrence. Int J Urol. 2003 Apr; 10: 183-9
12123
Jakse, G., Hall, R., Bono, A., Holtl, W., Carpentier, P., Spaander, J. P., van der Meijden, A. P.,
Sylvester, R. Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term
results of EORTC GU Group phase II protocol 30861. Eur Urol. 2001 Aug; 40: 144-50
11486
Kaasinen, E., Rintala, E., Hellstrom, P., Viitanen, J., Juusela, H., Rajala, P., Korhonen, H., Liukkonen, T.
Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently
recurring superficial bladder carcinoma. Eur Urol. 2002 Aug; 42: 167-74
13031
Kaasinen, E., Rintala, E., Pere, A. K., Kallio, J., Puolakka, V. M., Liukkonen, T., Tuhkanen, K. Weekly
mitomycin C followed by monthly bacillus Calmette-Guerin or alternating monthly interferon-alpha2B
and bacillus Calmette-Guerin for prophylaxis of recurrent papillary superficial bladder carcinoma. J
Urol. 2000 Jul; 164: 47-52
10888
Kaasinen, E., Wijkstrom, H., Malmstrom, P. U., Hellsten, S., Duchek, M., Mestad, O., Rintala, E.
Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of
the urinary bladder: a nordic study. Eur Urol. 2003 Jun; 43: 637-45
15475
Koga, H., Kuroda, M., Kudo, S., Yamaguchi, A., Usami, M., Suzuki, T., Naito, S. Adverse drug
reactions of intravesical bacillus Calmette-Guerin instillation and risk factors of the development of
adverse drug reactions in superficial cancer and carcinoma in situ of the bladder. Int J Urol. 2005 Feb; 12:
145-51
10465
Koga, H., Kuroiwa, K., Yamaguchi, A., Osada, Y., Tsuneyoshi, M., Naito, S. A randomized controlled
trial of short-term versus long-term prophylactic intravesical instillation chemotherapy for recurrence
after transurethral resection of Ta/T1 transitional cell carcinoma of the bladder. J Urol. 2004 Jan; 171:
153-7
11726
Kolodziej, A., Dembowski, J., Zdrojowy, R., Wozniak, P., Lorenz, J. Treatment of high-risk superficial
bladder cancer with maintenance bacille Calmette-Guerin therapy: preliminary results. BJU Int. 2002
Apr; 89: 620-2
13278
Kondas, J., Kiss, L., Hatar, A., Kiss, A., Lukacs, T., Szeldeli, P., Torzsok, F., Bodrogi, I. The effect of
intravesical mitomycin C on the recurrence of superficial (Ta-T1) bladder cancer. A Hungarian
Multicenter Study. Int Urol Nephrol. 1999; 31: 451-6
13744
Kondo, T., Onitsuka, S., Ryoji, O., Kihara, T., Goto, Y., Satoh, T., Nakazawa, H., Toma, H. Analysis
of prognostic factors related to primary superficial bladder cancer tumor recurrence in prophylactic
intravesical epirubicin therapy. Int J Urol. 1999 Apr; 6: 178-83
13176
Kondylis, F. I., Demirci, S., Ladaga, L., Kolm, P., Schellhammer, P. F. Outcomes after intravesical
bacillus Calmette-Guerin are not affected by substaging of high grade T1 transitional cell carcinoma. J
Urol. 2000 Apr; 163: 1120-3
11509
Kriegmair, M., Zaak, D., Rothenberger, K. H., Rassweiler, J., Jocham, D., Eisenberger, F., Tauber, R.,
Stenzl, A., Hofstetter, A. Transurethral resection for bladder cancer using 5-aminolevulinic acid induced
fluorescence endoscopy versus white light endoscopy. J Urol. 2002 Aug; 168: 475-8
11383
Kulkarni, J. N., Gupta, R. Recurrence and progression in stage T1G3 bladder tumour with intravesical
bacille Calmette-Guerin (Danish 1331 strain). BJU Int. 2002 Oct; 90: 554-7
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Kuroda, M., Niijima, T., Kotake, T., Akaza, H., Hinotsu, S. Effect of prophylactic treatment with
intravesical epirubicin on recurrence of superficial bladder cancer--The 6th Trial of the Japanese
Urological Cancer Research Group (JUCRG): a randomized trial of intravesical epirubicin at dose of
20mg/40ml, 30mg/40ml, 40mg/40ml. Eur Urol. 2004 May; 45: 600-5
10457
Lam, J. S., Benson, M. C., O'Donnell, M. A., Sawczuk, A., Gavazzi, A., Wechsler, M. H., Sawczuk, I.
S. Bacillus Calmete-Guerin plus interferon-alpha2B intravesical therapy maintains an extended treatment
plan for superficial bladder cancer with minimal toxicity. Urol Oncol. 2003 Sep-Oct; 21: 354-60
13175
Lamm, D. L., Blumenstein, B. A., Crissman, J. D., Montie, J. E., Gottesman, J. E., Lowe, B. A.,
Sarosdy, M. F., Bohl, R. D., Grossman, H. B., Beck, T. M., Leimert, J. T., Crawford, E. D.
Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ
transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000
Apr; 163: 1124-9
13430
Leblanc, B., Duclos, A. J., Benard, F., Cote, J., Valiquette, L., Paquin, J. M., Mauffette, F., Faucher, R.,
Perreault, J. P. Long-term followup of initial Ta grade 1 transitional cell carcinoma of the bladder. J Urol.
1999 Dec; 162: 1946-50
12681
Leblanc, B., Duclos, A. J., Benard, F., Valiquette, L., Paquin, J. M., Lapointe, S., Mauffette, F.,
Pharand, D., Faucher, R., Drouin, G., Perreault, J. P. Long term follow-up of intravesical Bacillus
Calmette-Guerin for the treatment of bladder transitional cell carcinoma. Can J Urol. 2000 Feb; 7: 944-8
13359
Lebret, T., Bohin, D., Kassardjian, Z., Herve, J. M., Molinie, V., Barre, P., Lugagne, P. M., Botto, H.
Recurrence, progression and success in stage Ta grade 3 bladder tumors treated with low dose bacillus
Calmette-Guerin instillations. J Urol. 2000 Jan; 163: 63-7
14170
Lebret, T., Gaudez, F., Herve, J. M., Barre, P., Lugagne, P. M., Botto, H. Low-dose BCG instillations in
the treatment of stage T1 grade 3 bladder tumours: recurrence, progression and success. Eur Urol. 1998;
34: 67-72
11205
Lockyer, C. R., Sedgwick, J. E., Gillatt, D. A. Beware the BCG failures: a review of one institution's
results. Eur Urol. 2002 Dec; 42: 542-6
13358
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158 articles listed
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Appendix
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Appendix 6: Efficacy Outcomes Balance Sheets*
Dual Arm Analysis
Efficacy – Recurrence
Difference
Treatment 1
TUR + Epirubicin
TUR + Interferon
TUR + Interferon
TUR + Epirubicin
TUR + BCG + Interferon
TUR + BCG + Interferon
TUR + Phototherapy
TUR + Epirubicin + Maintenance
TUR + Epirubicin + Maintenance
TUR + BCG + Isoniazid
TUR + Mitoxantrone 10 mg
TUR + Mitoxantrone 20 mg
TUR + Interferon + Maintenance
TUR + Mitoxantrone 20 mg
TUR + Interferon + Maintenance
TUR + Interferon + Maintenance
TUR + Interferon + Maintenance 40
TUR + Interferon + Maintenance 60
TUR + Interferon + Maintenance 80
TUR + Interferon + Maintenance 60
TUR + Interferon + Maintenance 80
TUR + Interferon + Maintenance 80
TUR + MMC
TUR + MMC + Maintenance
TUR + MMC + Maintenance
TUR + BCG + Maintenance
TUR + BCG + Maintenance
TUR + BCG
TUR + BCG + Maintenance
TUR + MMC single dose
Treatment 2
TUR
TUR
TUR + Epirubicin
TUR + BCG
TUR + BCG
TUR + Epirubicin
TUR
TUR + Epirubicin
TUR + BCG + Maintenance
TUR + BCG
TUR
TUR
TUR
TUR + Mitoxantrone 10 mg
TUR + Mitoxantrone 10 mg
TUR + Mitoxantrone 20 mg
TUR
TUR
TUR
TUR + Interferon + Maintenance 40
TUR + Interferon + Maintenance 40
TUR + Interferon + Maintenance 60
TUR
TUR
TUR + BCG
TUR + MMC + Maintenance
TUR + BCG
TUR
TUR
TUR
S/P
1/134
1/132
1/134
1/560
1/558
1/556
1/102
1/72
1/344
1/160
1/101
1/99
1/97
1/110
1/109
1/107
1/42
1/44
1/43
1/46
1/47
1/47
2/321
6/559
3/1066
1/377
4/645
1/47
5/629
2/427
Median CI (2.5 - 97.5)%
(-42 - -11)
-27%
(-20 - 11)%
-5%
(6 - 38)%
22%
(6 - 22)%
14%
(-6 - 10)%
2%
(-22 - -6)%
-14%
(-39 - -6)%
-24%
(-12 - 26)%
7%
(-9 - 19)%
5%
(-15 - 16)%
1%
(-42 - -5)%
-25%
(-43 - -5)%
-25%
(-50 - -13)%
-33%
(-18 - 18)%
0%
(-25 - 10)%
-8%
-8%
(-25 - 10)%
(-54 - 1)%
-28%
(-60 - -7)%
-35%
(-65 - -13)%
-41%
(-32 - 20)%
-7%
-13%
(-38 - 13)%
(-30 - 18)%
-6%
(-16 - 10)%
-3%
(-30 - -6)%
-18%
(-15 - -0)%
-7%
(-25 - -5)%
-15%
(-26 - -1)%
-14%
(-47 - -3)%
-24%
(-42 - -18)%
-31%
(-28 - -8)%
-17%
S/P
1/560
1/558
1/556
1/344
1/101
1/99
1/97
1/110
1/109
1/107
1/42
1/44
1/43
1/46
1/47
1/47
1/43
1/306
2/510
3/1680
2/126
1/387
1/380
Median
4%
0%
-4%
15%
-10%
-7%
-15%
2%
-5%
-7%
-16%
-25%
-25%
-9%
-9%
0%
8%
3%
-14%
8%
4%
0%
-5%
Dual Arm Analysis
Efficacy – Progression
Difference
Treatment 1
TUR + Epirubicin
TUR + BCG + Interferon
TUR + BCG + Interferon
TUR + Epirubicin + Maintenance
TUR + Mitoxantrone 10 mg
TUR + Mitoxantrone 20 mg
TUR + Interferon + Maintenance
TUR + Mitoxantrone 20 mg
TUR + Interferon + Maintenance
TUR + Interferon + Maintenance
TUR + Interferon + Maintenance 40
TUR + Interferon + Maintenance 60
TUR + Interferon + Maintenance 80
TUR + Interferon + Maintenance 60
TUR + Interferon + Maintenance 80
TUR + Interferon + Maintenance 80
TUR + MMC
TUR + MMC single dose
TUR + BCG + Maintenance
TUR + BCG + Maintenance
TUR + MMC + Maintenance
TUR + MMC + Maintenance
TUR + MMC + Maintenance
Treatment 2
TUR + BCG
TUR + BCG
TUR + Epirubicin
TUR + BCG + Maintenance
TUR
TUR
TUR
TUR + Mitoxantrone 10 mg
TUR + Mitoxantrone 10 mg
TUR + Mitoxantrone 20 mg
TUR
TUR
TUR
TUR + Interferon + Maintenance 40
TUR + Interferon + Maintenance 40
TUR + Interferon + Maintenance 60
TUR
TUR
TUR + BCG
TUR
TUR
TUR + BCG
TUR + BCG + Maintenance
CI (2.5 - 97.5)%
(0 - 8)%
(-3 - 3)%
(-8 - -0)%
(1 - 28)%
(-24 - 5)%
(-23 - 8)%
(-28 - -0)%
(-11 - 15)%
(-16 - 7)%
(-19 - 5)%
(-40 - 9)%
(-45 - -3)%
(-45 - -2)%
(-26 - 8)%
(-26 - 8)%
(-13 - 13)%
(-12 - 28)%
(-4 - 10)%
(-37 - 10)%
(-0 - 15)%
(-26 - 32)%
(-5 - 5)%
(-11 - 1)%
*Italics indicate statistical significance
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 27
Dual Arm Analysis
Efficacy – Disease Specific Survival
Difference
Treatment 1
TUR + Epirubicin
TUR + BCG + Interferon
TUR + BCG + Interferon
TUR + Epirubicin + Maintenance
TUR + BCG + Maintenance
TUR + MMC + Maintenance
Treatment 2
TUR + BCG
TUR + BCG
TUR + Epirubicin
TUR + BCG + Maintenance
TUR + BCG
TUR + BCG + Maintenance
S/P
1/560
1/558
1/556
1/161
1/126
2/494
Median
-3%
-1%
2%
-5%
-1%
3%
S/P
1/560
1/558
1/556
1/161
1/244
2/510
Median
-3%
1%
4%
-5%
-3%
1%
CI (2.5 - 97.5)%
(-6 - -0)%
(-4 - 1)%
(-1 - 5)%
(-16 - 6)%
(-9 - 6)%
(-3 - 8)%
Dual Arm Analysis
Efficacy – Overall Survival
Difference
Treatment 1
TUR + Epirubicin
TUR + BCG + Interferon
TUR + BCG + Interferon
TUR + Epirubicin + Maintenance
TUR + MMC + Maintenance
TUR + BCG + Maintenance
Treatment 2
TUR + BCG
TUR + BCG
TUR + Epirubicin
TUR + BCG + Maintenance
TUR + BCG + Maintenance
TUR + BCG
CI (2.5 - 97.5)%
(-9 - 3)%
(-5 - 7)%
(-2 - 10)%
(-17 - 7)%
(-11 - 7)%
(-7 - 8)%
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 28
Appendix 7: Efficacy Outcomes Balance Sheets and Forest Plots
Single Arm Analysis – RCT data only
Efficacy – Recurrence – Overall
1 Year
Treatmento
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
18/1057
2 Years
Median CI (2.5 - 97.5)%
(37 - 54)%
45%
G/P
21/802
3 Years
Median CI (2.5 - 97.5)%
(50 - 63)%
56%
G/P
12/586
Median CI (2.5 - 97.5)%
(47 - 65)%
56%
9/787
11/1426
26%
25%
(17 - 36)%
(17 - 36)%
9/787
11/1426
38%
33%
(30 - 47)%
(25 - 41)%
6/627
10/1398
37%
37%
(28 - 46)%
(30 - 45)%
3/220
11/1337
19%
28%
(10 - 31)%
(23 - 35)%
3/220
11/1337
28%
43%
(16 - 43)%
(36 - 49)%
3/220
11/1337
31%
50%
(17 - 47)%
(45 - 55)%
TURBT + interferon
TURBT + interferon + maintenance
1/53
0%
(0 - 0)%
1/53
27%
(16 - 39)%
4/122
30%
(21 - 40)%
TURBT + MMC
TURBT + MMC single dose
TURBT + MMC + maintenance
3/310
2/206
8/890
40%
13%
32%
(30 - 52)%
(1 - 40)%
(23 - 41)%
3/310
2/206
8/890
53%
28%
42%
(41 - 63)%
(11 - 50)%
(35 - 51)%
3/310
2/206
7/853
59%
31%
44%
(47 - 70)%
(14 - 53)%
(33 - 56)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 29
Single Arm Analysis – RCT data only
Efficacy – Recurrence – Overall
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
4/299
5/520
7/694
5 Years
Median CI (2.5 - 97.5)%
(30 - 59)%
44%
39%
39%
(29 - 51)%
(31 - 47)%
G/P
5/413
6/581
7/1169
Overall/Unspecified
Median CI (2.5 - 97.5)%
(29 - 55)%
41%
38%
42%
(27 - 50)%
(33 - 51)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
3/220
5/753
33%
59%
(20 - 49)%
(53 - 65)%
3/220
3/408
33%
61%
(20 - 49)%
(51 - 70)%
G/P
19/1019
Median CI (2.5 - 97.5)%
(49 - 61)%
55%
10/816
19/1427
1/37
36%
29%
59%
(27 - 45)%
(23 - 36)%
(43 - 74)%
2/30
32%
(15 - 54)%
3/178
3/167
29%
44%
(16 - 46)%
(31 - 58)%
1/66
4/122
68%
30%
(56 - 78)%
(21 - 40)%
1/92
46%
(36 - 56)%
11/1086
31%
(25 - 39)%
1/51
16%
(8 - 27)%
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC single dose
TURBT + MMC + maintenance
2/206
6/728
40%
43%
(28 - 54)%
(31 - 56)%
3/310
2/206
4/574
66%
46%
49%
(56 - 74)%
(37 - 55)%
(39 - 59)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 30
Single Arm Analysis – RCT data only
Efficacy – Recurrence – Overall - Graph
Recurrence - Overall
TURBT - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC single dose - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 31
Single Arm Analysis – RCT data only
Efficacy – Recurrence – High Risk
1 Year
Treatment#
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
2/132
2 Years
Median CI (2.5 - 97.5)%
(50 - 70)%
60%
G/P
2/132
3 Years
Median CI (2.5 - 97.5)%
(66 - 84)%
76%
G/P
2/124
Median CI (2.5 - 97.5)%
(56 - 91)%
77%
4/197
4/322
15%
16%
(8 - 23)%
(6 - 32)%
4/197
4/322
25%
24%
(18 - 34)%
(15 - 35)%
4/197
3/294
29%
28%
(21 - 37)%
(15 - 43)%
1/77
1/84
8%
46%
(3 - 15)%
(36 - 57)%
1/77
4/132
13%
44%
(7 - 22)%
(29 - 61)%
1/77
1/84
14%
65%
(8 - 23)%
(55 - 75)%
3/69
30%
(18 - 44)%
2/79
64%
(40 - 83)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
2/79
26%
(16 - 39)%
2/79
54%
(29 - 78)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 32
Single Arm Analysis – RCT data only
Efficacy – Recurrence – High Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Overall/Unspecified
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
3/136
2/229
33%
40%
(24 - 43)%
(29 - 52)%
3/170
3/294
32%
34%
(21 - 44)%
(18 - 54)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
1/77
1/84
17%
70%
(10 - 26)%
(60 - 79)%
1/77
4/132
17%
70%
(10 - 26)%
(43 - 89)%
G/P
11/441
Median CI (2.5 - 97.5)%
(51 - 68)%
60%
4/186
5/573
34%
27%
(24 - 45)%
(16 - 40)%
1/48
35%
(16 - 58)%
4/125
3/48
36%
43%
(20 - 54)%
(23 - 66)%
3/69
30%
(18 - 44)%
3/91
44%
(32 - 57)%
4/72
20%
(10 - 33)%
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
2/79
70%
(50 - 85)%
1/16
62%
(38 - 83)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 33
Single Arm Analysis – RCT data only
Efficacy – Recurrence – High Risk – Graph
Recurrence - High Risk
TURBT - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 34
Single Arm Analysis – RCT data only
Efficacy – Recurrence – Low Risk
1 Year
Treatment
G/P
2 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
3 Years
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 35
Single Arm Analysis – RCT data only
Efficacy – Recurrence – Low Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
Overall/Unspecified
G/P
2/24
Median CI (2.5 - 97.5)%
(8 - 46)%
23%
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
1/9
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 36
2%
(0 - 24)%
Single Arm Analysis – RCT data only
Efficacy – Progression – Overall
1 Year
Treatmento
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/157
2 Years
Median CI (2.5 - 97.5)%
(5 - 13)%
8%
G/P
1/157
3 Years
Median CI (2.5 - 97.5)%
(5 - 14)%
9%
G/P
1/157
Median CI (2.5 - 97.5)%
(8 - 18)%
12%
2/363
5/979
5%
4%
(3 - 8)%
(3 - 6)%
2/363
5/979
9%
8%
(4 - 15)%
(4 - 13)%
2/363
5/979
13%
9%
(6 - 24)%
(5 - 15)%
2/363
7%
(2 - 16)%
2/363
14%
(4 - 33)%
2/363
16%
(5 - 36)%
1/149
1/173
6%
0%
(3 - 11)%
(0 - 1)%
1/149
1/173
9%
3%
(5 - 14)%
(1 - 6)%
1/149
1/173
9%
5%
(5 -14)%
(3 - 9)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC single dose
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 37
Single Arm Analysis – RCT data only
Efficacy – Progression – Overall
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/157
2/363
3/421
5 Years
Median CI (2.5 - 97.5)%
(9 - 19)%
13%
17%
17%
(7 - 31)%
(13 - 23)%
G/P
1/157
2/363
5/979
Overall/Unspecified
Median CI (2.5 - 97.5)%
(14 - 27)%
20%
20%
14%
(9 - 37)%
(8 - 21)%
G/P
17/917
Median CI (2.5 - 97.5)%
(9 - 17)%
12%
8/546
17/1701
1/37
10%
9%
19%
(7 - 13)%
(7 - 12)%
(8 - 34)%
8/1160
5%
(2 - 9)%
4/122
9%
(4 - 17)%
3/343
1/57
9/928
6%
2%
11%
(2 - 12)%
(0 - 8)%
(8 - 16)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC single dose
TURBT + MMC + maintenance
1/149
1/173
12%
8%
(8 - 18)%
(5 - 13)%
1/149
1/173
16%
8%
(11 - 23)%
(5 - 13)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 38
Single Arm Analysis – RCT data only
Efficacy – Progression – Overall - Graph
Progression - Overall
TURBT - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction - Overall
TURBT + MMC single dose - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 39
Single Arm Analysis – RCT data only
Efficacy – Progression – High Risk
1 Year
Treatment
G/P
2 Years
Median CI (2.5 - 97.5)%
G/P
3 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
2/229
7%
(3 - 13)%
2/229
12%
(4 - 24)%
2/229
16%
(8 - 26)%
1/84
12%
(6 - 20)%
1/84
26%
(18 - 37)%
1/84
29%
(20 - 39)%
1/16
1%
(0 - 14)%
1/16
13%
(3 - 34)%
1/16
19%
(6 - 42)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 40
Single Arm Analysis – RCT data only
Efficacy – Progression – High Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Overall/Unspecified
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
2/48
Median CI (2.5 - 97.5)%
(3 - 46)%
17%
2/229
17%
(10 - 26)%
2/229
20%
(12 - 31)%
4/260
5/341
14%
14%
(9 - 19)%
(8 - 22)%
1/84
31%
(21 - 40)%
1/84
30%
(21 - 40)%
3/122
20%
(5 - 46)%
3/69
10%
(3 - 21)%
1/63
10%
(4 - 19)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
1/16
38%
(17 - 62)%
1/16
38%
(17 - 62)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 41
Single Arm Analysis – RCT data only
Efficacy – Progression – High Risk - Graph
Progression - High Risk
TURBT - Overall
TURBT + BCG Induction - Overall
TURBT + BCG Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 42
Single Arm Analysis – RCT data only
Efficacy – Progression – Low Risk
1 Year
Treatment
G/P
3 Years
2 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 43
Single Arm Analysis – RCT data only
Efficacy – Progression – Low Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
Overall/Unspecified
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 44
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – Overall
1 Year
Treatment
G/P
2 Years
Median CI (2.5 - 97.5)%
G/P
3 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
1/145
99%
(97 - 100)%
1/145
97%
(94 - 99)%
1/145
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 45
97%
(94 - 99)%
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – Overall
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Overall/Unspecified
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
1/145
95%
(91 - 98)%
1/145
95%
(91 - 98)%
G/P
4/383
Median CI (2.5 - 97.5)%
(89 - 97)%
94%
3/325
10/1442
89%
95%
(79 - 96)%
(92 - 97)%
6/1018
96%
(93 - 98)%
1/92
7/740
91%
93%
(84 - 96)%
(91 - 95)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 46
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – Overall - Graph
Disease Specific Survival - Overall
TURBT - Overall
TURBT + BCG Induction - Overall
TURBT + BCG Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction - Overall
TURBT + MMC Induction + maintenance - Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 47
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – High Risk
1 Year
Treatmento
G/P
2 Years
Median CI (2.5 - 97.5)%
G/P
3 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
1/145
99%
(97 - 100)%
1/145
97%
(94 - 99)%
1/145
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 48
97%
(94 - 99)%
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – High Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Overall/Unspecified
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
1/145
95%
(91 - 98)%
1/145
95%
(91 - 98)%
G/P
1/118
Median CI (2.5 - 97.5)%
(95 - 100)%
98%
2/164
3/294
87%
92%
(66 - 98)%
(87 - 95)%
1/84
83%
(74 - 90)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 49
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – High Risk - Graph
Disease Specific Survival - High Risk
TURBT - Overall
TURBT + BCG Induction - Overall
TURBT + BCG Induction + maintenance - 1 Yr
2 Yr
3 Yr
4 Yr
5 Yr
Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 50
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – Low Risk
1 Year
Treatmento
G/P
2 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
3 Years
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 51
Single Arm Analysis – RCT data only
Efficacy – Disease Specific Survival – Low Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
Overall/Unspecified
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 52
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – Overall
1 Year
Treatmento
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
2/225
2 Years
Median CI (2.5 - 97.5)%
(93 - 100)%
98%
G/P
2/225
3 Years
Median CI (2.5 - 97.5)%
(85 - 97)%
92%
G/P
2/225
Median CI (2.5 - 97.5)%
(81 - 95)%
90%
1/192
5/976
97%
97%
(94 - 99)%
(95 - 98)%
1/192
5/976
95%
93%
(91 - 97)%
(90 - 94)%
1/192
5/976
90%
88%
(85 - 94)%
(85 - 90)%
2/363
94%
(91 - 97)%
2/363
87%
(80 - 92)%
2/363
82%
(75 - 87)%
2/192
95%
(91 - 98)%
2/192
94%
(90 - 97)%
2/192
91%
(87 - 95)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 53
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – Overall
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
2/225
1/192
3/421
5 Years
Median CI (2.5 - 97.5)%
(76 - 91)%
85%
84%
83%
(78 - 88)%
(75 - 88)%
G/P
2/225
Overall/Unspecified
Median CI (2.5 - 97.5)%
(66 - 80)%
74%
G/P
5/505
Median CI (2.5 - 97.5)%
(73 - 92)%
84%
1/192
5/976
79%
77%
(73 - 84)%
(73 - 81)%
3/335
13/1557
1/37
73%
84%
92%
(56 - 87)%
(78 - 89)%
(80 - 98)%
2/363
70%
(60 - 79)%
6/1022
87%
(79 - 93)%
2/192
82%
(75 - 87)%
7/914
81%
(71 - 89)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
2/192
86%
(80 - 91)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 54
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – Overall – Graph
Overall Survival - Overall
TURBT - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + BCG Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
TURBT + MMC Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 55
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – High Risk
1 Year
Treatment
G/P
2 Years
Median CI (2.5 - 97.5)%
G/P
3 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
1/229
98%
(94 - 100)%
1/229
93%
(87 - 97)%
1/229
87%
(80 - 92)%
1/84
94%
(87 - 98)%
1/84
84%
(76 - 91)%
1/84
80%
(70 - 87)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 56
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – High Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Overall/Unspecified
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/118
Median CI (2.5 - 97.5)%
(66 - 82)%
75%
1/229
80%
(68 - 89)%
1/229
76%
(63 - 87)%
2/184
4/322
75%
79%
(45 - 94)%
(66 - 89)%
1/84
70%
(60 - 79)%
1/84
65%
(55 - 75)%
1/84
57%
(46 - 67)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 57
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – High Risk – Graph
Overall Survival - High Risk
TURBT - Overall
TURBT + BCG Induction - Overall
TURBT + BCG Induction + maintenance - 1 yr
2 yr
3 yr
4 yr
5 yr
Overall
0%
20%
40%
60%
80%
100%
Estimated Occurrence Rate with 95% CI
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 58
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – Low Risk
1 Year
Treatment
G/P
3 Years
2 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 59
Single Arm Analysis – RCT data only
Efficacy – Overall Survival – Low Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
Overall/Unspecified
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 60
Appendix 8: Efficacy Balance sheets
Single Arm Analysis
Efficacy – Recurrence – Overall
1 Year
Treatment
TURBT
G/P
31/2118
TURBT + BCG 21/1283
TURBT + BCG + maintenance 18/1841
TURBT + BGC + Interferon 1/230
TURBT + BGC + Interferon + maintenance
3/583
2 Years
Median CI (2.5 - 97.5)%
(26 - 38)%
32%
G/P
32/2079
3 Years
Median CI (2.5 - 97.5)%
(36 - 50)%
43%
G/P
27/1758
Median CI (2.5 - 97.5)%
(42 - 55)%
49%
23%
23%
16%
40%
(18 - 29)%
(17 - 30)%
(12 - 21)%
(36 - 45)%
21/1283
17/1800
2/262
3/583
36%
30%
31%
61%
(31 - 42)%
(25 - 37)%
(24 - 40)%
(31 - 86)%
19/1123
16/1598
1/230
39%
36%
42%
(33 - 48)%
(30 - 42)%
(36 - 49)%
24%
27%
(16 - 35)%
(20 - 34)%
3/220
12/1381
28%
40%
(16 - 43)%
(33 - 48)%
3/220
12/1381
31%
47%
(17 - 47)%
(41 - 54)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin 5/286
TURBT + epirubicin + maintenance 12/1381
TURBT + gemcitabine
1/116
75%
(66 - 82)%
TURBT + interferon
TURBT + interferon + maintenance
1/53
0%
(0 - 0)%
1/53
27%
(16 - 39)%
4/122
30%
(21 - 40)%
4/367
9/1012
29%
29%
(13 - 51)%
(23 - 37)%
4/367
9/1012
44%
41%
(28 - 60)%
(33 - 49)%
4/367
9/1012
50%
44%
(32 - 67)%
(35 - 54)%
TURBT + Valrubicin
2/138
79%
(69 - 87)%
Cystectomy
2/78
19%
(4 - 48)%
2/78
32%
(9 - 63)%
2/78
32%
(9 - 63)%
1/34
91%
(78 - 97)%
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 61
Single Arm Analysis
Efficacy – Recurrence – Overall
4 Years
Treatment
TURBT
G/P
8/449
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
6/538
10/912
1/230
5 Years
Median CI (2.5 - 97.5)%
(35 - 54)%
44%
G/P
20/1467
Overall/Unspecified
Median CI (2.5 - 97.5)%
(40 - 54)%
47%
G/P
42/2359
Median CI (2.5 - 97.5)%
(46 - 56)%
51%
TURBT + BGC + Interferon + maintenance
23/1484
31/3521
2/262
3/583
45%
29%
62%
49%
(37 - 53)%
(24 - 34)%
(47 - 75)%
(44 - 54)%
TURBT + doxorubicin + maintenance
2/30
32%
(15 - 54)%
5/252
4/211
31%
39%
(22 - 42)%
(27 - 52)%
TURBT + gemcitabine
1/116
26%
(19 - 35)%
TURBT + interferon
TURBT + interferon + maintenance
1/66
4/122
68%
30%
(56 - 78)%
(21 - 40)%
3/159
14/1453
50%
31%
(31 - 68)%
(24 - 39)%
TURBT + Valrubicin
1/90
93%
(87 - 97)%
Cystectomy
1/4
5%
(0 - 44)%
4/117
45%
(27 - 64)%
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + MMC
TURBT + MMC + maintenance
3/220
5/753
6/728
38%
35%
56%
33%
59%
43%
(29 - 49)%
(29 - 41)%
(50 - 62)%
(20 - 49)%
(53 - 65)%
(31 - 56)%
9/888
11/1681
1/230
3/220
4/452
4/367
6/874
43%
43%
64%
33%
51%
59%
51%
(34 - 52)%
(35 - 51)%
(58 - 70)%
(20 - 49)%
(35 - 67)%
(45 - 71)%
(40 - 62)%
TURBT + Mitoxantrone + maintenance
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 62
Single Arm Analysis
Efficacy – Recurrence – High Risk
1 Year
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
8/410
3 Years
2 Years
Median CI (2.5 - 97.5)%
(28 - 52)%
39%
12/601
5/414
19%
18%
(14 - 26)%
(8 - 33)%
1/5
59%
(21 - 91)%
TURBT + epirubicin
TURBT + epirubicin + maintenance
1/77
1/80
8%
46%
(3 - 15)%
(36 - 57)%
TURBT + gemcitabine
2/116
59%
(17 - 92)%
G/P
8/410
Median CI (2.5 - 97.5)%
(38 - 64)%
51%
G/P
8/402
Median CI (2.5 - 97.5)%
(43 - 70)%
57%
12/601
5/414
6/45
30%
26%
34%
(24 - 36)%
(18 - 36)%
(20 - 50)%
12/539
5/414
36%
30%
(30 - 43)%
(21 - 41)%
1/77
3/118
13%
44%
(7 - 22)%
(23 - 65)%
1/77
1/80
16%
65%
(9 - 25)%
(55 - 75)%
3/69
30%
(18 - 44)%
2/79
64%
(40 - 83)%
1/31
52%
(35 - 68)%
TURBT + doxorubicin + maintenance
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
2/79
26%
(16 - 39)%
2/79
54%
(29 - 78)%
TURBT + Valrubicin
1/89
81%
(72 - 88)%
1/89
85%
(77 - 92)%
Cystectomy
1/31
36%
(21 - 53)%
1/31
52%
(35 - 68)%
TURBT + Mitoxantrone + maintenance
(
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 63
Single Arm Analysis
Efficacy – Recurrence – High Risk
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/17
5/256
3/299
5 Years
Median CI (2.5 - 97.5)%
(9 - 47)%
24%
10/546
5/414
Overall/Unspecified
Median CI (2.5 - 97.5)%
(41 - 69)%
56%
Median CI (2.5 - 97.5)%
(48 - 68)%
58%
39%
34%
(32 - 48)%
(28 - 41)%
1/2
50%
(6 - 94)%
1/22
28%
(12 - 48)%
5/151
2/38
35%
39%
(21 - 51)%
(12 - 72)%
TURBT + gemcitabine
1/46
35%
(22 - 49)%
TURBT + interferon
TURBT + interferon + maintenance
2/37
3/69
75%
30%
(52 - 91)%
(18 - 44)%
1/10
5/119
79%
37%
(50 - 96)%
(24 - 51)%
TURBT + Valrubicin
1/89
93%
(87 - 97)%
Cystectomy
1/31
5%
(0 - 44)%
TURBT + Phototherapy
7/72
35%
(24 - 48)%
43%
37%
(34 - 52)%
(26 - 49)%
G/P
14/480
17/736
15/945
32%
37%
(26 - 39)%
(28 - 46)%
G/P
6/278
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + MMC
TURBT + MMC + maintenance
1/77
1/84
2/79
17%
70%
70%
(10 - 26)%
(60 - 79)%
(50 - 85)%
1/77
3/118
1/16
17%
63%
62%
(10 - 26)%
(35 - 86)%
(38 - 83)%
TURBT + Mitoxantrone + maintenance
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 64
Single Arm Analysis
Efficacy – Recurrence – Low Risk
1 Year
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
6/554
3 Years
2 Years
Median CI (2.5 - 97.5)%
(15 - 33)%
23%
1/6
4%
(0 - 33)%
1/18
28%
(11 - 51)%
G/P
5/468
1/6
Median CI (2.5 - 97.5)%
(28 - 50)%
38%
4%
(0 - 33)%
G/P
5/468
1/6
Median CI (2.5 - 97.5)%
(35 - 55)%
45%
19%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 65
(2 - 56)%
Single Arm Analysis
Efficacy – Recurrence – Low Risk
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/19
1/6
5 Years
Median CI (2.5 - 97.5)%
(31 - 73)%
53%
19%
(2 - 56)%
G/P
5/468
1/6
Overall/Unspecified
Median CI (2.5 - 97.5)%
(41 - 64)%
52%
19%
(2 - 56)%
G/P
8/546
Median CI (2.5 - 97.5)%
(34 - 59)%
46%
1/6
19%
(2 - 56)%
1/18
28%
(11 - 51)%
2/29
10%
(2 - 30)%
1/9
2%
(0 - 24)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 66
Single Arm Analysis
Efficacy – Progression – Overall
1 Year
Treatment#
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
8/578
2 Years
Median CI (2.5 - 97.5)%
(3 - 14)%
7%
G/P
10/646
3 Years
Median CI (2.5 - 97.5)%
(7 - 29)%
16%
G/P
7/458
Median CI (2.5 - 97.5)%
(12 - 40)%
24%
16/1229
8/1150
10%
6%
(7 - 14)%
(4 - 8)%
16/1229
8/1150
16%
8%
(12 - 21)%
(4 - 13)%
16/1229
8/1150
20%
9%
(16 - 25)%
(5 - 15)%
2/363
7%
(2 - 16)%
2/363
14%
(4 - 33)%
2/363
16%
(5 - 36)%
2/415
0%
(0 - 1)%
2/415
3%
(2 - 6)%
2/415
5%
(3 - 8)%
1/29
14%
(5 - 30)%
1/29
28%
(14 - 45)%
1/29
35%
(19 - 53)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 67
Single Arm Analysis
Efficacy – Progression – Overall
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/28
5 Years
Median CI (2.5 - 97.5)%
(49 - 83)%
68%
G/P
7/458
Overall/Unspecified
Median CI (2.5 - 97.5)%
(16 - 46)%
29%
G/P
38/2193
Median CI (2.5 - 97.5)%
(9 - 16)%
12%
20/1280
28/2627
2/267
3/502
16%
11%
20%
7%
(12 - 20)%
(9 - 14)%
(15 - 27)%
(4 - 11)%
TURBT + epirubicin
TURBT + epirubicin + maintenance
9/1204
5%
(2 - 8)%
TURBT + gemcitabine
1/116
6%
(3 - 11)%
TURBT + interferon
TURBT + interferon + maintenance
4/122
9%
(4 - 17)%
4/180
11/1180
7%
10%
(3 - 13)%
(7 - 14)%
1/90
49%
(39 - 59)%
19%
(10 - 30)%
19%
(7 - 37)%
4/561
4/491
22%
17%
(14 - 32)%
(12 - 22)%
16/1139
8/1150
28%
15%
(23 - 34)%
(10 - 20)%
TURBT + doxorubicin + maintenance
TURBT + MMC
TURBT + MMC + maintenance
1/173
8%
(5 - 13)%
2/415
7%
(4 - 11)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
1/29
Cystectomy
35%
(19 - 53)%
3/77
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 68
Single Arm Analysis
Efficacy – Progression – High Risk
1 Year
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
5/191
2 Years
Median CI (2.5 - 97.5)%
(9 - 34)%
19%
G/P
7/259
3 Years
Median CI (2.5 - 97.5)%
(16 - 42)%
27%
G/P
5/191
Median CI (2.5 - 97.5)%
(19 - 50)%
33%
13/581
5/400
13%
8%
(9 - 17)%
(5 - 13)%
13/631
5/400
20%
12%
(16 - 25)%
(8 - 17)%
13/539
5/400
24%
15%
(20 - 30)%
(11 - 20)%
1/84
12%
(6 - 20)%
1/84
26%
(18 - 37)%
1/84
29%
(20 - 39)%
1/16
1%
(0 - 14)%
1/16
13%
(3 - 34)%
1/16
19%
(6 - 42)%
1/29
14%
(5 - 30)%
1/29
28%
(14 - 45)%
1/29
35%
(19 - 53)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 69
Single Arm Analysis
Efficacy – Progression – High Risk
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/28
5 Years
Median CI (2.5 - 97.5)%
(49 - 83)%
68%
G/P
5/191
Overall/Unspecified
Median CI (2.5 - 97.5)%
(24 - 55)%
38%
G/P
8/370
Median CI (2.5 - 97.5)%
(12 - 30)%
20%
20/1104
15/791
21%
19%
(16 - 27)%
(16 - 23)%
2/7
14%
(1 - 50)%
3/122
20%
(5 - 46)%
TURBT + gemcitabine
2/116
8%
(1 - 23)%
TURBT + interferon
TURBT + interferon + maintenance
3/69
10%
(3 - 21)%
1/10
4/101
11%
8%
(1 - 38)%
(3 - 16)%
1/90
49%
(39 - 59)%
4/228
36%
(22 - 51)%
2/198
3/299
30%
16%
(16 - 46)%
(11 - 22)%
13/631
5/400
31%
19%
(27 - 36)%
(14 - 24)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + MMC
TURBT + MMC + maintenance
1/84
1/16
31%
38%
(21 - 40)%
(17 - 62)%
1/84
1/16
30%
38%
(21 - 40)%
(17 - 62)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
1/29
Cystectomy
35%
(19 - 53)%
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 70
Single Arm Analysis
Efficacy – Progression – Low Risk
1 Year
Treatment
TURBT
G/P
1/152
3 Years
2 Years
Median CI (2.5 - 97.5)%
(0 - 4)%
1%
G/P
1/152
Median CI (2.5 - 97.5)%
(4 - 13)%
8%
G/P
1/152
Median CI (2.5 - 97.5)%
(8 - 18)%
12%
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 71
Single Arm Analysis
Efficacy – Progression – Low Risk
4 Years
Treatment
TURBT
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
1/152
Median CI (2.5 - 97.5)%
(11 - 23)%
16%
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
Overall/Unspecified
G/P
4/907
Median CI (2.5 - 97.5)%
(2 - 17)%
8%
2/29
13%
(2 - 36)%
2/29
4%
(0- 18)%
1/1
16%
(0 - 85)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 72
Single Arm Analysis
Efficacy – Disease Specific Survival – Overall
1 Year
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
2/111
2 Years
Median CI (2.5 - 97.5)%
(89 - 99)%
96%
G/P
2/111
3 Years
Median CI (2.5 - 97.5)%
(78 - 95)%
89%
G/P
2/111
Median CI (2.5 - 97.5)%
(76 - 93)%
85%
7/523
3/285
98%
98%
(96 - 99)%
(96 - 100)%
7/523
3/285
94%
95%
(91 - 96)%
(91 - 98)%
7/523
3/285
89%
93%
(83 - 92)%
(86 - 97)%
3/107
92%
(80 - 98)%
4/121
89%
(72 - 97)%
3/107
85%
(62 - 97)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 73
Single Arm Analysis
Efficacy – Disease Specific Survival – Overall
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
2/198
1/145
80%
95%
(72 - 86)%
(91 - 98)%
G/P
2/111
7/523
3/285
Overall/Unspecified
Median CI (2.5 - 97.5)%
(64-87)%
77%
80%
86%
(71 - 86)%
(72 - 95)%
G/P
13/1162
Median CI (2.5 - 97.5)%
(86 - 96)%
92%
11/1018
17/1948
1/37
2/457
86%
89%
97%
99%
(79 - 90)%
(82 - 94)%
(88 - 100)%
(97 - 100)%
6/1018
96%
(93 - 98)%
2/102
9/1225
91%
94%
(79 - 98)%
(92 - 96)%
1/90
95%
(90 - 98)%
2/43
67%
(44 - 85)%
1/34
88%
(74 - 96)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
2/43
Cystectomy
61%
(38 - 81)%
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 74
Single Arm Analysis
Efficacy – Disease Specific Survival – High Risk
1 Year
Treatment
G/P
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
2 Years
Median CI (2.5 - 97.5)%
(89 - 99)%
96%
G/P
3 Years
Median CI (2.5 - 97.5)%
(78 - 95)%
89%
G/P
Median CI (2.5 - 97.5)%
(74 - 93)%
85%
10/528
3/285
96%
98%
(91 - 98)%
(96 - 100)%
10/528
3/285
92%
95%
(88 - 95)%
(91 - 98)%
10/528
3/285
86%
93%
(81 - 91)%
(86 - 97)%
2/60
88%
(70 - 98)%
3/74
78%
(64 - 89)%
2/60
76%
(58 - 89)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 75
Single Arm Analysis
Efficacy – Disease Specific Survival – High Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
2/198
1/145
80%
95%
(72 - 86)%
(91 - 98)%
10/528
3/285
Overall/Unspecified
Median CI (2.5 - 97.5)%
(64 - 87)%
77%
82%
86%
(74 - 89)%
(72 - 95)%
G/P
6/412
Median CI (2.5 - 97.5)%
(84 - 97)%
93%
8/590
12/813
83%
80%
(74 - 89)%
(67 - 89)%
1/84
83%
(74 - 90)%
1/10
98%
(78 - 100)%
1/90
95%
(90 - 98)%
1/14
57%
(32 - 80)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
2/43
61%
(38 - 81)%
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 76
Single Arm Analysis
Efficacy – Disease Specific Survival – Low Risk
1 Year
Treatment
G/P
2 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
3 Years
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 77
Single Arm Analysis
Efficacy – Disease Specific Survival – Low Risk
4 Years
Treatment /
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
Overall/Unspecified
G/P
4/907
1/23
Median CI (2.5 - 97.5)%
(95 - 99)%
97%
99%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 78
(90 - 100)%
Single Arm Analysis
Efficacy – Overall Survival – Overall
1 Year
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
G/P
3/286
2 Years
Median CI (2.5 - 97.5)%
(95 - 99)%
98%
G/P
3/286
3 Years
Median CI (2.5 - 97.5)%
(87 - 96)%
92%
G/P
3/286
Median CI (2.5 - 97.5)%
(80 - 93)%
88%
5/499
5/976
97%
97%
(95 - 99)%
(95 - 98)%
5/499
5/976
93%
93%
(88 - 96)%
(90 - 94)%
5/499
5/976
88%
88%
(79 - 93)%
(85 - 90)%
2/363
94%
(91 - 97)%
2/363
87%
(80 - 92)%
2/363
82%
(75 - 87)%
2/292
96%
(92 - 98)%
2/292
94%
(90 - 97)%
2/292
91%
(86 - 95)%
1/29
86%
(70 95)%
1/29
76%
(58 - 88)%
1/29
69%
(51 - 83)%
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 79
Single Arm Analysis
Efficacy – Overall Survival – Overall
4 Years
Treatment
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
G/P
2/225
1/192
3/421
5 Years
Median CI (2.5 - 97.5)%
(76 - 91)%
85%
84%
83%
(78 - 88)%
(75 - 88)%
G/P
3/286
Overall/Unspecified
Median CI (2.5 - 97.5)%
(66 - 79)%
73%
G/P
12/1142
Median CI (2.5 - 97.5)%
(70 - 87)%
79%
4/499
5/976
82%
77%
(72 - 90)%
(73 - 81)%
10/956
17/1714
1/37
2/490
72%
82%
92%
96%
(60 - 81)%
(77 - 86)%
(80 - 98)%
(94 - 98)%
2/363
70%
(60 - 79)%
6/1022
87%
(79 - 93)%
2/292
82%
(75 - 87)%
1/92
9/1213
85%
84%
(76 - 91)%
(76 - 91)%
1/90
92%
(85 - 96)%
1/29
52%
(34 - 69)%
1/34
65%
(48 - 79)%
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
2/292
86%
(80 - 91)%
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
1/29
TURBT + Phototherapy
55%
(37 - 72)%
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 80
Single Arm Analysis
Efficacy – Overall Survival – High Risk
1 Year
Treatmento
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/61
2 Years
Median CI (2.5 - 97.5)%
(93 - 100)%
98%
G/P
1/61
3 Years
Median CI (2.5 - 97.5)%
(83 - 97)%
92%
G/P
1/61
Median CI (2.5 - 97.5)%
(71 - 90)%
82%
3/188
1/229
98%
98%
(94 - 99)%
(94 - 100)%
3/188
1/229
93%
93%
(81 - 98)%
(87 - 97)%
3/188
1/229
88%
87%
(68 - 97)%
(80 - 92)%
1/84
94%
(87 - 98)%
1/84
84%
(76 - 91)%
1/84
80%
(70 - 87)%
1/29
86%
(70 - 95)%
1/29
76%
(58 - 88)%
1/29
69%
(51 - 83)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 81
Single Arm Analysis
Efficacy – Overall Survival – High Risk
4 Years
Treatmento
G/P
5 Years
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
G/P
1/61
Overall/Unspecified
Median CI (2.5 - 97.5)%
(58 - 81)%
70%
G/P
4/216
Median CI (2.5 - 97.5)%
(34 - 52)%
43%
1/229
80%
(68 - 89)%
3/188
1/229
81%
76%
(64 - 92)%
(63 - 87)%
6/465
7/546
80%
75%
(67 - 90)%
(68 - 81)%
1/84
70%
(60 - 79)%
1/84
65%
(55 - 75)%
1/84
57%
(46 - 67)%
1/90
92%
(85 - 96)%
1/29
52%
(34 - 69)%
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
1/29
55%
(37 - 72)%
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 82
Single Arm Analysis
Efficacy – Overall Survival – Low Risk
1 Year
Treatment
G/P
3 Years
2 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 83
Single Arm Analysis
Efficacy – Overall Survival – Low Risk
4 Years
Treatment
G/P
5 Years
Median CI (2.5 - 97.5)%
G/P
Median CI (2.5 - 97.5)%
TURBT
Overall/Unspecified
G/P
2/255
Median CI (2.5 - 97.5)%
(77 - 89)%
84%
TURBT + BCG
TURBT + BCG + maintenance
TURBT + BGC + Interferon
TURBT + BGC + Interferon + maintenance
TURBT + doxorubicin + maintenance
TURBT + epirubicin
TURBT + epirubicin + maintenance
TURBT + gemcitabine
TURBT + interferon
TURBT + interferon + maintenance
TURBT + MMC
TURBT + MMC + maintenance
TURBT + Mitoxantrone + maintenance
TURBT + Valrubicin
Cystectomy
TURBT + Phototherapy
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 84
Appendix 9: Complications and Adverse Events Categories
Complications Groupings
AUA Bladder Cancer Guideline Panel
Complications Groupings
Bladder Contracture
Bladder Contracture
Bladder contracture
Reduced bladder capacity
Bladder Contracture - Surgery Required
Bladder contracture - Surgery required
Death
Death
Death due to complications
Local Side Effects
Bladder Spasm/Pain
Abdominal pain
Adductor spasm
Bladder spams
Bladder spasm
Bladder spasms
Bladder spasms/dysuria
Cramp
Pain
Pelvic pain
Scrotal pain
Spasm
Suprapubic pain
Epid/Prost/Ureth Infections
Epid/prost/ureth. Infections
Epididymitis
Epididymo-orchitis
Prostatitis (granulamatous)
Hematuria
Clot retention
Gross hematuria
Hematuria
Impotence
Impotence
Incontinence
Incontinence
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 85
AUA Bladder Cancer Guideline Panel
Complications Groupings
LUTS
Cystitis - Bacterial
Cystitis - Non-bacterial
Cystitis N/S
Disturbing local @ 12 months
Disturbing local @ 12 months
Disturbing local @ 3 months
Disturbing local @ 3 months
Dysuria
Frequency lasting 3 weeks
Frequency/nocturia
Frequent dysuria, non-bacterial cystitis
Infection
Infection/inflammation
Irritation
Irritative voiding
Local
Local toxicity
Local ulceration
Mild dysuria/freq/hematuria
Mod dysuria/freq/hematuria
Other local
Other local side effects
Pain on urination
Painful urination
Pollakisuria
Pyuria
Thermal reaction
Tissue reaction
Urethral discomfort or pain
Urgency
Very distrubing local @ 12 months
Very disturbing local @ 12 months
Very disturbing local @ 3 months
Very disturbing local @ 3 months
Urethral Stricture
Difficulty catheterizing
Urethral stricture
Urinary Obstruction
Urinary obstruction
Urinary Retention
Hypotomic bladder
Urinary retention
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 86
AUA Bladder Cancer Guideline Panel
Complications Groupings
Skin Rash
Skin Rash
Palmar rash
Phototoxic skin reaction
Pruritis
Rash
Skin photoxicity
Skin rash
Systemic
Bowel Perforation/Injury - Surgery required
Bowel perforation/Injury - Surgery required
Cardiovascular
Cardiovascular
Tachycardia
Change in LFT
(Increased) transaminases
Alk Phos (elevated)
Alk Phos > 1.25 x ULN
Elevated LFTS (gr 1-2)
Gama GT > 1.25 x ULN
GPT (elevated)
Grandomatous hepatitis
Hepatitis
Hepatotoxicity
Hepatotoxicty
SGOT > 1.25 x ULN
SGPT > 1.25 x ULN
Fever/Chills/Flu Symptoms
Arthralgia
Arthritis
Asthenia
Back ache
Back pain
Fatigue
Fever
Fever only
Fever plus local side effects
Fever requiring delay or discontuation of instillations
Fever T < 38.5
Fever T > 38.5
Fever/anorexia/malaise
Fever/chills
Flu symptoms
Malaise
Malaise/chills
Malaise/fatigue
Muscaloskeletal
Myalgia/arthralgia
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 87
AUA Bladder Cancer Guideline Panel
Complications Groupings
Lung
Cough
Hypoxemia
Lung granuloma
Lung infection
Pneumonia
Pneumonia - interstitial
Nausea/Vomiting
All GI
Anorexia
GI
Nausea/vomiting
Neuro Changes
All CVS
Dizziness
Fear
Headache
Insomnia
Neurologic
Occular/visual
Renal Insufficiency
Renal dysfunction
Renal morbidity
Systemic - any
Allergic reaction
Allergic reactions
Allergy
Any consideracle side effects"
Disturbing systemic @ 12 months
Disturbing systemic @ 12 months
Disturbing systemic @ 3 months
Disturbing systemic @ 3 months
Hematologic abnormalities
Hemodynamic side effects
Hot flashes
Hypertension
Hypotension
Other systemic
Other systemic side effects
Patients hospitalized for complications
Systemic -any
Systemic side effects
Very disturbing systemic @ 12 months
Very disturbing systemic @ 3 months
Systemic - Infection
BCG lung
BCG sepsis
INH for toxicity
INH stop for toxicity
Systemic Infection
Urosepsis
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 88
AUA Bladder Cancer Guideline Panel
Complications Groupings
Transfusion
Transfusion intraoperative
Transfusion total
Treatment Delay/Cancellation
Treatment Delayed
Treatment delayed
Treatment Discontinued due to CX
Discontinue therapy for complications
Discontinued therapy due to complications
Patients discontinuing therapy due to complications
Severe symptoms requiring withdrawal of therapy
Treatment discontinued
Treatment stopped for complications
Treatment not Completed
Not completed instillation
Urinary Extravasation
Urine Extravasation/Obstruction
Urine extravasation/obstruct
Urine Extravasation/Obstruction - no Surgery required
Extraperitoneal perforation
Urine extravasation/obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
Intraperitoneal perforation
Required cystectomy
Urine extravasation/obstruction - Surgery required
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 89
Appendix 10: Complications Balance Sheets
Bladder Cancer Guideline Update Panel
Complications - Summary
Bladder Contracture
Med CI (2.5 - 97.5)%
Epid/Prost/Urethral
Infections
Med CI (2.5 - 97.5)%
Hematuria
Med CI (2.5 - 97.5)%
Med
LUTS
CI (2.5 - 97.5)%
3/3043
2%
(0 - 5)%
Fever/Chills/
Flu Symptoms
Med CI (2.5 - 97.5)%
Systemic Infection
Med CI (2.5 - 97.5)%
TURBT alone
Groups/Patients
Minimal Overlap (or none)
Maximal Overlap (if minimal)
1/27
1%
(0 - 9)%
Groups/Patients
Minimal Overlap (or none)
Maximal Overlap (if minimal)
1/21
1%
(0 - 11)%
2/168
4%
(0 - 16)%
11/527
29%
(21 - 38)%
17/1584
59%
38%
(42 - 74)%
(28 - 49)%
14/1233
26%
19%
(16 - 39)%
(13 - 28)%
8/949
3%
(2 - 6)%
6/443
4%
(2 - 6)%
17/1523
20%
(13 - 30%
22/1753
71%
57%
(56 - 83)%
(44 - 69)%
20/1667
30%
22%
(22 - 41)%
(16 - 30)%
2/209
2%
(0 - 8)%
3/309
30%
26%
(17 - 47)%
(13 - 43)%
2/220
16%
(11 - 23)%
TURBT + BCG Induction
1/23
1%
(0 - 10)%
4/255
7%
(2 - 17)%
TURBT + BCG Induction + BCG Maint
Groups/Patients
Minimal Overlap (or none)
Maximal Overlap (if minimal)
TURBT + MMC: Single Dose Post-op
Groups/Patients
Minimal Overlap (or none)
Maximal Overlap (if minimal)
TURBT + MMC Induction
Groups/Patients
Minimal Overlap (or none)
Maximal Overlap (if minimal)
5/418
16%
(9 - 25)%
7/657
58%
24%
(32 - 81)%
(16 - 34)%
4/544
19%
(10 - 31)%
9/843
31%
22%
(19 - 44)%
(15 - 30)%
TURBT + MMC Induction + MMC Maint
Groups/Patients
Minimal Overlap (or none)
Maximal Overlap (if minimal)
2/234
5%
(2 - 11)%
1/26
8%
(2 - 22)%
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 90
Bladder Cancer Guideline Update Panel
Complications
Bladder Contracture
Bladder Contracture
Bladder Contracture - Surgery required
Local Side Effects
Bladder Spasm/Pain
Epid/Prost/Ureth Infections
Hematuria
Impotence
Incontinence
LUTS
Urinary Obstruction
Urinary Retention
TURBT (1)
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
1/27
1%
(0 - 9)%
1/2821
2%
(1 - 2)%
3/3043
2%
TURBT + BCG Induction (2)
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
(0 - 5)%
Skin Rash
Systemic
Bowel Perforation/Injury - Surgery required
Cardiovascular
Change in LFT
Fever/Chills/Flu Symptoms
Lung
Nausea/Vomiting
Neuro Changes
Renal Insufficiency
Systemic - any
Systemic - Infection
Transfusion
1/2821
1%
1/2821
1/2821
1/2821
1%
2%
0%
1/21
1%
(0 - 11)%
2/168
11/527
4%
29%
(0 - 16)%
(21 - 38)%
17/1584
59%
(42 - 74)%
2/184
3%
(0 - 8)%
1/33
4%
(0 - 13)%
3/174
14/1233
1/91
3/277
1/123
1/21
4/752
1/23
10%
26%
2%
9%
1%
1%
4%
1%
(3 - 22)%
(16 - 39)%
(0 - 7)%
(5 - 14)%
(0 - 4)%
(0 - 11)%
(1 - 9)%
(0 - 10)%
4/364
1/88
8%
8%
(2 - 19)%
(4 - 15)%
1/93
2%
(0 - 7)%
(1 - 2)%
Treatment Delay/Cancellation
Treatment Discontinued due to CX
Treatment not Completed
Urinary Extravasation
Urine Extravasation/Obstruction
Urine Extravasation/Obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
(1 - 2)%
(2 - 3)%
(0 - 1)%
1%
0%
(1 - 2)%
(0 - 0)%
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 91
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
38%
(28 - 49)%
9%
19%
1%
(5 - 14)%
(13 - 28)%
(0 - 5)%
Bladder Cancer Guideline Update Panel
Complications
TURBT + BCG Induction + Maint (3)
G/P
Bladder Contracture
Bladder Contracture
Bladder Contracture - Surgery required
Local Side Effects
Bladder Spasm/Pain
Epid/Prost/Ureth Infections
Hematuria
Impotence
Incontinence
LUTS
Urinary Obstruction
Urinary Retention
Skin Rash
Systemic
Bowel Perforation/Injury - Surgery required
Cardiovascular
Change in LFT
Fever/Chills/Flu Symptoms
Lung
Nausea/Vomiting
Neuro Changes
Renal Insufficiency
Systemic - any
Systemic - Infection
Transfusion
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
8/949
1/100
3%
1%
(2 - 6)%
(0 - 5)%
1/236
6/443
17/1523
1/17
0%
4%
20%
74%
(0 - 3)%
(2 - 6)%
(13 - 30)%
(54 - 88)%
22/1753
71%
(56 - 83)%
1/236
1%
(0 - 2)%
3/205
5%
(2 - 11)%
1/236
20/1667
2/259
2/69
1/23
1%
30%
5%
17%
22%
(0 - 3)%
(22 - 41)%
(0 - 22)%
(8 - 30)%
(9 - 41)%
2/168
4/255
41%
7%
(7 - 85)%
(2 - 17)%
TURBT + BGC + Interferon (4)
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
1/32
53%
(36 - 70)%
57%
(44 - 69)%
1/32
99%
(93 - 100)%
22%
(16 - 30)%
1/32
96%
(86 - 100)%
14%
(4 - 31)%
24%
(7 - 51)%
Treatment Delay/Cancellation
Treatment Discontinued due to CX
Treatment not Completed
Urinary Extravasation
Urine Extravasation/Obstruction
Urine Extravasation/Obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 92
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
Bladder Cancer Guideline Update Panel
Complications
TURBT + BGC + Interferon + Maint (5)
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
1/12
10%
(1 - 33)%
3/469
6%
(2 - 13)%
1/245
0%
(0 - 1)%
2/457
1%
(0 - 3)%
1/12
10%
2/457
2/457
1%
1%
TURBT + Epirubicin (7)
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
Bladder Contracture
Bladder Contracture
Bladder Contracture - Surgery required
Local Side Effects
Bladder Spasm/Pain
Epid/Prost/Ureth Infections
Hematuria
Impotence
Incontinence
LUTS
Urinary Obstruction
Urinary Retention
Skin Rash
Systemic
Bowel Perforation/Injury - Surgery required
Cardiovascular
Change in LFT
Fever/Chills/Flu Symptoms
Lung
Nausea/Vomiting
Neuro Changes
Renal Insufficiency
Systemic - any
Systemic - Infection
Transfusion
1/30
1/91
6/373
50%
5%
17%
(33 - 67)%
(2 - 10)%
(8 - 29)%
5/343
43%
(26 - 62)%
(1 - 33)%
3/147
4%
(1 - 10)%
(0 - 2)%
(0 - 2)%
1/44
3%
(0 - 10)%
5%
(3 - 9)%
Treatment Delay/Cancellation
Treatment Discontinued due to CX
Treatment not Completed
Urinary Extravasation
Urine Extravasation/Obstruction
Urine Extravasation/Obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 93
26%
(18 - 36)%
Bladder Cancer Guideline Update Panel
Complications
TURBT + Epirubicin + Maintenance (8)
G/P
Bladder Contracture
Bladder Contracture
Bladder Contracture - Surgery required
Local Side Effects
Bladder Spasm/Pain
Epid/Prost/Ureth Infections
Hematuria
Impotence
Incontinence
LUTS
Urinary Obstruction
Urinary Retention
Skin Rash
Systemic
Bowel Perforation/Injury - Surgery required
Cardiovascular
Change in LFT
Fever/Chills/Flu Symptoms
Lung
Nausea/Vomiting
Neuro Changes
Renal Insufficiency
Systemic - any
Systemic - Infection
Transfusion
Treatment Delay/Cancellation
Treatment Discontinued due to CX
Treatment not Completed
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
3/614
1%
(0 - 2)%
2/122
29%
(10 - 55)%
5/740
30%
(21 - 41)%
8/931
45%
(30 - 61)%
1/82
1%
(0 - 6)%
1/82
0%
(0 - 3)%
2/138
2%
(0 - 7)%
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
26%
(20 - 32)%
TURBT + Gemcitabine (9)
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
2/128
12%
(6 - 21)%
1/116
5%
(2 - 10)%
Urinary Extravasation
Urine Extravasation/Obstruction
Urine Extravasation/Obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 94
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
Bladder Cancer Guideline Update Panel
Complications
TURBT + Interferon (10)
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
2/54
15%
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
TURBT + MMC Induction (12)
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
4/338
18%
(9 - 32)%
12%
(7 - 19)%
5/418
16%
(9 - 25)%
7/657
58%
(32 - 81)%
24%
(16 - 34)%
3/274
10%
(5 - 17)%
3/309
30%
(17 - 47)%
26%
(13 - 43)%
2/217
1/92
13%
1%
(8 - 20)%
(0 - 5)%
3/309
11%
(7 - 17)%
G/P
Bladder Contracture
Bladder Contracture
Bladder Contracture - Surgery required
Local Side Effects
Bladder Spasm/Pain
Epid/Prost/Ureth Infections
Hematuria
Impotence
Incontinence
LUTS
Urinary Obstruction
Urinary Retention
1/27
12%
(6 - 28)%
(3 - 27)%
Skin Rash
Systemic
Bowel Perforation/Injury - Surgery required
Cardiovascular
Change in LFT
Fever/Chills/Flu Symptoms
Lung
Nausea/Vomiting
Neuro Changes
Renal Insufficiency
Systemic - any
Systemic - Infection
Transfusion
2/54
13%
(5 - 26)%
Treatment Delay/Cancellation
Treatment Discontinued due to CX
Treatment not Completed
Urinary Extravasation
Urine Extravasation/Obstruction
Urine Extravasation/Obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 95
Bladder Cancer Guideline Update Panel
Complications
TURBT + MMC Induction + Maint (13)
G/P
Bladder Contracture
Bladder Contracture
Bladder Contracture - Surgery required
Local Side Effects
Bladder Spasm/Pain
Epid/Prost/Ureth Infections
Hematuria
Impotence
Incontinence
LUTS
Urinary Obstruction
Urinary Retention
Skin Rash
Systemic
Bowel Perforation/Injury - Surgery required
Cardiovascular
Change in LFT
Fever/Chills/Flu Symptoms
Lung
Nausea/Vomiting
Neuro Changes
Renal Insufficiency
Systemic - any
Systemic - Infection
Transfusion
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
2/234
5%
(2 - 11)%
1/26
4/544
8%
19%
(2 - 22)%
(10 - 31)%
9/843
31%
(19 - 44)%
1/57
7%
(2 - 16)%
2/220
16%
(11 - 23)%
2/415
10%
(6 - 16)%
TURBT + Valrubicin (15)
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
22%
(15 - 30)%
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
1/40
28%
(16 - 43)%
2/130
93%
(68 - 100)%
1/90
6%
(2 - 12)%
Treatment Delay/Cancellation
Treatment Discontinued due to CX
Treatment not Completed
Urinary Extravasation
Urine Extravasation/Obstruction
Urine Extravasation/Obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 96
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
56%
(37 - 75)%
Bladder Cancer Guideline Update Panel
Complications
Bladder Contracture
Bladder Contracture
Bladder Contracture - Surgery required
Local Side Effects
Bladder Spasm/Pain
Epid/Prost/Ureth Infections
Hematuria
Impotence
Incontinence
LUTS
Urinary Obstruction
Urinary Retention
Skin Rash
Systemic
Bowel Perforation/Injury - Surgery required
Cardiovascular
Change in LFT
Fever/Chills/Flu Symptoms
Lung
Nausea/Vomiting
Neuro Changes
Renal Insufficiency
Systemic - any
Systemic - Infection
Transfusion
TURBT + Phototherapy (17)
G/P
Minimal Overlap
(or none)
Med
CI (2.5 - 97.5)%
3/67
3%
(0 - 10)%
1/34
99%
(93 - 100%
1/31
23%
(11 - 39)%
1/31
4/101
1/31
1%
83%
1%
(0 - 8)%
(53 - 98)%
(0 - 8)%
4/101
2%
(0 - 7)%
1/24
42%
(24 - 61)%
1/24
50%
(31 - 69)%
2/36
38%
(2 - 90)%
1/34
6%
(1 - 18)%
Maximal Overlap
(if also minimal)
Med
CI (2.5 - 97.5)%
99%
(93 - 100%
83%
(53 - 98)%
Treatment Delay/Cancellation
Treatment Discontinued due to CX
Treatment not Completed
Urinary Extravasation
Urine Extravasation/Obstruction
Urine Extravasation/Obstruction - no Surgery required
Urine Extravasation/Obstruction - Surgery required
Copyright © 2007 American Urological Association Education and Research, Inc.®
October 2007
Appendix
Pg. 97