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 version 1
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
Though amenable to surgery, early bladder cancer can recur frequently. 3 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 Description AJCC American Joint Committee on Cancer AUC area under the curve BCG Bacillus Calmette-Guerin CBC complete blood count CIS carcinoma in situ CMV cisplatin, methotrexate, vinblastine Cr creatinine CT computer tomography CXR chest x-ray CUA Canadian Urology Association Gy unit of radiation dose IFN interferon MMC mitomycin C MRI magnetic resonance imaging MVAC methotrexate, vinblastine, adriamycin, and cisplatinum PLND pelvic lymph node dissection TURBT 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.
REFERENCES
1 American Cancer Society. Cancer Facts and Figures, 2010. URL: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Retrieved: June 3, 2013.
2 Canadian Cancer Society. Canadian Cancer Statistics 2013. URL: http://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/Canadian%20cancer%20statistic s/canadian-cancer-statistics-2013-EN.pdf. Retrieved: June 3, 2013.
3 Statistics Canada. CANSIM Tables. URL: http://cansim2.statcan.gc.ca/cgi-win/cnsmcgi.pgm. Retrieved: June 3, 2013.
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5 U.S. Department of Health and Human Services. Agency for Healthcare Research and Quality. National Guideline Clearinghouse. URL: http://www.guideline.gov/.
6 European Association of Urology (EAU). EAU Clinical Guidelines. URL: http://www.uroweb.org/.
7 Scottish Intercollegiate Guidelines Network (SIGN). Healthcare Improvement Scotland. Guidelines. URL: http://sign.ac.uk/guidelines/index.html.
8 American Urological Association (AUA). AUA Guidelines. URL: http://www.auanet.org/.
9 National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. URL: www.nccn.org.
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10 Canadian Urological Association (CUA). Guidelines. URL: http://www.cua.org/guidelines_e.asp.
11 American Joint Committee on Cancer (AJCC). Urinary bladder. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 497-505.
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24 Gülpinar Ö, Halilioglu AH, Gökçe MI, Göğüş Ç, Baltaci S. The value of perioperative mitomycin C instillation in improving subsequent bacillus calmette-guerin instillation efficacy in intermediate and high-risk patients with non- muscle invasive bladder cancer: a prospective randomized study. Int Braz J Urol. 2012 Jul-Aug;38(4):474-9.
25 Kunieda F, Kitamura H, Niwakawa M, Kuroiwa K, Shinohara N, Tobisu K, Nakamura K, Shibata T, Tsuzuki T, Tsukamoto T, Kakehi Y; Urologic Oncology Study Group of the Japan Clinical Oncology Group. Watchful waiting versus intravesical BCG therapy for high-grade pT1 bladder cancer with pT0 histology after second transurethral resection: Japan Clinical Oncology Group Study JCOG1019. Jpn J Clin Oncol. 2012 Nov;42(11):1094-8. Epub 2012 Sep 5.
26 Hinotsu S, Akaza H, Naito S, Ozono S, Sumiyoshi Y, Noguchi S, Yamaguchi A, Nagamori S, Terai A, Nasu Y, Kume H, Tomita Y, Tanaka Y, Samma S, Uemura H, Koga H, Tsushima T. Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer. BJU Int. 2011 Jul;108(2):187-95. Epub 2010 Dec 22.
27 Chiong E, Kesavan A, Mahendran R, Chan YH, Sng JH, Lim YK, Kamaraj R, Tan TM, Esuvaranathan K. NRAMP1 and hGPX1 gene polymorphism and response to bacillus Calmette-Guérin therapy for bladder cancer. Eur Urol. 2011 Mar;59(3):430-7. Epub 2010 Dec 1.
28 Nepple KG, Lightfoot AJ, Rosevear HM, O'Donnell MA, Lamm DL; Bladder Cancer Genitourinary Oncology Study Group. Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol. 2010 Nov;184(5):1915-9. Epub 2010 Sep 17.
29 Koga H, Ozono S, Tsushima T, Tomita K, Horiguchi Y, Usami M, Hirao Y, Akaza H, Naito S; BCG Tokyo Strain Study Group. Maintenance intravesical bacillus Calmette-Guérin instillation for Ta, T1 cancer and carcinoma in situ of the bladder: randomized controlled trial by the BCG Tokyo Strain Study Group. Int J Urol. 2010 Sep;17(9):759-66. Epub 2010 Jul 4.
30 Burger M, Thiounn N, Denzinger S, Kondas J, Benoit G, Chapado MS, Jimenz-Cruz FJ, Kisbenedek L, Szabo Z, Zsolt D, Grimm MO, Romics I, Thüroff JW, Kiss T, Tombal B, Wirth M, Munsell M, Mills B, Koh T, Sherman J. The application of adjuvant autologous antravesical macrophage cell therapy vs. BCG in non-muscle invasive bladder cancer: a multicenter, randomized trial. J Transl Med. 2010 Jun 8;8:54.
31 Porena M, Del Zingaro M, Lazzeri M, Mearini L, Giannantoni A, Bini V, Costantini E. Bacillus Calmette-Guérin versus gemcitabine for intravesical therapy in high-risk superficial bladder cancer: a randomised prospective study. Urol Int. 2010;84(1):23-7. Epub 2010 Feb 17.
32 Sylvester RJ, Brausi MA, Kirkels WJ, Hoeltl W, Calais Da Silva F, Powell PH, Prescott S, Kirkali Z, van de Beek C, Gorlia T, de Reijke TM; EORTC Genito-Urinary Tract Cancer Group. Long-term efficacy results of EORTC genito- urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette- Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010 May;57(5):766-73. Epub 2009 Dec 18.
33 Cho DY, Bae JH, Moon DG, Cheon J, Lee JG, Kim JJ, Yoon DK, Park HS. The effects of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin in superficial bladder cancer: a preliminary study. J Int Med Res. 2009 Nov-Dec;37(6):1823-30.
34 Duchek M, Johansson R, Jahnson S, Mestad O, Hellström P, Hellsten S, Malmström PU; Members of the Urothelial Cancer Group of the Nordic Association of Urology. Bacillus Calmette-Guérin is superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective, randomized, Nordic study. Eur Urol. 2010 Jan;57(1):25-31. Epub 2009 Oct 6.
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35 Böhle A, Leyh H, Frei C, Kühn M, Tschada R, Pottek T, Wagner W, Knispel HH, von Pokrzywnitzki W, Zorlu F, Helsberg K, Lübben B, Soldatenkova V, Stoffregen C, Büttner H; S274 Study Group. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double- blind, placebo-controlled phase III multicentre study. Eur Urol. 2009 Sep;56(3):495-503. Epub 2009 Jun 21.
36 Damiano R, De Sio M, Quarto G, Di Lorenzo G, Perdonà S, Palumbo IM, Azzarito G, Giugliano F, Autorino R. Short-term administration of prulifloxacin in patients with nonmuscle-invasive bladder cancer: an effective option for the prevention of bacillus Calmette-Guérin-induced toxicity? BJU Int. 2009 Sep;104(5):633-9. Epub 2009 Mar 6.
37 Mangiarotti B, Trinchieri A, Del Nero A, Montanari E. A randomized prospective study of intravesical prophylaxis in non-musle invasive bladder cancer at intermediate risk of recurrence: mitomycin chemotherapy vs BCG immunotherapy. Arch Ital Urol Androl. 2008 Dec;80(4):167-71.
38 Cai T, Nesi G, Tinacci G, Zini E, Mondaini N, Boddi V, Mazzoli S, Bartoletti R. Can early single dose instillation of epirubicin improve bacillus Calmette-Guerin efficacy in patients with nonmuscle invasive high risk bladder cancer? Results from a prospective, randomized, double-blind controlled study. J Urol. 2008 Jul;180(1):110-5. Epub 2008 May 15.
39 Pan CW, Shen ZJ, Ding GQ. The effect of intravesical instillation of antifibrinolytic agents on bacillus Calmette- Guerin treatment of superficial bladder cancer: a pilot study. J Urol. 2008 Apr;179(4):1307-11; discussion 1311-2. Epub 2008 Mar 4.
40 Sabichi AL, Lerner SP, Atkinson EN, Grossman HB, Caraway NP, Dinney CP, Penson DF, Matin S, Kamat A, Pisters LL, Lin DW, Katz RL, Brenner DE, Hemstreet GP 3rd, Wargo M, Bleyer A, Sanders WH, Clifford JL, Parnes HL, Lippman SM. Phase III prevention trial of fenretinide in patients with resected non-muscle-invasive bladder cancer. Clin Cancer Res. 2008 Jan 1;14(1):224-9.
41 Agrawal MS, Agrawal M, Bansal S, Agarwal M, Lavania P, Goyal J. The safety and efficacy of different doses of bacillus Calmette Guérin in superficial bladder transitional cell carcinoma. Urology. 2007 Dec;70(6):1075-8.
42 Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, Chantada V, Camacho JE, Piñeiro LM, Rodríguez RH, Isorna S, Blas M, Martínez-Piñeiro JA, Madero R; CUETO Group (Club Urológico Español De Tratamiento Oncológico). A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol. 2007 Nov;52(5):1398-406. Epub 2007 Apr 27.
43 Friedrich MG, Pichlmeier U, Schwaibold H, Conrad S, Huland H. Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with Bacillus Calmette-Guérin (BCG) in patients with non-muscle-invasive bladder carcinoma. Eur Urol. 2007 Oct;52(4):1123-29. Epub 2007 Mar 12.
44 Gårdmark T, Jahnson S, Wahlquist R, Wijkström H, Malmström PU. Analysis of progression and survival after 10 years of a randomized prospective study comparing mitomycin-C and bacillus Calmette-Guérin in patients with high- risk 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 calmette- guerin 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.
64 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.
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 Calmette- Guerin instillation therapy for carcinoma in situ of the bladder. The Finnbladder Group. J Urol. 1995 Dec;154(6):2050- 3.
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 Calmette- Guerin 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.
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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
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CLINICAL PRACTICE GUIDELINE GU-009 version 1 APPENDIX B:
EVIDENCE TABLE ON BCG THERAPY
Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Shang PF. Cochrane meta-analysis: n/a 1111 Ta and T1 bladder tumour recurrence: 35.5% (195/549) for BCG vs. 22 2011 1. Bacillus Calmette-Guérin (BCG) (5 RCTs) cancer 51.4% (289/562) for EPI (p<.05) 2. epirubicin (EPI) 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. Meta-analysis (individual patient data): 53 2820 intermediate recurrence rate: 43% (no difference in time to first 23 2009 1. BCG (9 RCTs) or high risk non- recurrence between BCG and MMC; p=0.09) 2. Mitomycin-C muscle-invasive bladder cancer 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 Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Gülpinar Ö. RCT: 41 51 intermediate and RFS: 36% (9/25) with mitomycin C pretreatment 24 2012 1. mitomycin C pretreatment (40 mg within 6 hrs high risk patients vs. 19.3 % (5/26) with BCG alone (p=.052) of surgery) + delayed (15+ days) BCG with non-muscle (1X/week 6 weeks, 5 x 108 colony-forming invasive bladder median time to the first recurrence: 8 mos with units in 50 mL saline) cancer MMC pretreatment vs. 7 mos with BCG alone 2. delayed BCG alone (p=.12)
Kunieda F. RCT (phase III, non-inferiority): n/a 835 high-grade pT1 Recruitment in progress. 25 2012 1. watchful waiting planned bladder cancer with (JCOG1019) 2. intravesical BCG therapy pT0 histology after Primary endpoint: RFS (excluding Tis or Ta second TUR intravesical recurrence). Secondary endpoints: OS, mets-free survival with bladder preserved, annual intravesical RFS, annual T2 or deeper RFS, adverse events.
Hinotsu S. RCT: 24 115 recurrent RFS (actuarial): 84.6% for maintenance vs. 26 2011 1. maintenance BCG (81 mg, 1X/wk x 6 weeks or multiple non- 65.4% for non-maintenance vs. 27.7% for + 3 1X/wk instillations at 3, 6, 12, 18 months) muscle-invasive epirubicin 2. non-maintenance BCG (81 mg, 1X/wk X 6 bladder cancer weeks) (stage Ta or T1) RFS following TURBT: significantly prolonged in 3. epirubicin (40 mg intravesically X 9) after TURBT the maintenance group vs. non-maintenance group (generalized Wilcoxon test, P= 0.0190)
Chiong E. RCT: 60 99 non-muscle- time to recurrence (multivariate analysis): 27 2011 1. postresection intravesical BCG (81 mg) invasive bladder BCG therapy decreased recurrence time in 2. postresection intravesical BCG (27 mg) cancer; subgroup patients with the NRAMP1 D543N G:G genotype 3. postresection intravesical IFN-α analysis by geno- (p=0.014) and allele 3 (GT)n polymorphism type NRAMP1 (p=0.03)
Nepple KG. RCT: 24 670 BCG naïve with RFS: 28 2010 1. BCG (81 mg, 1X/wk x 6 weeks) + carcinoma in situ, 63% for BCG + RDA vitamins group vs. maintenance at 4, 7, 13, 19, 25, 37 months Ta or T1 urothelial 59% for BCG + megadose vitamins vs. 2. BCG (as above) + interferon α-2b cancer 55% for BCG/IFN α-2b + RDA vitamins vs. 61% for BCG/IFN α-2b + megadose (p>0.05) (2nd randomization: megadose or RDA vitamins) 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)
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Koga H. RCT: 28 53 high-risk RFS (2-year): 95.8% for maintenance vs. 74.1% 29 2010 1. BCG induction (80 mg 1X/week for 8 weeks) non-muscle for observation (p=0.078) + maintenance (4 doses) if complete response invasive bladder 2. BCG induction (80 mg) + observation cancer Univariate analysis: maintenance therapy was a significant factor influencing recurrence.
Burger M. RCT: 12 137 TaG1-3, T1G1-2 AEs: 30 2010 1. autologous intravesical macrophage cell plurifocal or non-serious: BCG 85% vs. BEXIDEM 45% therapy (BEXIDEM) after TURB * unifocal tumours serious: BCG 26% vs. BEXIDEM 14% (p<0.001) 2. BCG after TURB * and ≥2 occurrences within 24 months recurrence: 12% for BCG vs. 38% for BEXIDEM * 6 weekly instillations and 2 cycles of 3 weekly (p<0.001) instillations at months 3 and 6
Porena M. RCT: 44 64 high-risk superficial tolerability: better for gemcitabine; 12.5% of BCG 31 2010 1. adjuvant intravesical gemcitabine (mean) bladder cancer group needed delayed treatment or withdrawal 2. BCG (pT1 and/or G3 and/or CIS) 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. RCT: 109 837 intermediate- or distant metastases: ~5% BCG vs. ~9% epiribicin 32 2010 1. epirubicin (1X/week x 6) high-risk stage Ta significantly longer in the BCG arms (p=0.046) (EORTC) 2. BCG (1X/week x 6) T1 urothelial 3. BCG plus isoniazid (INH) followed by three bladder cancer overall survival: ~69% BCG vs. ~62% epirubicin significantly longer in the BCG arms (p=0.023) weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, 36 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
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Cho DY. Prospective trial (non-randomized): 87 superficial bladder RFS: 24.1 months for GEM + BCG vs. 19.8 33 2009 1. gemcitabine (1000 mg after TURBT and 2000 cancer months for BCG alone mg 1 week later) + BCG (1X/wk X 6 wks) 2. BCG alone
Duchek M. RCT: 24 250 high-grade T1 DFS: 62% for epirubicin + IFN- alpha2b vs. 73% 34 2010 1. adjuvant BCG * tumours G2-G3 for BCG (p=0.065) (Nordic Trial) 2. adjuvant epirubicin and IFN-alpha2b * 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. RCT (double-blind): 24 248 primary or recurrent recurrences: 94; deaths: 11 35 2009 1. single GEM instillation (2000 mg) * non-muscle- (S274) 2. placebo * invasive bladder study terminated early based on predefined cancer (pTa/ decision criteria * immediately after TUR pT1,G1-3) RFS (1-year): 77.7% for GEM (95% CI 68.8-84.3) NOTE: a second TUR (no instillation) and vs. 75.3% for placebo (66.3-82.3); no significant adjuvant BCG were allowed. group difference (HR: 0.946; 0.64-1.39; p=0.777)
Damiano R. RCT: n/a 72 intermediate- or AEs: 36 2009 1. TUR + prulifloxacin (600 mg x 3) for toxicity high-risk ≥1 AE: less in prulifloxacin-treated vs. control (sig) + induction BCG therapy nonmuscle-invasive moderate to severe AEs: less in the prulifloxacin- 2. BCG + no treatment bladder cancer treated group (sig) treatment stops/delays: 34% control vs. 19% prulifloxacin (p=0.04)
Recurrence rates: not affected by prulifloxacin.
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Mangiarotti B. RCT: 66 96 low grade recurrent recurrence rate: 50% (23/46) for mitomycin C vs. 37 2008 1. intravesical BCG (mean) non-muscle 50% (23/46) for BCG 2. mitomycin C invasive bladder cancer time to recurrence: 17.5+/-15.4 mos for MMC vs. (Ta or T1) 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. RCT (double-blind): 15 161 high risk DFS: 57.5% (46/80) epirubicin vs. 50.6% (41/81) 38 2008 1. perioperative epirubicin (80 mg) + delayed nonmuscle invasive BCG alone BCG (5 x 108 colony-forming units) bladder cancer 2. delayed 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. RCT (double-blind): 24 257 superficial bladder Recurrence rates: 10.6% group 1, 11.1% group 2, 39 2008 1. 100-120 mg BCG + 100 mg para- cancer 10.0% group 3, 9.3% group 4, 31.8% group 5. aminomethylbenzoic acid 2. 50-60 mg BCG + 100 mg para- RFS (groups 1-4 vs. group 5): p=0.023, p=0.037, aminomethylbenzoic acid P=0.031, p=0.020); no differences between 3. 100-120 mg BCG + 2.0 g epsilon groups 1, 2, 3, 4 (each p>0.05) aminocaproic acid 4. 50-60 mg BCG + 2.0 g epsilon aminocaproic serious adverse events: 9.6% group 1, 3.9% acid group 2, 15.7% group 3, 5.9% group 4, 13.5% 5. 100-120 mg BCG alone group 5 (p=0.222)
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Sabichi AL. RCT (phase III): 15 137 non-muscle- recurrence risk: "low" in 72% (no prior BCG) and 40 2008 1. fenretinide (200 mg/day orally for 12 months) invasive bladder intermediate or high in 32% (prior BCG) 2. fenretinide + BCG TCC (Ta, Tis, or T1) after TUR 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. RCT: 36 128 superficial bladder recurrence rate: 20% vs. 25% vs. 20% (p>0.05) 41 2007 1. BCG 40 mg (mean) cancer 2. BCG 80 mg progression: none seen 3. BCG 120 mg 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. RCT: 430 intermediate-risk DFS: BCG 27 mg longer than MMC (p=0.006); 42 2007 1. BCG low dose (27 mg) * superficial bladder no difference between BCG 27 mg and 13.5mg (CUETO) 2. BCG (13.5 mg) * cancer (p=0.165) or BCG 13.5mg and MMC (p=0.183) 3. mitomycin C (MMC; 30 mg) * 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. RCT (phase IV): 36 495 intermediate- to RFS (3-yr): 65.5% (95%CI, 55.9-73.5%) for 43 2007 1. short-term chemoprophylaxis Mitomycin C high-risk (recurrent short-term BCG vs. 68.6% (59.9-75.7%) for short- (20 mg weekly for 6 wk) and/or multifocal) term MMC s. 86.1% (77.9-91.4%) for long-term 2. long-term chemoprophylaxis Mitomycin C (20 pTaG1, TaG2-3, MMC long-term therapy (log-rank test, p=0.001) mg weekly for 6 wk then monthly for 3 yr) and T1G1-3) who 3. short-term immunoprophylaxis BCG (RIVM 2 underwent TURB x 108 CFU/week x 6 wks
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Gårdmark T. RCT: 123 261 high-risk and non- progression: 23% (58 patients); 34 in MMC group 44 2007 1. BCG (120 mg) * muscle-invasive; vs. 24 in BCG group (p=0.26) 2. mitomycin-C (MMC; 40 mg) * recurring Ta/T1G1- G2, T1G3 or deaths: 140 patients; 68 in the BCG group vs. 72 * weekly for 6 weeks, then monthly up to a year primary Tis- in the MMC group (log-rank p=0.98); most died and finally every third month for a further year dysplasia from other causes
Colombel M. RCT (double-blind): 12 115 primary or recurrent moderate/severe AEs: 45 2006 1. ofloxacin (200 mg) + BCG (6 + 3 instillations) superficial bladder class II AEs: ofloxacin significantly decreased the 2. placebo + BCG (6 + 3 instillations) cancer (Ta/T1, CIS, incidence by 18.5% between instillations 4 and 6 G1-G3) and no class III AEs: significantly decreased by ofloxacin prior BCG between instillations 1 and 9 class I AEs: no difference
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. RCT: 88 212 stage pT1 bladder DFS: 69 months (55-86) for sequential BCG + 46 2006 1. BCG alone (81 mg for 6 weeks) * cancer who mitomycin vs. 21 months (15-54) for BCG alone 2. BCG (81 mg for 2 weeks) sequential with underwent TUR (p=0.0012) electromotive mitomycin (20 mA for 30 min) once a week as one cycle for three cycles * 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)
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Hinotsu S. RCT: 22.2 80 superficial bladder risk of recurrence: significantly lower in the BCG 47 2006 1. BCG (6 weekly instillations of 80 mg) cancer (Stage Ta group (p=0.017, log-rank test) 2. doxorubicin (17 instillations of 20 mg) or T1, grade 1 or 2) 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)
Martínez-Piñeiro RCT: 61 155 T1G3, Tis, recurrence: 32 patients (39%) for 81 mg vs. 33 48 JA. 2005 1. BCG (81 mg) * associated Tis (45%) for 27 mg (CUETO) 2. BCG (27 mg) * disease who median time to recurrence: not attained for 81 mg underwent TUR vs. 63 months for 27 mg (p=0.405) * 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. RCT: 61 209 Ta or T1, multiple RFS (10-year): 61% for BCG vs. 32% for epi 49 2005 1. BCG (81 mg) or recurrent tumors, 2. epirubicin (50 mg) * after complete PFS (10-year): 78% for BCG vs. 74% for epi TUR * crossover allowed DFS (10-year): 80% for BCG vs. 92% for epi de Reijke TM. RCT: 60 164 primary, secondary CR: 56% for epirubicin vs. 65% for BCG (p=0.21) 50 2005 1. BCG (81 mg; 6 weekly instillations) * or concurrent CIS time to bladder tumor recurrence after CR: 5.1 yrs (GUG30906) 2. epirubicin (50 mg; 8 weekly instillations) * of the bladder for BCG vs. 1.4 yrs for epirubicin
* if CR, maintenance instillations at months 3, 6, CIS recurrences: more frequent in complete 12, 18, 24, 30 and 36 responders to epirubicin (45% vs. 16%)
time to progression: no differences
side effects stopping treatment: 26 for BCG vs. 8 for epirubicin
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype DiStasi SM. RCT: 108 high risk superficial CR (6-mos): 58% electromotive MMC vs. 31% 51 2003 1. intravesical electromotive MMC (40 mg; with bladder cancer who passive MMC (p= 0.012) vs. 64% for BCG 20 mA electric current for 30 minutes) underwent TUR 2. passive MMC (40 mg) median time to recurrence: 35 vs. 19.5 months 3. BCG (81 mg; 6 weekly treatments +/- 6 (p=0.013) and for BCG it was 26 months weekly treatments for nonresponders and 10 monthly treatments for responders)
Kaasinen E. RCT: 56 304 carcinoma in situ DFS: BCG monotherapy was sig better than that 52 2003 1. mitomycin C (6-weekly instillations; 40 mg) (CIS) of the for alternating therapy (p=0.03; log rank test) and BCG (120 mg) alternating monthly urinary bladder 2. BCG monotherapy (120 mg, same schedule) 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. RCT: 23 102 high-risk superficial DFS: 81% (83/102) for BCG vs. 45% (24/53) for 53 2002 1. no additional treatment bladder cancer who TUR alone 2. BCG (6 consecutive weeks then 3-weekly underwent TUR instillations in months 3, 6, 12, 18, 24, 30, 36) tumour progression: 8% (8 pts) for BCG vs. 23% (12 pts) for TUR alone
Martínez-Piñeiro RCT: 69 499 superficial bladder recurrences: 71 patients (28%) for 81 mg vs. 76 54 JA. 2002 1. BCG (27 mg) cancer (Ta, T1, Tis) patients (31%) for 27 mg (CUETO) 2. BCG (81 mg) median time to recurrence: not yet attained RFS (5-yr): 70.5% for 81 mg vs. 70.4% for 27 mg
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
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype van der Meijden RCT: 957 intermediate and time to first recurrence: longer in patients treated 55 AP. 2001 1. weekly epirubicin high risk Ta, T1 with BCG +/- isoniazid vs. epirubicin (p=0.0001) (EORTC) 2. weekly BCG (6-week interval followed by 3- bladder cancer who (no difference between 2 BCG regimens; p=0.27) weekly maintenance at months 3, 6, 12, 18, underwent TUR 24, 30, 36) progression to muscle invasive cancer: rare (5%) and did not differ sig between arms (p=0.12) 3. BCG + isoniazid (6-week interval followed by 3-weekly maintenance at months 3, 6, 12, 18, drug-induced cystitis: 31% for epirubicin vs. 42% 24, 30, 36) for BCG vs. 45% for BCG + isoniazid systemic effects (fever/malaise): 0% epirubicin vs. 31% BCG vs. 36% for BCG + isoniazid
Palou J. RCT: 79 126 in situ and high recurrence: 16 patients (26.2%) for control vs. 10 56 2001 1. BCG: initial 6 instillations + maintenance grade patients (15.1%) for maintenance (p=0.07) (6 instillations q 6 months for 2 yrs) superficial bladder 2. BCG: initial therapy only tumors maintenance compliance: 33.85% (22/65) on maintenance therapy completed 2-yr treatment
Kaasinen E. RCT: 30.7 205 frequently recurrent time to initial recurrence: monthly BCG superior to 57 2000 1. mitomycin C initial instillation + 4-weekly stage Ta or T1 alternating MMC w/ IFN-α2b or BCG (p<0.00001) (Finnbladder IV) mitomycin C + monthly BCG up to 1 year bladder tumors who 2. mitomycin C initial instillation + 4-weekly underwent TUR recurrence rate: 0.4 vs. 0.9; p<0.00001 mitomycin C + monthly IFN-α2b up to 1 year 3. BCG monthly
Lamm DL. RCT: 384 in situ or high risk RFS (median): 35.7 months (95% CI 25.1-56.8) 58 2000 1. BCG 6-week induction + maintenance TCC (Ta or T1) for control vs. 76.8 months (64.3 to 93.2) for (SWOG) 2. BCG 6-week induction + no maintenance who underwent maintenance (p<0.0001) TUR maintenance = intravesical and percutaneous time for PFS (median): 111.5 months for control BCG each week for 3 weeks given 3, 6, 12, 18, vs. not reached for maintenance (p=0.04) 24, 30, 36 months OS (5-yr): 78% control vs. 83% for maintenance
Al Khalifa M. RCT (double-blind): n/a 160 urothelial cancer side-effects-free patients: 19% with isoniazid vs. 59 2000 1. BCG (6 weekly, 81 mg) + concomitant 3-day (pTa-T1, pTis, G1- 16% for placebo isoniazid (300 mg o.d.) 3) who underwent local side-effects confined to bladder: lower with 2. BCG + placebo TUR 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
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Ali-El-Dein B. RCT: 30.4 124 pTa and pT1 therapy discontinuation: 3 for sequential vs. 12 for 60 1999 1. BCG (150 mg) + epirubicin (50 mg) bladder TCC BCG alone due to severe side effects (excluded) sequential, 1 drug at a time * (superficial) 2. BCG alone * 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. RCT: 64 250 Tis, dysplasia G2, DFS: 42% (101/250); significantly higher with 61 1999 1. mitomycin C (40 mg) for 2 years T1 G3 and multiple BCG (p=0.04); most pronounced Tis disease (Swedish- 2. BCG (120 mg) for 2 years recurrent Ta/T1 Norwegian) G1-2 disease tumor progression: no differences
survival: no differences
Witjes JA. RCT: 32 182 Intermediate/high cystitis/other local side effects: similar b/t groups 62 1998 1. mitomycin C: 4 weekly instillations (40 mg) + risk papillary allergic reactions, including skin rash: more often 6 weekly instillations with BCG superficial and in for mitomycin C only (12/92 vs. 5/90; p=0.08) 2. mitomycin-C: 10 weekly instillations situ TCC who other systemic side effects: more frequent in the underwent TUR 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. RCT: 86 344 superficial bladder toxicity: not significantly different between groups 63 1998 1. intravesical MMC (30 mg, weekly for 4 weeks, cancer (pTa, pT1, and thereafter monthly for 5 months) pTis) recurrence: similar (no differences) 2. BCG (weekly for 6 weeks) progression to invasive disease: MMC more effective than BCG in patients without carcinoma in situ (CIS) (p=0.006)
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Yalçinkaya F. RCT: 80 superficial recurrence: 6 pts for 81 mg vs. 10 pts for 54 mg 64 1998 1. intravesical BCG (81 mg) once a week for 6 bladder cancer who recurrence rates per month: 0.71 for 81 mg vs. weeks underwent TUR 1.49 for 54 mg 2. intravesical BCG (54 mg) once a week for 6 weeks complication rates: no significant differences
Jimenez-Cruz RCT: 1081 110 recurrent tumour recurrence: 69.4% (34/49 patients) for IFN 65 JF. 1997 1. 150 mg BCG * superficial stage vs. 39.3% (24/61 patients) for BCG 2. 54 MU of recombinant IFN-alpha-2a * pT1, grade 1-3 tumors disease-free interval (mean): 19.3 months for * weekly during the first month, biweekly for 2 BCG vs. 15.3 months for IFN months, and monthly for 9 months 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. RCT: 28 70 high risk TCC of tumor-free rate: 70% (21 patients) for 12-week vs. 66 1997 1. 6-week BCG the 55% (22 patients) for 6-week 2. 12-week BCG bladder mean interval to recurrence: 12.9 months for 12- week vs. 12.3 months for 6-week
DFS: longer with 12-week but not statistically sig
Krege S. RCT: 20.2 337 superficial bladder recurrence rate: RR 0.508 for mitomycin C vs. 67 1996 1. no additional treatment (pTa/1 grades 1-3 TUR and RR 0.618 for BCG vs. TUR alone (no 2. mitomycin C (20 mg) q 2 wks for 1 year then except primary pTa sig difference between MMC and BCG) q 1 month grade 1) who 3. BCG (120 mg; once a week for 6 underwent TUR progression rate: comparable in all 3 groups weeks and once a month for 4 months) side effects: most common during or after BCG (most often cystitis); no systemic complications
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Lundholm C. RCT: 39 261 primary dysplasia, DFS: 49% for BCG vs. 34% for MMC (p<0.03) 68 1996 1. long-term mitomycin C (40 mg) * Tis, T1, grade 3, or 2. BCG (120 mg) * multiple recurrent Progression: 13% of patients (no sig difference between MMC and BCG) * weekly for 6 weeks, then monthly for up to 1 stage Ta/T1, grade year and every 3 months during year 2 1 or 2 disease side effects: more common after BCG (5 cases vs. 1 in MCC); treatment was stopped due to toxicity in 10% of the patients
Melekos MD. RCT: 43 132 recurrent and/or recurrence-free rates: 44% for epirubicin vs. 55% 69 1996 1. 6-week BCG * multiple superficial for BCG 2. 4-week epirubicin * tumours at high risk for recurrence and RR recurrence: significant benefit in favour of * maintenance therapy with single quarterly progression who BCG vs. epirubicin in T1 or grade 3 patients instillations if recurrence free underwent TUR 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. RCT: 34 188 rapidly recurring time to initial recurrence (med): 12 mos for MMC 70 1996 1. mitomycin C (mean) stage Ta or vs. 7 mos for alternating MMC and BCG 2. alternating mitomycin C and BCG instillations T1 cancer (p=0.976) for 2 years 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. RCT: 437 pTA/pT1 carcinoma toxicity: no differences between BCG strains but 71 1996 1. mitomycin and CIS of the local and systemic side effects were more (Dutch 2. BCG-Tice urinary bladder frequent in the BCG vs. mitomycin group Cooperative 3. BCG-RIVM after TUR Trial) 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
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Melekos MD. RCT: 35.1 94 high risk superficial RFS: 54% for epirubicin vs. 65% for BCG 72 1996 1. induction 6-week BCG (150 mg) and single (mean) bladder cancer who maintenance doses to responders underwent TUR Both drugs were proved to be safe with 2. early (on the 2nd post-op day) instillation manageable toxicity followed by 4 weekly epirubicin (50 mg) then 10 monthly treatments for responders
Rintala E. RCT: 33 68 carcinoma in situ of CR: 47% for MMC vs. 74% for C/BCG at 24 73 1995 1. mitomycin C in alternating courses (mean) the bladder months 2. BCG in alternating courses DF interval: superiority with alternating therapy (p=0.043)
Herr HW. RCT: 120 86 high-risk patients PFS (10-yr): 61.9% (95% CI 47.2% to 76.7%) for 74 1995 1, no additional treatment with superficial CG vs. 37% (95% CI 22.9% to 53.1%) for control 2. BCG weekly for 6 weeks. bladder cancer who Patients were evaluated every 3 to 6 months underwent TURB 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. RCT: 36 437 primary or recurrent papillary tumors: 75 1995 1. 30 mg mitomycin C once a week for 4 (mean) pTa and pT1 mitomycin C and RIVM-BCG treatments were consecutive weeks, then q 1 month for 6 mos bladder tumors, equally effective (p = 0.53), and mitomycin C was 2. BCG (5 x 108) or RIVM-BCG once a week for including CIS who more effective than Tice BCG therapy (p=0.01) 6 consecutive weeks underwent TUR
Akaza H. RCT: 45 120 Ta-T1 bladder who recurrence rate (3-year): 22.4% for maintenance 76 1995 1. maintenance BCG (40 mg monthly X12) underwent TUR vs. 25.8% for control 2. control group (untreated) and instillation BCG with a CR progression: observed rarely
Pagano F. RCT (phase III): 183 high risk bladder DFS: 77 1995 1. low dose BCG (75 mg) CIS and T1 after T1M – 82% low dose vs. 0% standard (p=0.07) 2. standard dose BCG (150 mg) TUR CIS – 64% low dose vs. 0% standard (p=0.0003)
progression: no differences observed
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Author Year Intervention Follow-up Number of Stage/Histologic Outcomes (Trial) (med mos) Patients (N) Subtype Martínez-Piñeiro RCT: 18.6 500 superficial bladder local severe toxicity: 22.6% for 81 mg vs. 4.2% for 78 JA. 1995 1. BCG (81 mg) (mean) cancer (TaG2-3, 27 mg (p<0.01) (CUETO) 2. BCG (27 mg) T1G1-3) 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. RCT: 32.9 161 high risk superficial RFS: 60% for epirubicin vs. 68% for BCG vs. 41% 79 1993 1. intravesical epirubicin (50 mg) (mean) bladder cancer for control 2. BCG (150 mg) after TUR 3. control (resection only) recurrence rate per 100 patient-months: epirubicin and BCG superior to resection alone * one 6- or 8-week course of instillations followed by single maintenance doses to the interval to recurrence: epirubicin and BCG responders at follow-up exams (high risk superior to resection alone patients received 1 additional 4-week course subgroup (T1 and G3 tumours): significant benefit of treatment 6 mos after start of therapy) in favor of BCG when compared with epirubicin
Melekos MD. RCT: 30.2 94 superficial bladder RFS: 68% for BCG vs. 41% for TUR only 80 1993 1. BCG * (mean) cancer who RR recurrence: significant benefit for BCG 2. No additional treatment underwent TUR recurrence rate per 100 patient-months: significant benefit for BCG * initial 6-week course of instillations and a single quarterly maintenance dose to the DF interval: significant benefit for BCG Responders (high risk patients received an additional separate 4-week course of therapy) Drug-induced toxicity was acceptable
Witjes JA. RCT: 32 437 pTa-pT1 papillary drug-induced cystitis: less in MMC group (p=.009) 81 1993 1. mitomycin-C (MMC) x 9 instillations carcinoma and other local effects: less in MMC group (p=.004) 2. BCG Tice x 6 weekly instillations primary carcinoma systemic effects: less in MMC group (p<.001) 3. BCG-RIVM x 6 weekly instillations in situ (CIS) of the bladder 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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