ࡱ> '` wbjbjLULU 4.?.?wJ J J J \   v$C$h: : Ojjj  jjjj V(J .j e0j6jjWL6j,WWW::TWWW   Complications of Intravesical Therapy Marc C. Smaldone Fellow in Urologic Oncology, Fox Chase Cancer Center for HYPERLINK "http://www.urologymatch.com/" Introduction More than 70% of urothelial carcinomas present as superficial, or non-muscle invasive bladder cancers (NMIBC). Recurrence and progression risk following transurethral resection (TUR) is multi-factorial, and is primarily associated with tumor size, stage, grade, and multifocality ADDIN EN.CITE Sylvester200655555517Sylvester, R. J.van der Meijden, A. P.Oosterlinck, W.Witjes, J. A.Bouffioux, C.Denis, L.Newling, D. W.Kurth, K.EORTC Data Center, Brussels, Belgium. richard.sylvester@eortc.bePredicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trialsEur UrolEur Urol466-5; discussion 475-7493AgedClinical Trials as Topic*Decision Support TechniquesDisease ProgressionFemaleFollow-Up StudiesHumansMaleMiddle AgedMultivariate AnalysisNeoplasm Recurrence, Local/*pathologyPrognosisRisk FactorsStatistics as TopicTime FactorsUrinary Bladder Neoplasms/*pathology/therapyUrologic Surgical Procedures2006Mar16442208http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=164422081. In 2007, the AUA guidelines committee released a consensus statement on the management of NMIBC (stages Ta, T1, & Tis), recommending a single dose of peri-operative intravesical therapy following TUR for papillary low volume non-histologically confirmed lesions as well as small volume, low grade Ta disease. They also recommended an induction course of intravesical therapy +/- maintenance therapy with either bacillus Calmette-Guerin (BCG) or Mitomycin C (MMC) for patients with multifocal, large volume, or recurrent histologically confirmed low grade Ta disease and induction + maintenance therapy for primary high grade Ta or T1 +/- CIS disease following TUR re-resection ADDIN EN.CITE  ADDIN EN.CITE.DATA 2. However, despite these recommendations it is important to consider that currently there is little level I evidence regarding optimal dosage, duration and timing of induction therapy, and role of maintenance therapy. The risks of intravesical therapy include local side effects such as hematuria and irritative voiding symptoms (urgency, frequency, and dysuria), more severe acute systemic effects such as sepsis, peritonitis, and myelosuppression, or chronic sequelae such as bladder contracture ADDIN EN.CITE Koya200622217Koya, M. P.Simon, M. A.Soloway, M. S.Department of Urology, University of Miami School of Medicine, Miami, Florida 33136, USA.Complications of intravesical therapy for urothelial cancer of the bladderJ UrolJ Urol2004-1017562006/05/16Adjuvants, Immunologic/*administration & dosage/*adverse effectsAdministration, IntravesicalAgedAntineoplastic Agents/*administration & dosage/*adverse effectsBCG Vaccine/*administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyHumansMaleMiddle AgedUrinary Bladder Neoplasms/*drug therapy2006Jun0022-5347 (Print) 0022-5347 (Linking)16697786http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697786S0022-5347(06)00264-3 [pii] 10.1016/S0022-5347(06)00264-3eng3. In general, it stands to reason that for tumors with low risk for progression, the risk for complications may outweigh any potential benefits from intravesical treatment. On the other hand, the risks of progression to muscle invasive disease may outweigh the risk of serious side effects in patients with high risk tumors. It is important that all urologists be able to risk stratify patients who are potential candidates for intravesical therapy and understand, recognize, and promptly treat its negative side effects ADDIN EN.CITE Koya200622217Koya, M. P.Simon, M. A.Soloway, M. S.Department of Urology, University of Miami School of Medicine, Miami, Florida 33136, USA.Complications of intravesical therapy for urothelial cancer of the bladderJ UrolJ Urol2004-1017562006/05/16Adjuvants, Immunologic/*administration & dosage/*adverse effectsAdministration, IntravesicalAgedAntineoplastic Agents/*administration & dosage/*adverse effectsBCG Vaccine/*administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyHumansMaleMiddle AgedUrinary Bladder Neoplasms/*drug therapy2006Jun0022-5347 (Print) 0022-5347 (Linking)16697786http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697786S0022-5347(06)00264-3 [pii] 10.1016/S0022-5347(06)00264-3eng3. Perioperative Single Shot Administration In a meta-analysis of 7 randomized trials comparing TUR alone to TUR plus one immediate instillation of chemotherapy, Sylvester et al. reported a 39% reduction in risk of recurrence (OR 0.61, p<0.0001) of NMIBC ADDIN EN.CITE Sylvester200499917Sylvester, R. J.Oosterlinck, W.van der Meijden, A. P.European Organization for the Research and Treatment of Cancer Data Center, Brussels, the Universitair Ziekenhuis Gent, Gent, Belgium. rsy@eortc.beA single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trialsJ UrolJ Urol2186-90, quiz 24351716 Pt 1Administration, IntravesicalAntineoplastic Agents/*administration & dosageCombined Modality TherapyHumansNeoplasm Recurrence, Local/epidemiology/*prevention & controlNeoplasm StagingPostoperative CareRandomized Controlled Trials as TopicRisk FactorsTime FactorsUrinary Bladder Neoplasms/*drug therapy/epidemiology/pathology/*surgery2004Jun15126782http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=151267824. As a general principal, there is substantially less risk of systemic absorption of compounds with a high molecular weight (MMC 329kD, Gemcitabine 299.66kD, Epirubicin 580kD), which facilitates immediate peri-operative treatment as long as there is no evidence of bladder perforation at TUR ADDIN EN.CITE Smaldone201066617Smaldone, M. C.Casella, D. P.Welchons, D. R.Gingrich, J. R.University of Pittsburgh Medical Center, Department of Urology, Kaufmann Building, 3471 5th Avenue, Pittsburgh, PA 15213, USA. smaldonemc@upmc.eduInvestigational therapies for non-muscle invasive bladder cancerExpert Opin Investig DrugsExpert Opin Investig Drugs371-831932010/01/19Adjuvants, Immunologic/adverse effects/therapeutic useAnimalsAntineoplastic Agents/adverse effects/*therapeutic useBCG Vaccine/adverse effects/therapeutic useClinical Trials as TopicCystectomy/methodsDisease ProgressionHumansImmunologic Factors/adverse effects/*therapeutic useNeoplasm Recurrence, LocalUrinary Bladder Neoplasms/pathology/*therapy2010Mar1744-7658 (Electronic) 1354-3784 (Linking)20078248http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2007824810.1517/13543780903563372eng5. However, unrecognized intra-peritoneal extravasation of chemotherapeutic agents can result in peritonitis, pelvic pain, fibrosis/necrosis, and ulceration, and if perforation is suspected intravesical therapy must only be administered following cystography demonstrating an intact bladder ADDIN EN.CITE Thrasher199277717Thrasher, J. B.Crawford, E. D.Division of Urology, Duke University Medical Center, Durham, North Carolina.Complications of intravesical chemotherapyUrol Clin North AmUrol Clin North Am529-391931992/08/01Administration, IntravesicalAntineoplastic Agents/administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyDoxorubicin/adverse effectsEpirubicin/adverse effectsEthoglucid/adverse effectsHumansMitomycin/adverse effectsMitoxantrone/adverse effectsThiotepa/adverse effectsUrinary Bladder Neoplasms/*drug therapy1992Aug0094-0143 (Print) 0094-0143 (Linking)1636237http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1636237eng6. More common sequelae following single intravesical administration of chemotherapy include chemical cystitis (ranging from 3-30% with MMC) which can be treated with phenazopyridine, anti-cholinergics, or drug discontinuation while less common effects include skin desquamation (eczema like reaction), myelosuppression, and very rarely bladder contracture ADDIN EN.CITE Koya200622217Koya, M. P.Simon, M. A.Soloway, M. S.Department of Urology, University of Miami School of Medicine, Miami, Florida 33136, USA.Complications of intravesical therapy for urothelial cancer of the bladderJ UrolJ Urol2004-1017562006/05/16Adjuvants, Immunologic/*administration & dosage/*adverse effectsAdministration, IntravesicalAgedAntineoplastic Agents/*administration & dosage/*adverse effectsBCG Vaccine/*administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyHumansMaleMiddle AgedUrinary Bladder Neoplasms/*drug therapy2006Jun0022-5347 (Print) 0022-5347 (Linking)16697786http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697786S0022-5347(06)00264-3 [pii] 10.1016/S0022-5347(06)00264-3eng3. Induction Therapy Intravesical administration of BCG as induction therapy for NMIBC has been shown to delay the time to first recurrence compared to transurethral resection alone ADDIN EN.CITE Shelley200012212212217Shelley, M. D.Court, J. B.Kynaston, H.Wilt, T. J.Fish, R. G.Mason, M.Research Laboratories, Velindre NHS Trust, Velindre Road, Whitchurch, Cardiff, Wales, UK, CF4 7XL. mike.shelley@velindre-tr.wales.nhs.ukIntravesical Bacillus Calmette-Guerin in Ta and T1 Bladder CancerCochrane Database Syst RevCochrane Database Syst RevCD0019864Adjuvants, Immunologic/*therapeutic useAdministration, IntravesicalBCG Vaccine/*therapeutic useFemaleHumansMaleNeoplasm Recurrence, Local/*prevention & controlNeoplasm StagingRandomized Controlled Trials as TopicTransurethral Resection of ProstateUrinary Bladder Neoplasms/pathology/*prevention & control200011034738http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=110347387 as well as tumor progression compared to TUR alone or other intravesical agents when maintenance therapy is utilized ADDIN EN.CITE Sylvester200277717Sylvester, R. J.van der, Meijden ApLamm, D. L.European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium.Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trialsJ UrolJ Urol1964-701685Administration, IntravesicalBCG Vaccine/*administration & dosage/adverse effectsCarcinoma in Situ/*drug therapy/mortality/pathology/surgeryCarcinoma, Transitional Cell/*drug therapy/mortality/pathology/surgeryDisease ProgressionHumansNeoplasm StagingRandomized Controlled Trials as TopicSurvival RateUrinary Bladder Neoplasms/*drug therapy/mortality/pathology/surgery2002Nov12394686http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=123946868. Induction treatment regimens of BCG typically begin 2 to 4 weeks following resection and are most commonly administered weekly for a six week interval. While the literature currently supports the superiority of BCG in limiting recurrence and progression compared to chemotherapeutic agents ADDIN EN.CITE  ADDIN EN.CITE.DATA 8-10, BCG toxicity limits its use in a significant number of patients, and recent evidence suggests that MMC induction therapy has a reduced incidence of local (30% vs. 44%) and systemic (12 vs. 19%) when compared to BCG ADDIN EN.CITE Shelley200312612612617Shelley, M. D.Court, J. B.Kynaston, H.Wilt, T. J.Coles, B.Mason, M.Research Laboratories, Velindre NHS Trust, Velindre Road, Whitchurch, Cardiff, Wales, UK, CF14 2TL.Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancerCochrane Database Syst RevCochrane Database Syst RevCD0032313Administration, IntravesicalAntibiotics, Antineoplastic/*therapeutic useBCG Vaccine/*therapeutic useCarcinoma in SituCarcinoma, Transitional Cell/drug therapyFemaleHumansMaleMitomycin/*therapeutic useRandomized Controlled Trials as TopicUrinary Bladder Neoplasms/*drug therapy200312917955http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=129179559. Local Symptoms Due to immune stimulation and inflammatory response, local symptoms following BCG administration include flu-like symptoms, low grade fever, and malaise which can be treated with acetaminophen, phenazopyridine, or non steroidal anti-inflammatory agents ADDIN EN.CITE Thrasher199277717Thrasher, J. B.Crawford, E. D.Division of Urology, Duke University Medical Center, Durham, North Carolina.Complications of intravesical chemotherapyUrol Clin North AmUrol Clin North Am529-391931992/08/01Administration, IntravesicalAntineoplastic Agents/administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyDoxorubicin/adverse effectsEpirubicin/adverse effectsEthoglucid/adverse effectsHumansMitomycin/adverse effectsMitoxantrone/adverse effectsThiotepa/adverse effectsUrinary Bladder Neoplasms/*drug therapy1992Aug0094-0143 (Print) 0094-0143 (Linking)1636237http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1636237eng6. Gross hematuria occurs in up to 30% of patients, and if hematuria does not resolve after 2-3 weeks of observation repeat cystoscopy is necessary to rule out persistent tumor. While local lower urinary tact symptoms are common, a bacterial urinary tract infection must be ruled out in cases of persistent symptoms, and should be evaluated with urine and blood cultures ADDIN EN.CITE Koya200622217Koya, M. P.Simon, M. A.Soloway, M. S.Department of Urology, University of Miami School of Medicine, Miami, Florida 33136, USA.Complications of intravesical therapy for urothelial cancer of the bladderJ UrolJ Urol2004-1017562006/05/16Adjuvants, Immunologic/*administration & dosage/*adverse effectsAdministration, IntravesicalAgedAntineoplastic Agents/*administration & dosage/*adverse effectsBCG Vaccine/*administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyHumansMaleMiddle AgedUrinary Bladder Neoplasms/*drug therapy2006Jun0022-5347 (Print) 0022-5347 (Linking)16697786http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697786S0022-5347(06)00264-3 [pii] 10.1016/S0022-5347(06)00264-3eng3. Although less rigorously studied than BCG, local and mild flu-like symptoms are common following administration of InterferonBCG (IFN) and chemotherapeutic agent induction therapy and can also be managed conservatively in a majority of cases. Adverse Events In a large review of more than 2,000 patients receiving BCG, Lamm et al. reported that high fever (>103 degrees F) was the most common severe adverse event, and occurred in 3% of patients ADDIN EN.CITE Lamm199288817Lamm, D. L.van der Meijden, P. M.Morales, A.Brosman, S. A.Catalona, W. J.Herr, H. W.Soloway, M. S.Steg, A.Debruyne, F. M.Department of Urology, West Virginia University School of Medicine, Morgantown.Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancerJ UrolJ Urol596-60014731992/03/01Administration, IntravesicalBCG Vaccine/administration & dosage/*adverse effects/therapeutic useContractureCystitis/epidemiology/etiologyHumansIncidenceNeoplasm StagingTuberculosis/drug therapy/epidemiology/etiologyUreteral Obstruction/epidemiology/etiologyUrinary Bladder Diseases/epidemiology/etiologyUrinary Bladder Neoplasms/pathology/*therapy1992Mar0022-5347 (Print) 0022-5347 (Linking)1538436http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1538436eng11. For the first 24-48 hours, antipyretics and fluids are appropriate therapy, but fevers greater than 48 hrs in duration should raise concern for disseminated systemic infection and all intravesical therapy should be withheld. Systemic absorption of BCG (BCG sepsis) is rare but potentially lethal. Most commonly diagnosed as a result of traumatic catheterization, patients present with fever, chills, hypotension, and confusion, and progression to clinical instability can be rapid. Cultures are often negative, and treatment with anti-tuberculosis therapy (Rifampin, Isoniazid for 6 months Ethambutol and/or Prednisone if treatment is ineffective) is initiated based on clinical suspicion ADDIN EN.CITE Koya200622217Koya, M. P.Simon, M. A.Soloway, M. S.Department of Urology, University of Miami School of Medicine, Miami, Florida 33136, USA.Complications of intravesical therapy for urothelial cancer of the bladderJ UrolJ Urol2004-1017562006/05/16Adjuvants, Immunologic/*administration & dosage/*adverse effectsAdministration, IntravesicalAgedAntineoplastic Agents/*administration & dosage/*adverse effectsBCG Vaccine/*administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyHumansMaleMiddle AgedUrinary Bladder Neoplasms/*drug therapy2006Jun0022-5347 (Print) 0022-5347 (Linking)16697786http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697786S0022-5347(06)00264-3 [pii] 10.1016/S0022-5347(06)00264-3eng3. While the role of Cycloserine as an adjunctive agent has diminished due to ineffectiveness, fluoroquinolone antibiotics have demonstrated efficacy and can be utilized in the case of severe systemic infection or if anti-tuberculous medications are poorly tolerated ADDIN EN.CITE Durek200011111117Durek, C.Rusch-Gerdes, S.Jocham, D.Bohle, A.Department of Urology, Medical University of Lubeck, National Reference Centre for Mycobacteria, Forschungszentrum Borstel, Germany.Sensitivity of BCG to modern antibioticsEur UrolEur Urol21-537 Suppl 11999/11/27Administration, IntravesicalAnti-Bacterial Agents/*pharmacologyAntibiotics, Antitubercular/pharmacologyBCG Vaccine/therapeutic useCycloserine/pharmacologyDrug Resistance, MicrobialHumansMicrobial Sensitivity TestsMycobacterium bovis/*drug effects/growth & developmentUrinary Bladder Neoplasms/therapy20000302-2838 (Print) 0302-2838 (Linking)10575268http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1057526852378 [pii]eng12. Granulomatous hepatitis and pneumonitis have also been described, which can be diagnosed with chest xray and/or liver function tests. For such cases hospitalization with supportive measures followed by 6 months of anti-tuberculosis therapy is often required. Additional less severe urologic manifestations of BCG adminstration include granulomatous prostatitis and epidymo-orchitis which range in clinical severity, with symptomatic patients requiring 3-6 months of Rifampin and Isoniazid therapy ADDIN EN.CITE Thrasher199277717Thrasher, J. B.Crawford, E. D.Division of Urology, Duke University Medical Center, Durham, North Carolina.Complications of intravesical chemotherapyUrol Clin North AmUrol Clin North Am529-391931992/08/01Administration, IntravesicalAntineoplastic Agents/administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyDoxorubicin/adverse effectsEpirubicin/adverse effectsEthoglucid/adverse effectsHumansMitomycin/adverse effectsMitoxantrone/adverse effectsThiotepa/adverse effectsUrinary Bladder Neoplasms/*drug therapy1992Aug0094-0143 (Print) 0094-0143 (Linking)1636237http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1636237eng6. Extremely uncommon chronic adverse events following BCG administration include ureteral obstruction and bladder contracture. Although rare, these complications can be quite severe, and may require ureteral reimplantion or cystectomy when conservative measures such as long term anti-tuberculosis, steroid, and/or antibiotic therapy are ineffective ADDIN EN.CITE Koya200622217Koya, M. P.Simon, M. A.Soloway, M. S.Department of Urology, University of Miami School of Medicine, Miami, Florida 33136, USA.Complications of intravesical therapy for urothelial cancer of the bladderJ UrolJ Urol2004-1017562006/05/16Adjuvants, Immunologic/*administration & dosage/*adverse effectsAdministration, IntravesicalAgedAntineoplastic Agents/*administration & dosage/*adverse effectsBCG Vaccine/*administration & dosage/*adverse effectsCarcinoma, Transitional Cell/*drug therapyHumansMaleMiddle AgedUrinary Bladder Neoplasms/*drug therapy2006Jun0022-5347 (Print) 0022-5347 (Linking)16697786http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16697786S0022-5347(06)00264-3 [pii] 10.1016/S0022-5347(06)00264-3eng3. Risk of common minor reactions with intravesical chemotherapeutic agents is similar to BCG, and consists primarily of local irritative voiding symptoms (MMC, anthracyclines, taxoids), and more uncommonly desquamation of the skin and myelosuppression (MMC). Since most of the chemotherapeutic agents currently in use have a high molecular weight, the risk for absorption and systemic effects are minimal and they are usually well tolerated, even in patients intolerant of BCG ADDIN EN.CITE Smaldone201066617Smaldone, M. C.Casella, D. P.Welchons, D. R.Gingrich, J. R.University of Pittsburgh Medical Center, Department of Urology, Kaufmann Building, 3471 5th Avenue, Pittsburgh, PA 15213, USA. smaldonemc@upmc.eduInvestigational therapies for non-muscle invasive bladder cancerExpert Opin Investig DrugsExpert Opin Investig Drugs371-831932010/01/19Adjuvants, Immunologic/adverse effects/therapeutic useAnimalsAntineoplastic Agents/adverse effects/*therapeutic useBCG Vaccine/adverse effects/therapeutic useClinical Trials as TopicCystectomy/methodsDisease ProgressionHumansImmunologic Factors/adverse effects/*therapeutic useNeoplasm Recurrence, LocalUrinary Bladder Neoplasms/pathology/*therapy2010Mar1744-7658 (Electronic) 1354-3784 (Linking)20078248http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2007824810.1517/13543780903563372eng5. Maintenance Therapy Although BCG remains first line intravesical therapy for patients with high grade, T1, CIS or other aggressive disease characteristics, it is unclear if there are differences in toxicity between induction and maintenance regimens ADDIN EN.CITE  ADDIN EN.CITE.DATA 13, 14. In a SWOG trial examining the role of maintenance BCG for NMIBC, toxicity was higher in the maintenance arm, and only 16% of patients randomized to the maintenance arm completed all 7 cycles ADDIN EN.CITE Lamm200079797917Lamm, D. L.Blumenstein, B. A.Crissman, J. D.Montie, J. E.Gottesman, J. E.Lowe, B. A.Sarosdy, M. F.Bohl, R. D.Grossman, H. B.Beck, T. M.Leimert, J. T.Crawford, E. D.West Virginia University Medical Center, Morgantown, USA.Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group StudyJ UrolJ Urol1124-91634Adjuvants, Immunologic/*therapeutic useAgedBCG Vaccine/*therapeutic useCarcinoma in Situ/*pathology/*therapyCarcinoma, Transitional Cell/*pathology/*therapyFemaleHumansImmunotherapyMaleMiddle AgedNeoplasm Recurrence, Local/*pathology/*therapyNeoplasms, Multiple Primary/*pathology/*therapyUrinary Bladder Neoplasms/*drug therapy/*pathology2000Apr10737480http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1073748015. Some recent trials have demonstrated that a reduced regimen (one-third dose) may be as effective as standard dosing with fewer side effects ADDIN EN.CITE  ADDIN EN.CITE.DATA 16 while other methods such as prolonging the interval between dosing or number of doses per cycle have been less rigorously evaluated in the literature. References  ADDIN EN.REFLIST  1. Sylvester, R. J., van der Meijden, A. P., Oosterlinck, W. et al.: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol, 49: 466, 2006 2. Hall, M. C., Chang, S. S., Dalbagni, G. et al.: Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol, 178: 2314, 2007 3. Koya, M. P., Simon, M. A., Soloway, M. S.: Complications of intravesical therapy for urothelial cancer of the bladder. J Urol, 175: 2004, 2006 4. Sylvester, R. J., Oosterlinck, W., van der Meijden, A. P.: A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol, 171: 2186, 2004 5. Smaldone, M. C., Casella, D. P., Welchons, D. R. et al.: Investigational therapies for non-muscle invasive bladder cancer. Expert Opin Investig Drugs, 19: 371, 2010 6. Thrasher, J. B., Crawford, E. D.: Complications of intravesical chemotherapy. Urol Clin North Am, 19: 529, 1992 7. Shelley, M. D., Court, J. B., Kynaston, H. et al.: Intravesical Bacillus Calmette-Guerin in Ta and T1 Bladder Cancer. Cochrane Database Syst Rev: CD001986, 2000 8. Sylvester, R. J., van der, M. A., Lamm, D. L.: Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol, 168: 1964, 2002 9. Shelley, M. D., Court, J. B., Kynaston, H. et al.: Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev: CD003231, 2003 10. Sylvester, R. J., van der Meijden, A. P., Witjes, J. A. et al.: Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol, 174: 86, 2005 11. Lamm, D. L., van der Meijden, P. M., Morales, A. et al.: Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J Urol, 147: 596, 1992 12. Durek, C., Rusch-Gerdes, S., Jocham, D. et al.: Sensitivity of BCG to modern antibiotics. Eur Urol, 37 Suppl 1: 21, 2000 13. Bohle, A., Jocham, D., Bock, P. R.: Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol, 169: 90, 2003 14. van der Meijden, A. P., Sylvester, R. J., Oosterlinck, W. et al.: Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol, 44: 429, 2003 15. Lamm, D. L., Blumenstein, B. A., Crissman, J. D. et al.: 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, 163: 1124, 2000 16. Martinez-Pineiro, J. A., Martinez-Pineiro, L., Solsona, E. et al.: 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, 174: 1242, 2005   INCLUDEPICTURE "http://www.auanet.org/content/residency/residents-committee/images/msmaldone.jpg" \* MERGEFORMATINET  Marc C. 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2h 4BM`RDo͝q.4ap75I`=S' @&g B$>`1i8lM%$\p%cUȔ^NYfxww}o֑\mӴ=A@h Q+ʳ4rHέmp{꽇WHɉS{[=OL A \|0M&ar0/uup;jK텒SrݥgJ}X1dI3_f@h`O ^&4 h 44PrT9W<N7oW/%ȩYro|G6S\ϯĹg @؏#{8G#=,O}@Kdano99GϖT[/4\/`mcY (Sk@hj if@h \\'@`@rr~/)(Dmj{OdVJI 3lj>[Eh 4 Pz@) @e!`!`t gKTJI3ø9,UK%pߓ+ @ 8S٧{fu/}?<.E,F2JLQC 2/8Rc uX/Eh 4H!Qd)4# v>P}^9Gb"+&ͨq[_JњU꾗"z@wN I-[d)o |#ytJSR_QY[WBϟ+TdOfZ@h 4I3$p@h ܑz;Id"=z̔t"h~^ 0rrҗy'N  \@>'(: 뿽\FD)G ozޟޝ eHYgd;ب6{!P@h 5|bMiuIENDB`DHall200711411411417Hall, M. C.Chang, S. S.Dalbagni, G.Pruthi, R. S.Seigne, J. D.Skinner, E. C.Wolf, J. S., Jr.Schellhammer, P. F.American Urological Association Education and Research, Inc., USA. Craig.Hall@cornerstonehealthcare.comGuideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 updateJ UrolJ Urol2314-301786Administration, IntravesicalAgedAged, 80 and overBCG Vaccine/therapeutic useCarcinoma, Transitional Cell/mortality/*pathology/*therapyChemotherapy, AdjuvantCystectomy/methodsDisease-Free SurvivalFemaleHumansImmunohistochemistryMaleMiddle AgedNeoplasm Invasiveness/*pathologyNeoplasm StagingPatient SelectionPrognosisRisk AssessmentSurvival AnalysisTreatment OutcomeUrinary Bladder Neoplasms/mortality/*pathology/*therapy2007Dec17993339http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17993339VDShelley200312612612617Shelley, M. D.Court, J. B.Kynaston, H.Wilt, T. J.Coles, B.Mason, M.Research Laboratories, Velindre NHS Trust, Velindre Road, Whitchurch, Cardiff, Wales, UK, CF14 2TL.Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancerCochrane Database Syst RevCochrane Database Syst RevCD0032313Administration, IntravesicalAntibiotics, Antineoplastic/*therapeutic useBCG Vaccine/*therapeutic useCarcinoma in SituCarcinoma, Transitional Cell/drug therapyFemaleHumansMaleMitomycin/*therapeutic useRandomized Controlled Trials as TopicUrinary Bladder Neoplasms/*drug therapy200312917955http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12917955Sylvester200277717Sylvester, R. J.van der, Meijden ApLamm, D. L.European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium.Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trialsJ UrolJ Urol1964-701685Administration, IntravesicalBCG Vaccine/*administration & dosage/adverse effectsCarcinoma in Situ/*drug therapy/mortality/pathology/surgeryCarcinoma, Transitional Cell/*drug therapy/mortality/pathology/surgeryDisease ProgressionHumansNeoplasm StagingRandomized Controlled Trials as TopicSurvival RateUrinary Bladder Neoplasms/*drug therapy/mortality/pathology/surgery2002Nov12394686http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12394686Sylvester200551515117Sylvester, R. J.van der Meijden, A. P.Witjes, J. A.Kurth, K.European Organization for the Research and Treatment of Cancer Data Center, Brussels, Belgium. richard.sylvester@eortc.beBacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trialsJ UrolJ Urol86-91; discussion 91-21741Adjuvants, Immunologic/*administration & dosageAdministration, IntravesicalAntineoplastic Agents/*administration & dosageBCG Vaccine/*administration & dosageCarcinoma in Situ/*drug therapyHumansRandomized Controlled Trials as TopicUrinary Bladder Neoplasms/*drug therapy2005Jul15947584http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15947584D DBohle200355517Bohle, A.Jocham, D.Bock, P. R.Department of Urology, Medical University of Lubeck, Lubeck, Germany.Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicityJ UrolJ Urol90-51691Adjuvants, Immunologic/*administration & dosageAdministration, IntravesicalAntibiotics, Antineoplastic/adverse effects/*therapeutic useBCG Vaccine/*administration & dosage/adverse effectsCystitis/chemically inducedDose-Response Relationship, DrugHumansMitomycin/adverse effects/*therapeutic useNeoplasm Recurrence, LocalUrinary Bladder Neoplasms/*drug therapy2003Jan12478111http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12478111van der Meijden200388888817van der Meijden, A. P.Sylvester, R. J.Oosterlinck, W.Hoeltl, W.Bono, A. V.Department of Urology, Jeroen Bosch Hospital, P.O. Box 90153, 5200 ME, 's Hertogenbosch, The NetherlandsMaintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III TrialEur UrolEur Urol429-34444Adjuvants, Immunologic/adverse effects/*therapeutic useBCG Vaccine/adverse effects/*therapeutic useCarcinoma, Transitional Cell/*drug therapyHumansTime FactorsUrinary Bladder Neoplasms/*drug therapy2003Oct14499676http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14499676: DMartinez-Pineiro200512512512517Martinez-Pineiro, J. A.Martinez-Pineiro, L.Solsona, E.Rodriguez, R. H.Gomez, J. M.Martin, M. G.Molina, J. R.Collado, A. G.Flores, N.Isorna, S.Pertusa, C.Rabadan, M.Astobieta, A.Camacho, J. 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Results of a prospective randomized trialJ UrolJ Urol1242-71744 Pt 1Adjuvants, Immunologic/*administration & dosageAdministration, IntravesicalAgedBCG Vaccine/*administration & dosageCause of DeathCystectomyDisease ProgressionFemaleHumansMaleNeoplasm Recurrence, Local/*prevention & controlProportional Hazards ModelsProspective StudiesRegression AnalysisUrinary Bladder Neoplasms/*drug therapy/mortality/pathology/prevention &control/surgery2005Oct16145378http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16145378DdX  S 4AmsmaldoneR3пt8#nQFпt8#nQJFIFC      """"""""""C  ! !!! !!!!!!!!"""""""""""""""=!1AQ"2aq#BRb$3r%4Cs(!1AQ"a2q#B ?XcL,{hQ2A +Ę0U9bQz$(ZX"S7FOW9pR^5J6CdR@Ҡt"LDWH04Ci j/(|zE7)"6hsKTq N%6B&V:Z=p}<+Ulw]!6W1Ј|~ϛc,+fi/0;lE+H2nxpԌy@2LԈ*9G m1!5r ༲Ꭾ,b&o;/CBia]EAL6Đ~b-YA)MJ`b6rD˜1BC W<RU+9]#ۧ^i-2REQf9eO) Y[wƥ~ '$N^儞)d5%e{\yG1J%*.n)ssNGrelKHFsg b eC@H) 0w#Vb$W|$y&ZW!_vwFiF}֓>aFu̥BE˯=ʪغ80V?)ӶYY9Z)ZZy 3}6;m6.u%t":\9R] nXX`rL6x@K Q< ~zRՃo6D$k*vNX;@Q8ˋt}gݾf^_2n^OTdCHiW-Bua}5>- EV`^ጽvR\v" "  e3I4^Ѹ#䥙lsazH\TU2C*^.g5IMG>P ϔJmׯgJy-t1-K~]`$O!]ՠxՅ$Q䝕V|n]C˼Z5" 1:GP" / TAڄJu TP~V(KO5zf{ ʦqEV|==FyxK8sg/:COMn}m?1=nPZVUXmbMbb:N$&;yXK*UZw52Gܤˡ{Nk7e}D_ǣiV/;y c=d  Y[|:b[TT78( Qi:m \d, nn7D٢u"U:q3bԽWf4fӘȱv#a/YuKzs9m4/aW] }* 4M)TDf0SC4Fd08ǦcG)qd}\T"q+:yFK]6}Hlţ-lפ}jI9_Y.S-,Aٴks&RJQqUV[bJ*;cc=߉ +?7*䳪i ")i^j"u O]#PlXpmhW8K-2eIqRn>Q )=FR`<>ص3uTbʶt  felx6āPRۧe̳&RnM;-Rji`ˠ+qOwR[%X8]8VXQbBSӭf&fHܲ-Ucݍy,P_@ RMiז6#mZ>6QUS3|B,s&*Tl}ߎ-g&2yxECKr4,6.<ڛqf5MKLPli6*^qwI&t'uʤ h=]&ͨP8NN=&u+2Q,&%<sŻM'*ԙ2.ur!o:x9o i $| ft'k@1D{[@Sb2׶qڶ׾АfVVɰ"(QyũLiKV1XFW[ss/mi]o2v 2Ln}Ik^P61q᪚(lxO3rpuGMy qPg;n):LiЧ`Srh:kfśU>DS}#?s ҥĎYD)H| Um5u*vW?ObGmXȯ 8,,J:u.K(PcIOe>2N "`\{ Aǜ:jL\DOoQ󈞄'N 0MqQ}aC5Iy| `G^Ecؿ666666666vvvvvvvvv666666>6666666666666666666666666666666666666666666666666hH666666666666666666666666666666666666666666666666666666666666666666J@J tbNormal dCJ_HaJmH sH tH DA@D Default Paragraph FontRi@R 0 Table Normal4 l4a (k( 0No List w&lb ^@_@q@XXXcidisiȄǩȩөAh*0 ٲW9q~,Avy000000000000000000000000000000000000000000000@00l,Avy00000 000 00R'_HzY,q)wadefghijklnӱwbmwcq 5 E [ \ ^ R''=(//177+9X@Z@AGGQHNOPOtPPPPPyQ X XY__=ajhlh0jqqt{{|dfčіvsv*+.ө(*wXQTQQDTQTQTQTQTQTQTQTQTQQDTQTQTQTQTQTQTQTQTQTQQDQTQQDTQTC8@0(  B S  ? _Hlt295591010 _Hlt295591011 _Hlt295591063 _Hlt295591064y@@@@ykUkdkLkLk2G^^bhoyagnuuy=*urn:schemas-microsoft-com:office:smarttags PlaceType=*urn:schemas-microsoft-com:office:smarttags PlaceName9*urn:schemas-microsoft-com:office:smarttagsplace ?7=  ' + 6 B v 5 = N W H T !.6#.:''''''0,000007777n8}88889r@~@H%HXX__``G`Q`hhiirr't/t1t:tJtTt{{:|I|||ăу(, "#.3C.67CGQ&r|ߕžΞy.kloy33&E \ !"00^@_@PPXXrrss ss1s;sHZ-č+ǩҩvy7=y=[ a }'r+86"]tb:cyc\dPoThxTREQm#_h"GdsJdaL\lyEN.InstantFormat4L EN.Layout; EN.Libraries<4w<ENInstantFormat><Enabled>1</Enabled><ScanUnformatted>1</ScanUnformatted><ScanChanges>1</ScanChanges></ENInstantFormat>M<ENLayout><Style>J Urology</Style><LeftDelim>{</LeftDelim><RightDelim>}</RightDelim><FontName>Calibri</FontName><FontSize>11</FontSize><ReflistTitle></ReflistTitle><StartingRefnum>1</StartingRefnum><FirstLineIndent>0</FirstLineIndent><HangingIndent>720</HangingIndent><LineSpacing>0</LineSpacing><SpaceAfter>0</SpaceAfter></ENLayout><ENLibraries><Libraries><item>intravesical chemo-Converted.enl</item><item>Complications of intravesical therapy.enl</item></Libraries></ENLibraries>@77977w`@UnknownGz Times New Roman5Symbol3& z Arial7&{ @Calibri"qh]ƍ]^N^N!242qHP)$PaL2%Complications of Intravesical TherapyMarc C. 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