Download Non-Muscle Invasive Bladder Cancer

CLINICAL PRACTICE GUIDELINE GU-009
version 1
NONMUSCLE INVASIVE BLADDER CANCER
Effective Date: October 2013
The recommendations contained in this guideline are a consensus of the Alberta Genitourinary Tumour Team and
are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific
literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical
judgment in the context of individual clinical circumstances to direct care.
CLINICAL PRACTICE GUIDELINE GU-009
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BACKGROUND
Bladder cancer is the fourth most common cancer among men, accounting for 6.1% of all new male
cancers. Bladder cancer is less common among women (ranked twelfth) and accounts for 2.2% of all new
female cancers. 1,2 In 2013, an estimated 7,900 Canadians will have been diagnosed with bladder cancer;
however, the five-year survival rate for bladder cancer, overall, is about 80%. 3 Bladder cancer accounts
for 3.8% of all male cancer deaths and 1.7% of all female cancer deaths. 2
3
Though amenable to surgery, early bladder cancer can recur frequently. The risk of recurrence is
affected by factors such as size, number, T category, tumour grade, concomitant CIS, and prior
recurrence. 4 Following curative surgery, adjuvant therapy to prevent recurrences is an important aspect
of bladder cancer treatment. Several agents have been studied in the adjuvant setting with outcomes of
progression-free survival and disease-free survival as the primary endpoints; these agents include
epirubicin, doxorubicin, interferon (IFN)-α2b, mitomycin C (MMC), and bacillus calmette-guerin (BCG).
The purpose of this guideline is to establish best practice for the surgical management of patients with
nonmuscle invasive bladder cancer, as well as to describe patient selection criteria for adjuvant therapy,
appropriate agents, dosing, and duration of therapy.
TARGET POPULATION
The target population for this guideline is patients with nonmuscle invasive bladder cancer (i.e., stages
Tis, Ta, and T1).
GUIDELINE QUESTIONS
1. What is the appropriate primary therapy for patients with nonmuscle invasive bladder cancer?
2. Which patients are appropriate for adjuvant therapy?
3. Which agents are most efficacious in preventing bladder tumour recurrences?
4. What is the appropriate dosing and duration of adjuvant therapy?
5. How often are follow-up examinations required and for what duration?
DEVELOPMENT PANEL
This guideline was reviewed and endorsed by the Alberta Genitourinary Tumour Team. Members of the
Alberta Genitourinary Tumour Team include medical oncologists, radiation oncologists, urologists,
pathologists, nurses, and pharmacists. Evidence was selected and reviewed by a working group
comprised of members from the Alberta Genitourinary Tumour Team and a Knowledge Management
Specialist from the Guideline Utilization Resource Unit. A detailed description of the methodology followed
during the guideline development process can be found in the Guideline Utilization Resource Unit
handbook.
SEARCH STRATEGY
An original guideline on bladder cancer was developed in 2005 and then updated in 2009, 2010, and
2011. The document contained recommendations and evidence on both noninvasive disease and invasive
disease. In 2013 the guideline was divided into two distinct documents: a guideline on noninvasive
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disease (GU-009) and a guideline on muscle-invasive and locally advanced or unresectable/metastatic
disease (GU-002). The guideline on noninvasive disease includes an update of the original search
strategy and recommendations, but incorporates a new literature search and more in-depth
recommendations on bacillus calmette-guerin (BCG) therapy. The guideline on invasive disease includes
an update of the original search strategy. The original literature search included the Medline and EMBASE
databases. The search term bladder cancer was used and results were limited to clinical trials,
randomized controlled trials, and phase III studies. A total of nine citations identified from the original
search were relevant to the updated noninvasive bladder cancer guideline.
The search for literature on adjuvant BCG therapy included the PubMED database only, which was
searched for relevant literature published between 1993 and 2013 May 28. The search terms, urothelial
carcinoma or transitional cell carcinoma or bladder cancer AND bacillus calmette guerin were used and
results limited to meta-analyses, randomized controlled trials, and phase III clinical trials conducted in
humans and published in English. The search initially returned 105 citations; further exclusion criteria
included studies that did not examine the efficacy of BCG or interventions for BCG toxicity as primary
endpoints, studies on prognostic factors only, studies with less than 50 patients in total, older (pre-2000)
studies examining toxicity reduction strategies, older (pre-2000) studies comparing a new treatment with
BCG as the established standard, as well as previous versions of a Cochrane review, meta-analyses older
than 2006 May, phase II trials, retrospective analyses of single RCT data, reviews, and in vitro studies.
After applying the exclusion criteria, a total of 60 citations remained and were included in the literature
review.
In addition, the National Guidelines Clearinghouse 5 database was searched for relevant guidelines
published between 2008 and 2013 June 3. The single search term, bacillus calmette guerin was used.
The search returned three relevant guidelines from the European Association of Urology, 6 the Scottish
Intercollegiate Guidelines Network, 7 and the American Urological Association. 8 Two additional guidelines
were identified on the National Comprehensive Cancer Network website 9 and the Canadian Urology
Association website. 10 The American Joint Committee on Cancer (AJCC) staging definitions for bladder
cancer was also included as a reference document. 11
RECOMMENDATIONS
American Joint Committee on Cancer (AJCC) staging definitions for bladder cancer are included in
Appendix A (page 14). 11
Management of Ta
Staging
Complete resection, including muscularis propria, is recommended.
Risk Stratification
Low risk: solitary, primary, low grade pTa
Intermediate risk: multiple or recurrent, large, low grade pTa
High risk: any >pTa, CIS, >low grade
Adjuvant Therapy
Post-TURBT chemotherapy is recommended for all risk categories of pTa patients, especially for low risk
patients, as these patients benefit most in terms of recurrence rates at 2 years.
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• The standard of care is adjuvant-immediate chemotherapy instillation post-TUR, unless the bladder is
perforated with TUR or if there is a significant risk of vessico-ureteral reflux. Chemotherapy should
consist of: epirubicin (100 mg/100 mL) or mitomycin C (MMC; 40 mg/40 mL weekly x 8 weeks then
monthly for a year).
• If there is a recurrence, repeat TUR and consider proceeding to intravesical bacillus calmette-guerin
(BCG) therapy.
Induction and Maintenance Therapy
Induction and maintenance therapy is recommended for intermediate and high risk patients, including
those with multifocal tumours or frequent recurrences.
• BCG: induction therapy for 4-6 weeks then 3-weekly injections at 3-month intervals; continue for 12-24
months, if patient is disease-free at three months. Therapy may be continued at 30 and 36 months, at
which time a clinical decision should be made as to whether or not to proceed with maintenance.
• MMC: 40 mg/ mL monthly; continue for 12-24 months.
Second-line treatment for Ta BCG failure
• Surgery consisting of aggressive TURBT is recommended.
• Intravesical chemotherapy options include:
o Interferon alpha-2b (IFN-α2b): 50 million units instillation weekly for 6-8 weeks
− if residual disease at 3 months (cystoscopy): repeat with a second course at either 50 or 100
million units.
− if BCG and IFN-α2b failure: 100 million units in 50 mL bladder instillation weekly for 6-8 weeks.
o Gemcitabine: 2000 mg instillation weekly for 6 weeks (induction) followed by 2000 mg instillation
monthly for 10 doses (maintenance)
o Mytomycin C: administer intravesically at a dose of 40 mg weekly for 4 weeks
o Consider cystectomy if subsequent failure occurs.
Management of Tis BCG Failure
First-line
• Mandatory repeat TURBT (including muscularis propria) in 2-3 months or discussion of immediate
cystectomy is recommended
In the event of an early BCG failure
• Surgery is recommended, if the patient is fit.
• Radiotherapy can be considered.
• Staging: upper tract imaging (CT abdomen/pelvis with contrast) is recommended.
In the event of a late BCG failure
• Surgery is recommended, if the patient is fit.
• Radiotherapy can be considered.
• Staging: upper tract imaging (CT abdomen/pelvis with contrast) is recommended.
Management of T1 high grade BCG Failure
First-line
• Mandatory induction BCG
• Mandatory repeat TURBT (including muscularis propria) in 2-3 months or discussion of immediate
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cystectomy
In the event of an early BCG failure
• Surgery, if fit
• Radiotherapy
• Staging: upper tract imaging (CT abdomen/pelvis with contrast)
In the event of a late BCG failure
• Consider reinduction with BCG therapy
Maintenance Therapy for Ta, T1 high-grade, and Tis BCG Failure
• Maintenance therapy with the following agents is recommended if the patient is disease free at first
cystoscopy:
o BCG
o IFN-α2b
o Mitomycin C
o Gemcitabine: 2000 mg instillation monthly for 10 doses
BCG Administration
• Start date must be at least 3 weeks after last TURBT
• No liquids x 4 hours prior
• Catheterize patient to ensure bladder is empty
• 1 vial of BCG (PACIS, Immucyst, or OncoTice) diluted in 50cc normal saline instilled via catheter
weekly x 6 weeks
• Patient should hold BCG x 2 hours, rolling every 15 minutes at home before voiding (sitting) into toilet
• Clean toilet bowl with 2 cups of bleach left in bowl for 15 minutes prior to flushing
• Cystoscopy to be performed within 6 weeks of induction
Follow-up
• Cystoscopic evaluation q 3 months for the first 24 months, then annually for 10 years
• Radiological evaluation of lymph nodes and contra lateral upper tract as clinically indicated
• Duration: as clinically indicated; cystoscopic evaluation and CXR as clinically indicated and then at
increasing intervals
DISCUSSION
The management of Ta and T1 bladder cancer includes resection plus adjuvant-immediate
chemotherapy, consisting of epirubicin or mitomycin C. 12,13 Recurrences are common in bladder cancer 14
and management consists of bacillus calmette-guerin therapy (BCG). In intermediate to high risk patients,
the addition of prulifloxacin has not been shown to improve recurrence rates at six months (21.6 vs.
23.0%); 15 however, in another study, the addition of gemcitabine to BCG therapy increased the time to
recurrence by 4.3 months (24.1 vs. 19.8 months; P<.05). 16 Recently, an EORTC trial (Sylvester, et al.
2010) showed that in intermediate and high risk patients (n=820), BCG significantly reduced the rate of
recurrence (36.7 versus 52.7% epirubicin; P<.05) and increased the rate of overall survival (70.1 versus
62.0%; P<.05), with a median follow-up of 110 months. 17 Another smaller study (n=89 Ta/T1 patients)
showed that, after a median follow-up of 102 months, BCG resulted in a significantly lower recurrence rate
versus mitomycin-C (59.1 versus 80%; P<.05); disease-free survival was also higher in patients treated
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with BCG (90.9 versus 80.0%). 18 A complete summary of the evidence on BCG therapy is provided in
Appendix B (page 15).
For Ta disease, in the event of a failure on BCG therapy, options include salvage surgery, BCG therapy
plus alpha-2b interferon, or mitomycin C. 12 Gemcitabine has also demonstrated efficacy: overall survival
rate was approximately 20% higher (approximately 70 versus 50%; P<.05) versus mitomycin-C at a
median follow-up of 36 months; 19 recurrence rate was 35% lower (52.5 versus 87.5%; P<.05) versus
BCG; 20 and recurrence free survival rate was approximately 16% higher (19 versus 3%; P<.05) versus
BCG (median follow-up of 12 months). 20 However, in a smaller study of high risk patients, BCG was more
efficacious than gemcitabine, in terms of recurrence rate (28.1 versus 53.1%; P<.05). 21 Larger trials with
gemcitabine are required and currently BCG plus alpha-2b interferon or mitomycin-C remains the
standard of care for first-line treatment of recurrent disease.
For Tis disease, in the event of a failure on BCG therapy, and for T1 high-grade disease, BCG therapy
followed by repeat TURBT or discussion of immediate cystectomy is mandatory. 12 Adjuvant therapy
consists of immediate instillation with epirubicin. Maintenance therapy consists of BCG with alpha-2b
interferon, if the patient is disease free at first cystoscopy. In patients with stage Ta or T1 bladder cancer
(n=115) given one of the following three treatments, post-TURBT: (1) maintenance therapy with BCG (81
mg, intravesically) once weekly for 6 weeks followed by three once-weekly instillations at 3, 6, 12 and 18
months; (2) BCG (81 mg, intravesically) once weekly for 6 weeks; or (3) epirubicin (40 mg, intravesically)
instilled nine times, the recurrence-free survival rates after two years of follow-up were 84.6%, 65.4%, and
27.7%, respectively. 13 Maintenance therapy with BCG is an important component of care in this setting.
GLOSSARY OF ABBREVIATIONS
Acronym
AJCC
AUC
BCG
CBC
CIS
CMV
Cr
CT
CXR
CUA
Gy
IFN
MMC
MRI
MVAC
PLND
TURBT
Description
American Joint Committee on Cancer
area under the curve
Bacillus Calmette-Guerin
complete blood count
carcinoma in situ
cisplatin, methotrexate, vinblastine
creatinine
computer tomography
chest x-ray
Canadian Urology Association
unit of radiation dose
interferon
mitomycin C
magnetic resonance imaging
methotrexate, vinblastine, adriamycin, and cisplatinum
pelvic lymph node dissection
transurethral resection of bladder tumour
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DISSEMINATION
•
•
•
Present the guideline at the local and provincial tumour team meetings and weekly rounds.
Post the guideline on the Alberta Health Services website.
Send an electronic notification of the new guideline to all members of CancerControl Alberta.
MAINTENANCE
A formal review of the guideline will be conducted at the Alberta Genitourinary Tumour Team Annual
Meeting in 2015. If critical new evidence is brought forward before that time, however, the guideline
working group members will revise and update the document accordingly.
CONFLICT OF INTEREST
Participation of members of the Alberta Genitourinary Tumour Team in the development of this guideline
has been voluntary and the authors have not been remunerated for their contributions. There was no
direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta
recognizes that although industry support of research, education and other areas is necessary in order to
advance patient care, such support may lead to potential conflicts of interest. Some members of the
Alberta Genitourinary Tumour Team are involved in research funded by industry or have other such
potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an
unbiased manner.
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years of a randomized prospective study comparing mitomycin-C and bacillus Calmette-Guérin in patients with highrisk bladder cancer. BJU Int. 2007 Apr;99(4):817-20. Epub 2007 Jan 22.
45
Colombel M, Saint F, Chopin D, Malavaud B, Nicolas L, Rischmann P. The effect of ofloxacin on bacillus calmetteguerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind,
placebo controlled, multicenter study. J Urol. 2006 Sep;176(3):935-9.
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46
Di Stasi SM, Giannantoni A, Giurioli A, Valenti M, Zampa G, Storti L, Attisani F, De Carolis A, Capelli G, Vespasiani
G, Stephen RL. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder
cancer: a randomised controlled trial. Lancet Oncol. 2006 Jan;7(1):43-51.
47
Hinotsu S, Akaza H, Isaka S, Kanetake H, Kubota Y, Kuroda M, Shinohara N, Shinka T, Tachibana M, Naito S,
Hirao Y; BCG Tokyo 172 Strain Study Group. Sustained prophylactic effect of intravesical bacille Calmette-Guérin for
superficial bladder cancer: a smoothed hazard analysis in a randomized prospective study. Urology. 2006
Mar;67(3):545-9.
48
Martínez-Piñeiro JA, Martínez-Piñeiro L, Solsona E, Rodríguez RH, Gómez JM, Martín MG, Molina JR, Collado AG,
Flores N, Isorna S, Pertusa C, Rabadán M, Astobieta A, Camacho JE, Arribas S, Madero R; Club Urológico Español
de Tratamiento Oncológico (CUETO). Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy
against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a
prospective randomized trial. J Urol. 2005 Oct;174(4 Pt 1):1242-7.
49
Cheng CW, Chan SF, Chan LW, Chan CK, Ng CF, Cheung HY, Chan SY, Wong WS, Lai FM, To KF, Li ML.
Twelve-year follow up of a randomized prospective trial comparing bacillus Calmette-Guerin and epirubicin as
adjuvant therapy in superficial bladder cancer. Int J Urol. 2005 May;12(5):449-55.
50
de Reijke TM, Kurth KH, Sylvester RJ, Hall RR, Brausi M, van de Beek K, Landsoght KE, Carpentier P; European
Organization for the Research and Treatment of Cancer-Genito-Urinary Group. 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(2):405-9.
51
Di Stasi SM, Giannantoni A, Stephen RL, Capelli G, Navarra P, Massoud R, Vespasiani G. Intravesical
electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a
prospective randomized study. J Urol. 2003 Sep;170(3):777-82.
52
Kaasinen E, Wijkström H, Malmström PU, Hellsten S, Duchek M, Mestad O, Rintala E; Nordic Urothelial Cancer
Group. 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(6):637-45.
53
Kolodziej A, Dembowski J, Zdrojowy R, Wozniak P, Lorenz J. Treatment of high-risk superficial bladder cancer with
maintenance bacilli Calmette-Guérin therapy: preliminary results. BJU Int. 2002 Apr;89(6):620-2.
54
Martínez-Piñeiro JA, Flores N, Isorna S, Solsona E, Sebastián JL, Pertusa C, Rioja LA, Martínez-Piñeiro L, Vela R,
Camacho JE, Nogueira JL, Pereira I, Resel L, Muntañola P, Galvis F, Chesa N, De Torres JA, Carballido J, Bernuy C,
Arribas S, Madero R; for CUETO (Club Urológico Español de Tratamiento Oncológico). Long-term follow-up of a
randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guérin with a reduced
dose of 27 mg in superficial bladder cancer. BJU Int. 2002 May;89(7):671-80.
55
van der Meijden AP, Brausi M, Zambon V, Kirkels W, de Balincourt C, Sylvester R; Members of the EORTC
Genito-Urinary Group. Intravesical instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin
plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for
Research and Treatment of Cancer genito-urinary group randomized phase III trial. J Urol. 2001 Aug;166(2):476-81.
56
Palou J, Laguna P, Millán-Rodríguez F, Hall RR, Salvador-Bayarri J, Vicente-Rodríguez J. Control group and
maintenance treatment with bacillus Calmette-Guerin for carcinoma in situ and/or high grade bladder tumors. J Urol.
2001 May;165(5):1488-91.
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57
Kaasinen E, Rintala E, Pere AK, Kallio J, Puolakka VM, 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(1):47-52.
58
Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman
HB, Beck TM, Leimert JT, Crawford ED. 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(4):1124-9.
59
Al Khalifa M, Elfving P, Månsson W, Colleen S, Hellsten S, Duchek M, Nyberg G, Callaghan P, Rademark C,
Eriksson R, Olsson R, Hagberg G, Nelson CE. The effect of isoniazid on BCG-induced toxicity in patients with
superficial bladder cancer. Eur Urol. 2000;37 Suppl 1:26-30.
60
Ali-El-Dein B, Nabeeh A, Ismail EH, Ghoneim MA. Sequential bacillus Calmette-Guerin and epirubicin versus
bacillus Calmette-Guerin alone for superficial bladder tumors: a randomized prospective study. J Urol. 1999
Aug;162(2):339-42.
61
Malmström PU, Wijkström H, Lundholm C, Wester K, Busch C, Norlén BJ. 5-year followup of a randomized
prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder
carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol. 1999 Apr;161(4):1124-7.
62
Witjes JA, Caris CT, Mungan NA, Debruyne FM, Witjes WP. Results of a randomized phase III trial of sequential
intravesical therapy with mitomycin C and bacillus Calmette-Guerin versus mitomycin C alone in patients with
superficial bladder cancer. J Urol. 1998 Nov;160(5):1668-71; discussion 1671-2.
63
Witjes JA, v d Meijden AP, Collette L, Sylvester R, Debruyne FM, van Aubel A, Witjes WP. Long-term follow-up of
an EORTC randomized prospective trial comparing intravesical bacille Calmette-Guérin-RIVM and mitomycin C in
superficial bladder cancer. EORTC GU Group and the Dutch South East Cooperative Urological Group. European
Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group. Urology. 1998
Sep;52(3):403-10.
Yalçinkaya F, Kamiş L, Ozteke O, Günlüsoy B, Yigitbaşi O, Unal S. Prospective randomized comparison of
intravesical BCG therapy with standard dose versus low doses in superficial bladder cancer. Int Urol Nephrol.
1998;30(1):41-4.
64
65
Jimenez-Cruz JF, Vera-Donoso CD, Leiva O, Pamplona M, Rioja-Sanz LA, Martinez-Lasierra M, Flores N, Unda M.
Intravesical immunoprophylaxis in recurrent superficial bladder cancer (Stage T1): multicenter trial comparing bacille
Calmette-Guérin and interferon-alpha. Urology. 1997 Oct;50(4):529-35.
66
Gruenwald IE, Stein A, Rashcovitsky R, Shifroni G, Lurie A. A 12 versus 6-week course of bacillus Calmette-Guerin
prophylaxis for the treatment of high risk superficial bladder cancer. J Urol. 1997 Feb;157(2):487-91.
67
Krege S, Giani G, Meyer R, Otto T, Rübben H. A randomized multicenter trial of adjuvant therapy in superficial
bladder cancer: transurethral resection only versus transurethral resection plus mitomycin C versus transurethral
resection plus bacillus Calmette-Guerin. Participating Clinics. J Urol. 1996 Sep;156(3):962-6.
68
Lundholm C, Norlén BJ, Ekman P, Jahnson S, Lagerkvist M, Lindeborg T, Olsson JL, Tveter K, Wijkstrom H,
Westberg R, Malmström PU. A randomized prospective study comparing long-term intravesical instillations of
mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol. 1996 Aug;156(2 Pt
1):372-6.
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69
Melekos MD, Zarakovitis IE, Fokaefs ED, Dandinis K, Chionis H, Bouropoulos C, Dauaher H. Intravesical bacillus
Calmette-Guérin versus epirubicin in the prophylaxis of recurrent and/or multiple superficial bladder tumours.
Oncology. 1996 Jul-Aug;53(4):281-8.
70
Rintala E, Jauhiainen K, Kaasinen E, Nurmi M, Alfthan O. Alternating mitomycin C and bacillus Calmette-Guerin
instillation prophylaxis for recurrent papillary (stages Ta to T1) superficial bladder cancer. Finnbladder Group. J Urol.
1996 Jul;156(1):56-9; discussion 59-60.
71
Witjes WP, Witjes JA, Oosterhof GO, Debruyne MJ. Update on the Dutch Cooperative Trial: mitomycin versus
bacillus Calmette-Guérin-Tice versus bacillus Calmette-Guérin RIVM in the treatment of patients with pTA-pT1
papillary carcinoma and carcinoma in situ of the urinary bladder. Dutch South East Cooperative Urological Group.
Semin Urol Oncol. 1996 Feb;14(1 Suppl 1):10-6.
72
Melekos MD, Zarakovitis I, Dandinis K, Fokaefs E, Chionis H, Dauaher H, Barbalias G. BCG versus epirubicin in
the prophylaxis of multiple superficial bladder tumours: results of a prospective randomized study using modified
treatment schemes. Int Urol Nephrol. 1996;28(4):499-509.
73
Rintala E, Jauhiainen K, Rajala P, Ruutu M, Kaasinen E, Alfthan O. Alternating mitomycin C and bacillus CalmetteGuerin instillation therapy for carcinoma in situ of the bladder. The Finnbladder Group. J Urol. 1995 Dec;154(6):20503.
74
Herr HW, Schwalb DM, Zhang ZF, Sogani PC, Fair WR, Whitmore WF Jr, Oettgen HF. Intravesical bacillus
Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of
a prospective randomized trial. J Clin Oncol. 1995 Jun;13(6):1404-8.
75
Vegt PD, Witjes JA, Witjes WP, Doesburg WH, Debruyne FM, van der Meijden AP. A randomized study of
intravesical mitomycin C, bacillus Calmette-Guerin Tice and bacillus Calmette-Guerin RIVM treatment in pTa-pT1
papillary carcinoma and carcinoma in situ of the bladder. J Urol. 1995 Mar;153(3 Pt 2):929-33.
76
Akaza H, Hinotsu S, Aso Y, Kakizoe T, Koiso K. Bacillus Calmette-Guérin treatment of existing papillary bladder
cancer and carcinoma in situ of the bladder. Four-year results. The Bladder Cancer BCG Study Group. Cancer. 1995
Jan 15;75(2):552-9.
77
Pagano F, Bassi P, Piazza N, Abatangelo G, Drago Ferrante GL, Milani C. Improving the efficacy of BCG
immunotherapy by dose reduction. Eur Urol. 1995;27 Suppl 1:19-22.
78
Martínez-Piñeiro JA, Solsona E, Flores N, Isorna S. Improving the safety of BCG immunotherapy by dose
reduction. Cooperative Group CUETO. Eur Urol. 1995;27 Suppl 1:13-8.
79
Melekos MD, Chionis HS, Paranychianakis GS, Dauaher HH. Intravesical 4'-epi-doxorubicin (epirubicin) versus
bacillus Calmette-Guérin. A controlled prospective study on the prophylaxis of superficial bladder cancer. Cancer.
1993 Sep 1;72(5):1749-55.
80
Melekos MD, Chionis H, Pantazakos A, Fokaefs E, Paranychianakis G, Dauaher H. Intravesical bacillus CalmetteGuerin immunoprophylaxis of superficial bladder cancer: results of a controlled prospective trial with modified
treatment schedule. J Urol. 1993 Apr;149(4):744-8.
81
Witjes JA, vd Meijden AP, Witjes WP, Doesburg W, Schaafsma HE, Debruyne FM. A randomised prospective
study comparing intravesical instillations of mitomycin-C, BCG-Tice, and BCG-RIVM in pTa-pT1 tumours and primary
carcinoma in situ of the urinary bladder. Dutch South-East Cooperative Urological Group. Eur J Cancer.
1993;29A(12):1672-6.
Page 13 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
APPENDIX A
th
AJCC 2010 (7 Edition) Anatomic Stage Groupings for Bladder Cancer 11
Primary Tumour (T)
Tx: primary tumour cannot be assessed
T0: No evidence of primary tumour
Ta: Non-invasive papillary carcinoma
Tis: Carcinoma in situ: “flat tumour”
T1: Tumour invades subepithelial connective tissue
T2: Tumour invades muscularis propria
• pT2a: Tumour invades superficial muscularis propria (inner half)
• pT2b : Tumour invades deep muscularis propria (outer half)
T3 : Tumour invades perivesical tissue
• pT3a : Microscopically
• pT3b : Macroscopically (extra vesical mass)
T4: Tumour invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall,
abdominal wall
• T4a: Tumour invades prostatic stroma, uterus, vagina
• T4b : Tumour invades pelvic wall, abdominal wall
Regional Lymph Nodes (N)
Nx: Lymph nodes cannot be assessed
N0: No lymph node metastasis
N1: Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or
presacral lymph node)
N2: Multiple regional lymph node metastases in the true pelvis (hypogastric, obturator, external iliac, or
presacral lymph node)
N3: Lymph node metastases to the common iliac lymph nodes
Distant Metastasis (M)
M0: No distant metastasis
M1: Distant metastasis
Page 14 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
APPENDIX B:
EVIDENCE TABLE ON BCG THERAPY
Author Year
(Trial)
Shang PF.
22
2011
Intervention
Cochrane meta-analysis:
1. Bacillus Calmette-Guérin (BCG)
2. epirubicin (EPI)
Follow-up
(med mos)
n/a
Number of
Patients (N)
1111
(5 RCTs)
Stage/Histologic
Subtype
Ta and T1 bladder
cancer
Outcomes
tumour recurrence: 35.5% (195/549) for BCG vs.
51.4% (289/562) for EPI (p<.05)
disease progression: BCG 44/549 vs. EPI 58/562
(p=0.19)
distant metastases: BCG 23/487 vs. EPI 31/495
(p=0.29)
disease-specific survival: BCG 22/383 vs. EPI
26/386 (p=0.93)
mortality: BCG 125/383 vs. EPI 147/386 (p=0.12)
cystitis: 54.1% (232/429) BCG vs. 31.7%
(140/441) EPI
hematuria: 30.8% (132/429) BCG vs. 16.1%
(71/440) EPI
systemic toxicity: 34.8% (134/385) BCG vs. 1.3%
(5/393) EPI
treatment delays or stops: 40/431 BCG vs. 33/441
EPI (p=0.82)
Malmström PU.
23
2009
Meta-analysis (individual patient data):
1. BCG
2. Mitomycin-C
53
2820
(9 RCTs)
intermediate
or high risk nonmuscle-invasive
bladder cancer
recurrence rate: 43% (no difference in time to first
recurrence between BCG and MMC; p=0.09)
risk of recurrence:
32% lower with BCG vs. MMC (p<0.0001)
28% higher with BCG induction only vs. MMC
(p=0.006)
BCG with maintenance was more effective than
MMC in both patients previously treated and
those not previously treated with chemotherapy.
progression (n=1880): 12%
deaths (n=1880): 24% (30% due to bladder
cancer); no statistically significant differences.
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Gülpinar Ö.
24
2012
Intervention
RCT:
1. mitomycin C pretreatment (40 mg within 6 hrs
of surgery) + delayed (15+ days) BCG
8
(1X/week 6 weeks, 5 x 10 colony-forming
units in 50 mL saline)
2. delayed BCG alone
Follow-up
(med mos)
41
Number of
Patients (N)
51
Outcomes
high-grade pT1
bladder cancer with
pT0 histology after
second TUR
Recruitment in progress.
recurrent
or multiple nonmuscle-invasive
bladder cancer
(stage Ta or T1)
after TURBT
RFS (actuarial): 84.6% for maintenance vs.
65.4% for non-maintenance vs. 27.7% for
epirubicin
RFS: 36% (9/25) with mitomycin C pretreatment
vs. 19.3 % (5/26) with BCG alone (p=.052)
median time to the first recurrence: 8 mos with
MMC pretreatment vs. 7 mos with BCG alone
(p=.12)
Kunieda F.
25
2012
(JCOG1019)
RCT (phase III, non-inferiority):
1. watchful waiting
2. intravesical BCG therapy
n/a
Hinotsu S.
26
2011
RCT:
1. maintenance BCG (81 mg, 1X/wk x 6 weeks
+ 3 1X/wk instillations at 3, 6, 12, 18 months)
2. non-maintenance BCG (81 mg, 1X/wk X 6
weeks)
3. epirubicin (40 mg intravesically X 9)
24
Chiong E.
27
2011
RCT:
1. postresection intravesical BCG (81 mg)
2. postresection intravesical BCG (27 mg)
3. postresection intravesical IFN-α
60
99
non-muscleinvasive bladder
cancer; subgroup
analysis by genotype NRAMP1
time to recurrence (multivariate analysis):
BCG therapy decreased recurrence time in
patients with the NRAMP1 D543N G:G genotype
(p=0.014) and allele 3 (GT)n polymorphism
(p=0.03)
Nepple KG.
28
2010
RCT:
1. BCG (81 mg, 1X/wk x 6 weeks) +
maintenance at 4, 7, 13, 19, 25, 37 months
2. BCG (as above) + interferon α-2b
24
670
BCG naïve with
carcinoma in situ,
Ta or T1 urothelial
cancer
RFS:
63% for BCG + RDA vitamins group vs.
59% for BCG + megadose vitamins vs.
55% for BCG/IFN α-2b + RDA vitamins vs.
61% for BCG/IFN α-2b + megadose (p>0.05)
(2
nd
randomization: megadose or RDA vitamins)
835
planned
Stage/Histologic
Subtype
intermediate and
high risk patients
with non-muscle
invasive bladder
cancer
115
Primary endpoint: RFS (excluding Tis or Ta
intravesical recurrence).
Secondary endpoints: OS, mets-free survival with
bladder preserved, annual intravesical RFS,
annual T2 or deeper RFS, adverse events.
RFS following TURBT: significantly prolonged in
the maintenance group vs. non-maintenance
group (generalized Wilcoxon test, P= 0.0190)
fever: higher with IFN α-2b (11% vs. 5%; p<0.05)
constitutional symptoms: higher with IFN α-2b
(18% vs. 11%; p<0.05)
Page 16 of 29
CLINICAL PRACTICE GUIDELINE GU-009
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Author Year
(Trial)
Koga H.
29
2010
Burger M.
30
2010
Intervention
RCT:
1. BCG induction (80 mg 1X/week for 8 weeks)
+ maintenance (4 doses) if complete response
2. BCG induction (80 mg) + observation
RCT:
1. autologous intravesical macrophage cell
therapy (BEXIDEM) after TURB *
2. BCG after TURB *
Follow-up
(med mos)
28
12
Number of
Patients (N)
53
137
Stage/Histologic
Subtype
high-risk
non-muscle
invasive bladder
cancer
Outcomes
TaG1-3, T1G1-2
plurifocal or
unifocal tumours
and ≥2 occurrences
within 24 months
AEs:
non-serious: BCG 85% vs. BEXIDEM 45%
serious: BCG 26% vs. BEXIDEM 14% (p<0.001)
high-risk superficial
bladder cancer
(pT1 and/or G3
and/or CIS)
tolerability: better for gemcitabine; 12.5% of BCG
group needed delayed treatment or withdrawal
* 6 weekly instillations and 2 cycles of 3 weekly
instillations at months 3 and 6
Porena M.
31
2010
RCT:
1. adjuvant intravesical gemcitabine
2. BCG
44
(mean)
64
RFS (2-year): 95.8% for maintenance vs. 74.1%
for observation (p=0.078)
Univariate analysis: maintenance therapy was a
significant factor influencing recurrence.
recurrence: 12% for BCG vs. 38% for BEXIDEM
(p<0.001)
recurrence rate: 28.1% for BCG vs. 53.1% for
gemcitabine (p=0.037)
time to recurrence: 25.6 months for BCG vs. 39.4
months for gem (p=0.042); no patients developed
disease progression.
Sylvester RJ.
32
2010
(EORTC)
RCT:
1. epirubicin (1X/week x 6)
2. BCG (1X/week x 6)
3. BCG plus isoniazid (INH) followed by three
weekly maintenance instillations at
months 3, 6, 12, 18, 24, 30, 36
109
837
intermediate- or
high-risk stage Ta
T1 urothelial
bladder cancer
distant metastases: ~5% BCG vs. ~9% epiribicin
significantly longer in the BCG arms (p=0.046)
overall survival: ~69% BCG vs. ~62% epirubicin
significantly longer in the BCG arms (p=0.023)
disease-specific survival: significantly longer in
the BCG arms (p=0.026); bladder cancer death
rate ~4% BCG vs. ~8% epirubicin
progression: ~9% both; no differences (p=0.55)
subgroup analysis (high vs. intermediate risk):
treatment benefit was at least as large, if not
larger, in the intermediate-risk patients compared
with the high-risk patients
Page 17 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Cho DY.
33
2009
Duchek M.
34
2010
(Nordic Trial)
Intervention
Follow-up
(med mos)
Prospective trial (non-randomized):
1. gemcitabine (1000 mg after TURBT and 2000
mg 1 week later) + BCG (1X/wk X 6 wks)
2. BCG alone
RCT:
1. adjuvant BCG *
2. adjuvant epirubicin and IFN-alpha2b *
24
Number of
Patients (N)
87
250
Stage/Histologic
Subtype
superficial bladder
cancer
Outcomes
high-grade T1
tumours G2-G3
DFS: 62% for epirubicin + IFN- alpha2b vs. 73%
for BCG (p=0.065)
RFS: 24.1 months for GEM + BCG vs. 19.8
months for BCG alone
recurrence (2-year): favored BCG (p=0.012)
* induction for 6 wk then maintenance for 2 yrs
progression: no difference
subgroup analysis (concomitant CIS vs. no CIS):
BCG superiority in those with concomitant CIS
multivariate analysis:
recurrence/progression status significantly related
to type of drug, tumour size, multiplicity, status at
second-look resection, and grade.
Böhle A.
35
2009
(S274)
RCT (double-blind):
1. single GEM instillation (2000 mg) *
2. placebo *
24
248
* immediately after TUR
primary or recurrent
non-muscleinvasive bladder
cancer (pTa/
pT1,G1-3)
RCT:
1. TUR + prulifloxacin (600 mg x 3) for toxicity
+ induction BCG therapy
2. BCG + no treatment
study terminated early based on predefined
decision criteria
RFS (1-year): 77.7% for GEM (95% CI 68.8-84.3)
vs. 75.3% for placebo (66.3-82.3); no significant
group difference (HR: 0.946; 0.64-1.39; p=0.777)
NOTE: a second TUR (no instillation) and
adjuvant BCG were allowed.
Damiano R.
36
2009
recurrences: 94; deaths: 11
n/a
72
intermediate- or
high-risk
nonmuscle-invasive
bladder cancer
AEs:
≥1 AE: less in prulifloxacin-treated vs. control (sig)
moderate to severe AEs: less in the prulifloxacintreated group (sig)
treatment stops/delays: 34% control vs. 19%
prulifloxacin (p=0.04)
Recurrence rates: not affected by prulifloxacin.
Page 18 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Mangiarotti B.
37
2008
Intervention
RCT:
1. intravesical BCG
2. mitomycin C
Follow-up
(med mos)
66
(mean)
Number of
Patients (N)
96
Stage/Histologic
Subtype
low grade recurrent
non-muscle
invasive bladder
cancer
(Ta or T1)
Outcomes
recurrence rate: 50% (23/46) for mitomycin C vs.
50% (23/46) for BCG
time to recurrence: 17.5+/-15.4 mos for MMC vs.
21.9+/-24.8 mos for BCG (p=0.47)
progression to muscle-invasive tumour: none
toxicity:
grade 1/2: 11 pts in MMC group vs. 19 BCG
group
grade 3: 11 pts in MCC group vs. 3 BCG group
treatment discontinuation:
11 pts MMC group vs. 2 pts BCG group (p=0.008)
Cai T.
38
2008
RCT (double-blind):
1. perioperative epirubicin (80 mg) + delayed
8
BCG (5 x 10 colony-forming units)
2. delayed BCG alone
15
161
high risk
nonmuscle invasive
bladder cancer
DFS: 57.5% (46/80) epirubicin vs. 50.6% (41/81)
BCG alone
recurrence rate: no differences (p=0.82)
time to first recurrence: no differences (p=0.095)
multivariate: early single dose epirubicin was not
an independent factor (HR 0.50 95% CI 0.3-1.2)
Pan CW.
39
2008
RCT (double-blind):
1. 100-120 mg BCG + 100 mg paraaminomethylbenzoic acid
2. 50-60 mg BCG + 100 mg paraaminomethylbenzoic acid
3. 100-120 mg BCG + 2.0 g epsilon
aminocaproic acid
4. 50-60 mg BCG + 2.0 g epsilon aminocaproic
acid
5. 100-120 mg BCG alone
24
257
superficial bladder
cancer
Recurrence rates: 10.6% group 1, 11.1% group 2,
10.0% group 3, 9.3% group 4, 31.8% group 5.
RFS (groups 1-4 vs. group 5): p=0.023, p=0.037,
P=0.031, p=0.020); no differences between
groups 1, 2, 3, 4 (each p>0.05)
serious adverse events: 9.6% group 1, 3.9%
group 2, 15.7% group 3, 5.9% group 4, 13.5%
group 5 (p=0.222)
Page 19 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Sabichi AL.
40
2008
Intervention
RCT (phase III):
1. fenretinide (200 mg/day orally for 12 months)
2. fenretinide + BCG
Follow-up
(med mos)
15
Number of
Patients (N)
137
Stage/Histologic
Subtype
non-muscleinvasive bladder
TCC (Ta, Tis, or
T1) after TUR
Outcomes
recurrence risk: "low" in 72% (no prior BCG) and
intermediate or high in 32% (prior BCG)
recurrence rates (1-year): 32.3% (placebo) vs.
31.5% (fenretinide); p=0.88
Fenretinide was well tolerated and had no
unexpected toxic effects; only elevated serum
triglyceride levels were significantly more frequent
Agrawal MS.
41
2007
RCT:
1. BCG 40 mg
2. BCG 80 mg
3. BCG 120 mg
36
(mean)
128
superficial bladder
cancer
recurrence rate: 20% vs. 25% vs. 20% (p>0.05)
progression: none seen
local toxicity: 30% for 40 mg vs. 41.7% for 80 mg
vs. 70% for 120 mg (p<0.01)
systemic toxicity: more common in group C vs.
groups B and A (p<0.01)
Ojea A.
42
2007
(CUETO)
430
RCT:
1. BCG low dose (27 mg) *
2. BCG (13.5 mg) *
3. mitomycin C (MMC; 30 mg) *
intermediate-risk
superficial bladder
cancer
DFS: BCG 27 mg longer than MMC (p=0.006);
no difference between BCG 27 mg and 13.5mg
(p=0.165) or BCG 13.5mg and MMC (p=0.183)
multivariate: DFS better with BCG 27 mg
* once a week for 6 wk followed by another six
instillations given once every 2 wk during 12 wk.
time to progression: no sig differences b/t groups
cancer-specific survival: no sig diff b/t groups
local and systemic toxicity: higher in BCG groups
Friedrich MG.
43
2007
RCT (phase IV):
1. short-term chemoprophylaxis Mitomycin C
(20 mg weekly for 6 wk)
2. long-term chemoprophylaxis Mitomycin C (20
mg weekly for 6 wk then monthly for 3 yr)
3. short-term immunoprophylaxis BCG (RIVM 2
8
x 10 CFU/week x 6 wks
36
495
intermediate- to
high-risk (recurrent
and/or multifocal)
pTaG1, TaG2-3,
and T1G1-3) who
underwent TURB
RFS (3-yr): 65.5% (95%CI, 55.9-73.5%) for
short-term BCG vs. 68.6% (59.9-75.7%) for shortterm MMC s. 86.1% (77.9-91.4%) for long-term
MMC long-term therapy (log-rank test, p=0.001)
Page 20 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Gårdmark T.
44
2007
Intervention
RCT:
1. BCG (120 mg) *
2. mitomycin-C (MMC; 40 mg) *
Follow-up
(med mos)
123
Number of
Patients (N)
261
* weekly for 6 weeks, then monthly up to a year
and finally every third month for a further year
Colombel M.
45
2006
RCT (double-blind):
1. ofloxacin (200 mg) + BCG (6 + 3 instillations)
2. placebo + BCG (6 + 3 instillations)
12
115
Stage/Histologic
Subtype
high-risk and nonmuscle-invasive;
recurring Ta/T1G1G2, T1G3 or
primary Tisdysplasia
Outcomes
primary or recurrent
superficial bladder
cancer (Ta/T1, CIS,
G1-G3) and no
prior BCG
moderate/severe AEs:
class II AEs: ofloxacin significantly decreased the
incidence by 18.5% between instillations 4 and 6
class III AEs: significantly decreased by ofloxacin
between instillations 1 and 9
class I AEs: no difference
progression: 23% (58 patients); 34 in MMC group
vs. 24 in BCG group (p=0.26)
deaths: 140 patients; 68 in the BCG group vs. 72
in the MMC group (log-rank p=0.98); most died
from other causes
compliance w/BCG: 80.7% received 9 instillations
in group 1 vs. 65.5% in group 2 (p=0.092)
recurrence rate (12 months): 12.7% vs. 17.2%
progression rates (12 months): 5.5% vs. 1.7%
DiStasi SM.
46
2006
RCT:
1. BCG alone (81 mg for 6 weeks) *
2. BCG (81 mg for 2 weeks) sequential with
electromotive mitomycin (20 mA for 30 min)
once a week as one cycle for three cycles *
88
212
stage pT1 bladder
cancer who
underwent TUR
DFS: 69 months (55-86) for sequential BCG +
mitomycin vs. 21 months (15-54) for BCG alone
(p=0.0012)
recurrence: 41.9% (32.7-51.5) for sequential vs.
57.9% (48.7-67.5) for BCG alone (p=0.0012)
* complete responders underwent maintenance
progression: 9.3% (3.8-14.8) for sequential vs.
21.9% (17.9-25.9) for BCG alone (p=0.004)
overall mortality: 21.5% (13.5-29.5) for sequential
vs. 32.4% (23.4-41.4) for BCG alone (p=0.045)
disease-specific mortality: 5.6% (1.2-10.0) for
sequential vs. 16.2% (6.1-23.3) for BCG alone
(p=0.01)
Page 21 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Hinotsu S.
47
2006
Martínez-Piñeiro
48
JA. 2005
(CUETO)
Intervention
RCT:
1. BCG (6 weekly instillations of 80 mg)
2. doxorubicin (17 instillations of 20 mg)
RCT:
1. BCG (81 mg) *
2. BCG (27 mg) *
Follow-up
(med mos)
22.2
61
Number of
Patients (N)
80
155
Stage/Histologic
Subtype
superficial bladder
cancer (Stage Ta
or
T1, grade 1 or 2)
Outcomes
T1G3, Tis,
associated Tis
disease who
underwent TUR
recurrence: 32 patients (39%) for 81 mg vs. 33
(45%) for 27 mg
median time to recurrence: not attained for 81 mg
vs. 63 months for 27 mg (p=0.405)
risk of recurrence: significantly lower in the BCG
group (p=0.017, log-rank test)
BCG is not only efficacious in the early phase of
recurrence (up to 500 days after TURBT), but
also in the late phase, and the latter is thought to
include second primary tumors (new tumors)
* weekly x 6 and 2-weekly x 6 thereafter
progression: 20 patients (24.7%) for 81 mg vs. 19
(26%) for 27 mg
median time to progression: not attained in either
arm (p=0.7997)
disease specific mortality: 12.2% for 81 mg vs.
16.4% for 27 mg
mean disease specific survival: 87.0 +/- 4.1 mos
for 81 mg vs. 83.7 +/- 4.7 mos for 27 mg
Cheng CW.
49
2005
RCT:
1. BCG (81 mg)
2. epirubicin (50 mg) *
61
209
* crossover allowed
de Reijke TM.
50
2005
(GUG30906)
RCT:
1. BCG (81 mg; 6 weekly instillations) *
2. epirubicin (50 mg; 8 weekly instillations) *
* if CR, maintenance instillations at months 3, 6,
12, 18, 24, 30 and 36
60
164
Ta or T1, multiple
or recurrent tumors,
after complete
TUR
RFS (10-year): 61% for BCG vs. 32% for epi
primary, secondary
or concurrent CIS
of the bladder
CR: 56% for epirubicin vs. 65% for BCG (p=0.21)
PFS (10-year): 78% for BCG vs. 74% for epi
DFS (10-year): 80% for BCG vs. 92% for epi
time to bladder tumor recurrence after CR: 5.1 yrs
for BCG vs. 1.4 yrs for epirubicin
CIS recurrences: more frequent in complete
responders to epirubicin (45% vs. 16%)
time to progression: no differences
side effects stopping treatment: 26 for BCG vs. 8
for epirubicin
Page 22 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
DiStasi SM.
51
2003
Kaasinen E.
52
2003
Intervention
Follow-up
(med mos)
RCT:
1. intravesical electromotive MMC (40 mg; with
20 mA electric current for 30 minutes)
2. passive MMC (40 mg)
3. BCG (81 mg; 6 weekly treatments +/- 6
weekly treatments for nonresponders and
10 monthly treatments for responders)
RCT:
1. mitomycin C (6-weekly instillations; 40 mg)
and BCG (120 mg) alternating monthly
2. BCG monotherapy (120 mg, same schedule)
Number of
Patients (N)
108
Stage/Histologic
Subtype
high risk superficial
bladder cancer who
underwent TUR
Outcomes
CR (6-mos): 58% electromotive MMC vs. 31%
passive MMC (p= 0.012) vs. 64% for BCG
median time to recurrence: 35 vs. 19.5 months
(p=0.013) and for BCG it was 26 months
56
304
carcinoma in situ
(CIS) of the
urinary bladder
DFS: BCG monotherapy was sig better than that
for alternating therapy (p=0.03; log rank test)
progression risk: lower in the BCG monotherapy
group (p=0.07)
OS: no differences
side effects:
BCG monotherapy caused more local side effects
and premature treatment cessation; no difference
in serious side effects
Kolodziej A.
53
2002
Martínez-Piñeiro
54
JA. 2002
(CUETO)
RCT:
1. no additional treatment
2. BCG (6 consecutive weeks then 3-weekly
instillations in months 3, 6, 12, 18, 24, 30, 36)
23
RCT:
1. BCG (27 mg)
2. BCG (81 mg)
69
102
499
high-risk superficial
bladder cancer who
underwent TUR
DFS: 81% (83/102) for BCG vs. 45% (24/53) for
TUR alone
superficial bladder
cancer (Ta, T1, Tis)
recurrences: 71 patients (28%) for 81 mg vs. 76
patients (31%) for 27 mg
median time to recurrence: not yet attained
RFS (5-yr): 70.5% for 81 mg vs. 70.4% for 27 mg
tumour progression: 8% (8 pts) for BCG vs. 23%
(12 pts) for TUR alone
subgroup analyses (recurrences):
multifocal tumours: lower for 81 mg (p=0.015)
G3 tumours: 81 mg marginally better (p=0.06)
high-risk: 81 mg marginally better (p=0.08)
progression: 29 tumours (11.5%) for 81 mg vs. 33
tumours (13.3%) for 27 mg
median time to progression: not yet attained
PFS (5-yr): 88.8% for 81 mg vs. 86.9% for 27 mg
Page 23 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
van der Meijden
55
AP. 2001
(EORTC)
Palou J.
56
2001
Kaasinen E.
57
2000
(Finnbladder IV)
Lamm DL.
58
2000
(SWOG)
Intervention
Follow-up
(med mos)
RCT:
1. weekly epirubicin
2. weekly BCG (6-week interval followed by 3weekly maintenance at months 3, 6, 12, 18,
24, 30, 36)
3. BCG + isoniazid (6-week interval followed by
3-weekly maintenance at months 3, 6, 12, 18,
24, 30, 36)
RCT:
1. BCG: initial 6 instillations + maintenance
(6 instillations q 6 months for 2 yrs)
2. BCG: initial therapy only
RCT:
1. mitomycin C initial instillation + 4-weekly
mitomycin C + monthly BCG up to 1 year
2. mitomycin C initial instillation + 4-weekly
mitomycin C + monthly IFN-α2b up to 1 year
3. BCG monthly
Number of
Patients (N)
957
79
30.7
RCT:
1. BCG 6-week induction + maintenance
2. BCG 6-week induction + no maintenance
RCT (double-blind):
1. BCG (6 weekly, 81 mg) + concomitant 3-day
isoniazid (300 mg o.d.)
2. BCG + placebo
Outcomes
time to first recurrence: longer in patients treated
with BCG +/- isoniazid vs. epirubicin (p=0.0001)
(no difference between 2 BCG regimens; p=0.27)
progression to muscle invasive cancer: rare (5%)
and did not differ sig between arms (p=0.12)
drug-induced cystitis: 31% for epirubicin vs. 42%
for BCG vs. 45% for BCG + isoniazid
systemic effects (fever/malaise): 0% epirubicin vs.
31% BCG vs. 36% for BCG + isoniazid
126
205
384
maintenance = intravesical and percutaneous
BCG each week for 3 weeks given 3, 6, 12, 18,
24, 30, 36 months
Al Khalifa M.
59
2000
Stage/Histologic
Subtype
intermediate and
high risk Ta, T1
bladder cancer who
underwent TUR
in situ and high
grade
superficial bladder
tumors
recurrence: 16 patients (26.2%) for control vs. 10
patients (15.1%) for maintenance (p=0.07)
frequently recurrent
stage Ta or T1
bladder tumors who
underwent TUR
time to initial recurrence: monthly BCG superior to
alternating MMC w/ IFN-α2b or BCG (p<0.00001)
in situ or high risk
TCC (Ta or T1)
who underwent
TUR
RFS (median): 35.7 months (95% CI 25.1-56.8)
for control vs. 76.8 months (64.3 to 93.2) for
maintenance (p<0.0001)
maintenance compliance: 33.85% (22/65) on
maintenance therapy completed 2-yr treatment
recurrence rate: 0.4 vs. 0.9; p<0.00001
time for PFS (median): 111.5 months for control
vs. not reached for maintenance (p=0.04)
OS (5-yr): 78% control vs. 83% for maintenance
n/a
160
urothelial cancer
(pTa-T1, pTis, G13) who underwent
TUR
side-effects-free patients: 19% with isoniazid vs.
16% for placebo
local side-effects confined to bladder: lower with
isoniazid (35% vs. 48%, p<0.01)
local side-effects + systemic adverse effects
(fever, nausea or skin rash): 30% in each arm
recurrence: no differences between groups
Page 24 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Ali-El-Dein B.
60
1999
Intervention
RCT:
1. BCG (150 mg) + epirubicin (50 mg)
sequential, 1 drug at a time *
2. BCG alone *
Follow-up
(med mos)
30.4
Number of
Patients (N)
124
Stage/Histologic
Subtype
pTa and pT1
bladder TCC
(superficial)
Outcomes
therapy discontinuation: 3 for sequential vs. 12 for
BCG alone due to severe side effects (excluded)
recurrence rate: no differences
progression rates: no differences
* 6 weeks followed by 10 monthly
instillations.
time to first recurrence with or without
progression: longer in sequential group (p=0.05)
toxicity/complications: lower for sequential vs.
only BCG: 27.3% (18 pts) vs. 70.7% (41 pts);
p=0.001
Malmström PU.
61
1999
(SwedishNorwegian)
RCT:
1. mitomycin C (40 mg) for 2 years
2. BCG (120 mg) for 2 years
64
250
Tis, dysplasia G2,
T1 G3 and multiple
recurrent Ta/T1
G1-2 disease
DFS: 42% (101/250); significantly higher with
BCG (p=0.04); most pronounced Tis disease
tumor progression: no differences
survival: no differences
Witjes JA.
62
1998
RCT:
1. mitomycin C: 4 weekly instillations (40 mg) +
6 weekly instillations with BCG
2. mitomycin-C: 10 weekly instillations
32
182
Intermediate/high
risk papillary
superficial and in
situ TCC who
underwent TUR
cystitis/other local side effects: similar b/t groups
allergic reactions, including skin rash: more often
for mitomycin C only (12/92 vs. 5/90; p=0.08)
other systemic side effects: more frequent in the
sequential group (16/90 vs. 8/92; p=0.07)
recurrences: 35/90 patients for sequential vs.
42/92 for mitomycin C only (p=0.36)
progression: 5/90 vs. 4/92 (p=0.70)
Witjes JA.
63
1998
RCT:
1. intravesical MMC (30 mg, weekly for 4 weeks,
and thereafter monthly for 5 months)
2. BCG (weekly for 6 weeks)
86
344
superficial bladder
cancer (pTa, pT1,
pTis)
toxicity: not significantly different between groups
recurrence: similar (no differences)
progression to invasive disease: MMC more
effective than BCG in patients without carcinoma
in situ (CIS) (p=0.006)
Page 25 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Yalçinkaya F.
64
1998
Jimenez-Cruz
65
JF. 1997
Intervention
Follow-up
(med mos)
RCT:
1. intravesical BCG (81 mg) once a week for 6
weeks
2. intravesical BCG (54 mg) once a week for 6
weeks
RCT:
1. 150 mg BCG *
2. 54 MU of recombinant IFN-alpha-2a *
Number of
Patients (N)
80
Stage/Histologic
Subtype
superficial
bladder cancer who
underwent TUR
Outcomes
recurrence: 6 pts for 81 mg vs. 10 pts for 54 mg
recurrence rates per month: 0.71 for 81 mg vs.
1.49 for 54 mg
complication rates: no significant differences
1081
110
recurrent
superficial stage
pT1, grade 1-3
tumors
* weekly during the first month, biweekly for 2
months, and monthly for 9 months
tumour recurrence: 69.4% (34/49 patients) for IFN
vs. 39.3% (24/61 patients) for BCG
disease-free interval (mean): 19.3 months for
BCG vs. 15.3 months for IFN
index of recurrence: 2.2 for BCG vs. 5.5 for IFN
(p=0.001) in favor of BCG
progression to invasive carcinoma: similar in both
study arms
Gruenwald IE.
66
1997
RCT:
1. 6-week BCG
2. 12-week BCG
28
70
high risk TCC of
the
bladder
tumor-free rate: 70% (21 patients) for 12-week vs.
55% (22 patients) for 6-week
mean interval to recurrence: 12.9 months for 12week vs. 12.3 months for 6-week
DFS: longer with 12-week but not statistically sig
Krege S.
67
1996
RCT:
1. no additional treatment
2. mitomycin C (20 mg) q 2 wks for 1 year then
q 1 month
3. BCG (120 mg; once a week for 6
weeks and once a month for 4 months)
20.2
337
superficial bladder
(pTa/1 grades 1-3
except primary pTa
grade 1) who
underwent TUR
recurrence rate: RR 0.508 for mitomycin C vs.
TUR and RR 0.618 for BCG vs. TUR alone (no
sig difference between MMC and BCG)
progression rate: comparable in all 3 groups
side effects: most common during or after BCG
(most often cystitis); no systemic complications
Page 26 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Lundholm C.
68
1996
Melekos MD.
69
1996
Intervention
RCT:
1. long-term mitomycin C (40 mg) *
2. BCG (120 mg) *
* weekly for 6 weeks, then monthly for up to 1
year and every 3 months during year 2
RCT:
1. 6-week BCG *
2. 4-week epirubicin *
Follow-up
(med mos)
39
43
Number of
Patients (N)
261
132
* maintenance therapy with single quarterly
instillations if recurrence free
T1 any grade or Ta grade 2-3 got 3-weekly
epirubicin at months 3 and 6 or a 3-week
course of BCG at month 6 of follow-up
Rintala E.
70
1996
RCT:
1. mitomycin C
2. alternating mitomycin C and BCG instillations
for 2 years
34
(mean)
188
Stage/Histologic
Subtype
primary dysplasia,
Tis, T1, grade 3, or
multiple recurrent
stage Ta/T1, grade
1 or 2 disease
Outcomes
recurrent and/or
multiple superficial
tumours at high risk
for recurrence and
progression who
underwent TUR
recurrence-free rates: 44% for epirubicin vs. 55%
for BCG
rapidly recurring
stage Ta or
T1 cancer
time to initial recurrence (med): 12 mos for MMC
vs. 7 mos for alternating MMC and BCG
(p=0.976)
DFS: 49% for BCG vs. 34% for MMC (p<0.03)
Progression: 13% of patients (no sig difference
between MMC and BCG)
side effects: more common after BCG (5 cases
vs. 1 in MCC); treatment was stopped due to
toxicity in 10% of the patients
RR recurrence: significant benefit in favour of
BCG vs. epirubicin in T1 or grade 3 patients
treatment failure: 21.5% for MMC vs. 18.9% for
alternating MMC and BCG
recurrence rates during instillation: 1.01 for MMC
vs. 0.86 for alternating MMC and BCG (p=0.376)
DF interval: no diff between groups (p=0.976)
Witjes W.
71
1996
(Dutch
Cooperative
Trial)
RCT:
1. mitomycin
2. BCG-Tice
3. BCG-RIVM
437
pTA/pT1 carcinoma
and CIS of the
urinary bladder
after TUR
toxicity: no differences between BCG strains but
local and systemic side effects were more
frequent in the BCG vs. mitomycin group
response rate: no diff b/w groups in CIS patients;
sig diff for MMC in papillary tumor patients
recurrence: 43% for MMC vs. 64% for BCG-Tice
vs. 46% for BCG-Rivm in pts with papillary tumors
Page 27 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Melekos MD.
72
1996
Rintala E.
73
1995
Intervention
RCT:
1. induction 6-week BCG (150 mg) and single
maintenance doses to responders
nd
2. early (on the 2 post-op day) instillation
followed by 4 weekly epirubicin (50 mg) then
10 monthly treatments for responders
RCT:
1. mitomycin C in alternating courses
2. BCG in alternating courses
Follow-up
(med mos)
35.1
(mean)
33
(mean)
Number of
Patients (N)
94
68
Stage/Histologic
Subtype
high risk superficial
bladder cancer who
underwent TUR
Outcomes
carcinoma in situ of
the bladder
CR: 47% for MMC vs. 74% for C/BCG at 24
months
RFS: 54% for epirubicin vs. 65% for BCG
Both drugs were proved to be safe with
manageable toxicity
DF interval: superiority with alternating therapy
(p=0.043)
Herr HW.
74
1995
RCT:
1, no additional treatment
2. BCG weekly for 6 weeks.
Patients were evaluated every 3 to 6 months
120
86
high-risk patients
with superficial
bladder cancer who
underwent TURB
PFS (10-yr): 61.9% (95% CI 47.2% to 76.7%) for
CG vs. 37% (95% CI 22.9% to 53.1%) for control
median PFS: not reached for BCG vs. 46 months
for control group (p=.0063)
DSS (10-yr): 75% for BCG vs. 55% for TUR (p=.03)
Vegt PD.
75
1995
RCT:
1. 30 mg mitomycin C once a week for 4
consecutive weeks, then q 1 month for 6 mos
8
2. BCG (5 x 10 ) or RIVM-BCG once a week for
6 consecutive weeks
Akaza H.
76
1995
RCT:
1. maintenance BCG (40 mg monthly X12)
2. control group (untreated)
Pagano F.
77
1995
RCT (phase III):
1. low dose BCG (75 mg)
2. standard dose BCG (150 mg)
36
(mean)
437
primary or recurrent
pTa and pT1
bladder tumors,
including CIS who
underwent TUR
papillary tumors:
mitomycin C and RIVM-BCG treatments were
equally effective (p = 0.53), and mitomycin C was
more effective than Tice BCG therapy (p=0.01)
45
120
Ta-T1 bladder who
underwent TUR
and instillation BCG
with a CR
recurrence rate (3-year): 22.4% for maintenance
vs. 25.8% for control
high risk bladder
CIS and T1 after
TUR
DFS:
T1M – 82% low dose vs. 0% standard (p=0.07)
CIS – 64% low dose vs. 0% standard (p=0.0003)
183
progression: observed rarely
progression: no differences observed
Page 28 of 29
CLINICAL PRACTICE GUIDELINE GU-009
version 1
Author Year
(Trial)
Martínez-Piñeiro
78
JA. 1995
(CUETO)
Intervention
RCT:
1. BCG (81 mg)
2. BCG (27 mg)
Follow-up
(med mos)
18.6
(mean)
Number of
Patients (N)
500
Stage/Histologic
Subtype
superficial bladder
cancer (TaG2-3,
T1G1-3)
Outcomes
local severe toxicity: 22.6% for 81 mg vs. 4.2% for
27 mg (p<0.01)
systemic toxicity: more common in 81 mg
(p<0.01)
pulmonary: 2.3% for 81 mg vs. 0.4% (p<0.01)
fever: 26.9% for 81 mg vs. 12.9% (p<0.01)
malaise: 16.2% for 81 mg vs. 8.4% (p<0.01)
recurrence rate: 18.1% for 81 mg vs. 19.5%
progression rate: 2.4% for 81 mg vs. 4.8%
Melekos MD.
79
1993
RCT:
1. intravesical epirubicin (50 mg)
2. BCG (150 mg)
3. control (resection only)
32.9
(mean)
161
high risk superficial
bladder cancer
after TUR
* one 6- or 8-week course of instillations
followed by single maintenance doses to the
responders at follow-up exams (high risk
patients received 1 additional 4-week course
of treatment 6 mos after start of therapy)
Melekos MD.
80
1993
RCT:
1. BCG *
2. No additional treatment
RCT:
1. mitomycin-C (MMC) x 9 instillations
2. BCG Tice x 6 weekly instillations
3. BCG-RIVM x 6 weekly instillations
recurrence rate per 100 patient-months:
epirubicin and BCG superior to resection alone
interval to recurrence: epirubicin and BCG
superior to resection alone
subgroup (T1 and G3 tumours): significant benefit
in favor of BCG when compared with epirubicin
30.2
(mean)
94
superficial bladder
cancer who
underwent TUR
* initial 6-week course of instillations and a
single quarterly maintenance dose to the
Responders (high risk patients received an
additional separate 4-week course of therapy)
Witjes JA.
81
1993
RFS: 60% for epirubicin vs. 68% for BCG vs. 41%
for control
RFS: 68% for BCG vs. 41% for TUR only
RR recurrence: significant benefit for BCG
recurrence rate per 100 patient-months:
significant benefit for BCG
DF interval: significant benefit for BCG
Drug-induced toxicity was acceptable
32
437
pTa-pT1 papillary
carcinoma and
primary carcinoma
in situ (CIS) of the
bladder
drug-induced cystitis: less in MMC group (p=.009)
other local effects: less in MMC group (p=.004)
systemic effects: less in MMC group (p<.001)
DFS: no significant difference between groups for
papillary tumours (p=0.08), nor the CIS (p=0.20)
Abbreviations: BCG = bacillus Calmette-Guérin; RFS = recurrence/relapse-free survival; OS = overall survival; PFS = progression-free survival; NR = not reported; PS =
performance status; *significant (p<0.05)
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