BCG in CaBladder

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  Intravesical Instillation Treatment of Non–muscle-invasiveBladder Cancer  Matthew R. Braasch a , Andreas Bo¨ hle b , Michael A. O’Donnell a, * a University of Iowa Department of Urology, Iowa City, Iowa, USA b Helios Agnes Karll Hospital, Bad Schwartau, Germany 1. Introduction Various forms of non–muscle-invasive bladder cancer(NMIBC) comprise  > 70% of all new bladder cancer (BC)diagnoses [1]. About half of these are low-grade, Ta tumorswith low risk ( < 5%) of progression. The others representmore worrisome lesions with higher risk of progression [2].Standardtreatmentconsistsoftransurethralresectionof bladder tumors (TURBT), with the addition of intravesicaladjuvant therapy when indicated. The most widely usedagents include the immunotherapy drugs bacillus Cal-mette-Gue´rin (BCG), interferon- a  (IFN- a ), and the che-motherapy agent mitomycin C (MMC), among others. BCGrepresentstheonlyagentknowntoreduce progressionintomuscle-invasive bladder cancer (MIBC) [2]. 2. Recommendations for treatment-naı¨ ve patients In patients who have not previously been treated withintravesical agents, induction therapy should be precededby adequate and safe transurethral resection (TUR) of allvisible tumors. Intravesical therapy should never beconsidered an alternative to satisfactory extirpation. Incases of high-grade T1 disease, it is strongly advised thatrepeat TURBT be considered 4–6 wk after the originalresection, primarily because of frequent clinical under-staging and the presence of unresected residual disease.Muscleinvasionhasbeenfoundonre-resectioninupto49%of cases when no muscularis propria was present and in upto 14% of cases when muscle was present in an srcinal T1tumor [3]. Residual disease has been found in 20–40% of cases [4]. The European Association of Urology (EAU) hasrecommended re-resection for all TaT1, high-grade tumors[5].The optimalschedulefor BCGremains unknown.Typicalinduction treatment for BCG-naı¨ve patients begins 2–4 wkafter TURBT and consists of six weekly instillations of a fullvial of BCG suspension. Using a linear regression model, adose-response relationship was found wherein at least 12BCG doses were needed to show superiority over MMC in EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 549–555 available at www.sciencedirect.comjournal homepage:  Article info Keywords: Bladder cancerImmunotherapyChemotherapy  Abstract Bacillus Calmette-Gue´rin (BCG) is a proven and valuable adjunct to transurethralresection(TUR)fordecreasingrecurrenceandprogressionof non–muscle-invasivebladdercancer (NMIBC).The European Association of Urology (EAU) and AmericanUrological Association (AUA) have similar recommendations for induction andmaintenancetreatment in patients based onclinical and pathologic risk factors. Tomost effectively treat this disease, clinicians must be aware of the risk factors fortreatment failure, strategies to deal with failures and BCG intolerance, and theappropriate threshold to proceed with radical cystectomy (RC). Combination,alternative, and multimodal intravesical treatments for patients with BCG failurehave arisen in recent years, and the outcomes data are reviewed here. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. University of Iowa, Department of Urology, 200 Hawkins Dr., 3 RCP, IowaCity, IA 52242-1089, USA. Tel. +1 319 384 691; Fax: +1 319 356 3900.E-mail address: (M.A. O’Donnell). 1569-9056/$ – see front matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2009.06.009  preventing recurrence [6]. Currently, the general consensuscalls for at least 1 yr [5] and even up to 3 yr of maintenancetherapy [4], if tolerated.The 2007 update to the American Urological Association(AUA) BC guidelines [4] and the 2008 EAU guidelines onNMIBC [5] generally agree on the recommendations foradjuvant immunotherapy in low-, intermediate-, and high-risk NMIBC. A summary of the general recommendations isprovided below.  2.1. Low-risk disease (small volume, primary, low grade, stageTa) Neither the AUA nor the EAU have made BCG therapy apractice standard for this category, which generallyincludes patients with low to moderate risk of recurrence(  15%) and very low risk of progression (  0.2%) at 1 yr [5].Surgical eradication of all visible tumors is a standard. TheEAU advocates a single dose of intravesical chemotherapy(primarily MMC) postoperatively, but the AUA considersthis optional.  2.2. Intermediate-risk disease (multifocal, large volume or recurrent, low grade Ta or T1) There is a heterogeneous group of patients who fall in theintermediate-risk category as defined by the EAU guide-lines, with low to moderate risk of progression (  1% at 1 yr,  6% at 5 yr), and recurrence risk of 46–62% at 5 yr [5]. Ingeneral, this would include patients with multifocal,recurrent, and/or large-volume, low-grade Ta (and some-timesT1)diseasewithoutcarcinomainsitu(CIS)inboththeEAU and AUA risk-stratification schemes.Both organizations recommend an induction course of either BCG or intravesical cytotoxic chemotherapy (usuallyMMC), as there is a paucity of data to confirm a distinctadvantage of BCG over chemotherapy for this cohort. Inaddition,theEAUmoreconfidentlyrecommends1yrofBCGmaintenance or 6–12 mo of maintenance chemotherapy.The AUA considers maintenance therapy with either agentoptional but acknowledges the superiority of maintenanceover non-maintenance for MMC.  2.3. High-risk disease (high-grade Ta or T1 and/or carcinoma insitu) Little controversy exists about the adequate treatment of high risk tumors, which generally include high-grade T1tumors, CIS, or a combination of high-grade Ta disease andCIS. In general, this group has a  17% risk of progression toMIBC at 1 yr and 45% risk at 5 yr [5]. Both the EAU and theAUA recommend TURBT (with possible re-resection),followed by induction BCG, and then at least 1 yr of maintenance intravesical therapy. If cytotoxic chemother-apy is chosen instead, induction treatment should befollowed by at least 6–12 mo of maintenance therapy.The AUA, although falling short of declaring BCG main-tenancethe standardof care, emphasizesthatthere isstillalack of data showing a clear progression advantage overMMC,withmaintenance,potentialsideeffectsoftreatment,and financial burdens that may outweigh the benefits insome patients.It is also important to consider the risks and benefits of early radical cystectomy (RC) in this patient cohort. Thisdecision weighs heavily on issues of BCG failure risk andtreatment side effects in high-risk patients. These areperhaps the most difficult and disputed treatment dilem-mas regarding immunotherapy. 3. Effectiveness of intravesical treatment inpreventing recurrence and progression  3.1. Papillary (Ta, T1) disease The odds ratio for recurrence is 0.39 with the use of postsurgical BCG versus TURBT alone [7]. Several meta-analyses have shown the superiority of BCG overintravesical cytotoxic chemotherapy (primarily MMC) inpreventing tumor recurrence and progression. However, itis essential to institute regular maintenance therapy inorder to achieve a significant advantage with BCG therapy[2,5]. In a meta-analysis of more than 2700 patients with amedian follow-up of 26 mo, the relative risk of recurrencewas 0.75 with BCG compared to MMC, which decreasedfurtherto0.64insubgroupstreatedwithBCGmaintenancetherapy [6].  3.2. Carcinoma in situ AsimilartreatmenteffectisseeninpatientswithCIS,whereBCGremainsthetreatmentofchoice.Approximately5–10%of all NMIBC patients harbor this high-grade and oftenmultifocal form of urothelial carcinoma (UC) [7]. A meta-analysis of more than 700 patients showed completeresponse (CR) rates of 68% and 52% and disease-free rates(at 3.6 yr) of 47% and 26% for BCG versus chemotherapy,respectively [8]. Justification for BCG maintenance treatment can reason-ably be extrapolated from papillary carcinoma data.However, it was demonstrated in the Southwest OncologyGroup (SWOG) 8507 study that the addition of even one 3-wkmaintenancecyclecouldimprovethe6-moCRratefrom68% to 84% [9]. 4. BCG failure The decision to employ intravesical immunotherapy, oralternatively, when toabandon treatment,is typically morecomplex than simply inserting an index patient into theEAU or AUA guidelines. Many patients bring an array of other comorbidities and treatment obstacles to the table.Also, each risk group is heterogeneous and assumes othervariables (eg, recurrence patterns, histologic variants, andmolecular characteristics) that cannot easily be applied tostraightforward algorithms. To fully understand andmanage this complex issue, one must be versed on thetypes of BCG failure and strategies to manage BCGintolerance. EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 549–555 550   4.1. Types of bacillus Calmette-Gue´ rin failure Traditionally, the term  BCG failure  has been appliedgenerically in the literature, usually referring to patientswho have recurrent disease any time after initiation of therapy. In fact, failure patients can roughly be divided intothe categories of   BCG intolerant, refractory, resistant,  and relapsing disease.BCG intolerance  is defined as recurrence after aninadequate treatment course, halted prematurely becauseof symptomatic intolerance or serious adverse events. Incontrast,BCG-refractorypatientsfailtoachievedisease-freestatus by 6 mo after induction with either maintenance orre-inductionat 3mo.Thisgroup alsoincludespatientswithprogression in grade or stage by 3 mo after the firstinduction cycle. BCG-resistant patients have recurrent orpersistent disease (of lesser degree, stage, or grade) afterinitial induction but then have complete response at 6 moafter TURBT. In essence, the disease initially improves, andthen resolves with BCG. In contrast, BCG relapsing patientsachieve disease-free status before 6 mo post-TURBT butthen have early (within 12 mo), intermediate (12–24 mo),or late ( > 24 mo) recurrence [10]. 5. BCG intolerance Serious side effects occur in < 5% of all patients undergoingBCG treatment, and a vast majority of these can beeffectively treated [5]. Although a slightly higher rate of side effects has been associated with BCG over MMC, it isestimated that only 5–10% of patients fail to completeinduction treatment, and about 5–11% have interruptionbut eventual completion [6,16]. However, 84% of patientson full-dose BCG using the rigorous SWOG 3-yr main-tenance plan did not receive all of their planned doses [9].BCG toxicity can be divided into local and systemic sideeffects. Localtoxicities are generally more frequent and lesssevere than systemic toxicity, but they are more often thecause of treatment stoppage [11]. However, most local sideeffectsare brief  [10,12].The incidence of localside effectsissimilar with or without maintenance therapy. For patientswho receive or do not receive maintenance therapy,respectively, these include lower urinary tract symptoms(57–71%, 38–59%), hematuria (20%, 29%), and bladdercontracture (3%, 1%) [4].Similarly, others have found no difference in systemicside effects between maintenance and non-maintenancegroups [6] and even reduced toxicity in the period after thefirst 6 mo of treatment [11]. Systemic side effects can bedivided into infectious (bacterial cystitis, epididymitis/prostatitis/urethral infections, systemic infection) and non-infectious types (arthralgias, skin reactions, anaphylaxis).The most common systemic toxicities reported in the 2007AUA guidelines update [4] include fevers, chills, and flusymptoms (22–30%, 19–26%); epididymitis, prostatitis, andurethral infections (4%, 4%); and systemic infection (7%, 1%)for patients treated with maintenance versus no main-tenance, respectively. Less severe systemic toxicities suchas fever ( > 39.5  8 C), skin rash, arthralgias, and  BCGitis (established BCG infection with organ manifestation[epididymal-orchitis, pneumonitis, hepatitis]) occur at arate of 2–6% [10,13]. 6. Treatment strategies for bacillus Calmette-Gue´rin intolerance 6.1. Dose adjustment  Dose adjustment remains one of the most commonmethods to manage BCG intolerance and is frequentlyemployed to reduce dropout during maintenance treat-ments. A one-third dose of BCG showed similar efficacy inpreventing recurrence and progression with significantlyless toxicity, but there has been some concern aboutapplying this strategy routinely in multifocal and high -risktumors [14,15]. In one randomized, prospective trial, a one-third dose of BCG was more effective than MMC inpreventing recurrence in intermediate-risk disease. How-ever,a1/6doseofBCGwaslesseffectivewithoutthebenefitof decreased toxicity in these patients [16]. Further dosereduction (1/10, 1/30, and even 1/100 of BCG) in combina-tion with IFN- a in patients with severe toxicity may also beefficacious for cancer control, but there is a paucity of published data at this time. 6.2. Treatment schedule One potential strategy to decrease side effects and improvetolerance is increasing the instillation interval duringinduction or maintenance (eg, doubling from 1 to 2 wk).Unfortunately, there is little data on the efficacy of thistactic. One small phase 2 trial showed decreased rates of mild to moderate side effects in the slow-rate groupcompared to standard rate. Twenty-five percent of patientsin the standard rate cohort experienced severe side effectsrequiring delay of instillation, and 6% required treatmentinterruption, but no patient required delay or interruptionin the slow-rate cohort [17]. 6.3. Dwell time Inpatientswithsignificantsideeffects,Andiusetalshowedimprovement in fevers, chills, dysuria, and overall time torecovery by reducing BCG dwell time from 2 hr to  30 min[18]. Compared to a control group with normal dwell time,these patients had similar tumor-free results. Although thismayrepresentatreatmentalternativeforpatientswithBCGintolerance, long-term efficacy data are currently lacking. 6.4. Pharmacologic  Most BCG-associated cystitis symptoms can be effectivelymanaged with aspirin, nonsteroidal anti-inflammatorydrugs, urinary analgesics, and antispasmodics [10]. Inaddition,200 mgofloxacingiven6and18hraftertreatmenthas shown promise in a prospective, placebo-controlled,randomized, controlled trial [19]. There was a significantreduction in moderate to severe adverse events during the EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 549–555  551  second half of the BCG induction cycle and severe eventsthroughouttheinductionandmaintenanceperiods.Despitebeing tuberculostatic, more patients in the ofloxacin groupcompleted all treatments without an obvious detriment toBCG efficacy. A newer fluoroquinolone antibiotic—pruli-floxacin—significantly decreased moderate to severeadverse events and treatment interruption without affect-ing 6-mo recurrence rates in a prospective, randomized,controlled trial [20]. Here again, long-term data are lacking. 7. Refractory, resistant, and relapsing disease inbacillus Calmette-Gue´rin–naı¨ ve patients High-risk NMIBC patients undergoing BCG treatmentrequire diligent monitoring, as they face a rather grim fatewith disease progression and fare as poorly as, or evenworse than, patients who present with primary muscle-invasive disease. A clinician must be mindful of the riskcategories for BCG failure when guiding intravesicaltreatment decisions. 7.1. Groups at highest risk for bacillus Calmette-Gue´ rin failure For patients in the highest risk group, it is suggested that aclinician more strongly consider radical therapy if a patientdemonstrates significant BCG intolerance, resistance, or aconcerning relapse pattern—particularly in patients withfewer comorbidities. The risk factors most clearly asso-ciated with recurrence and progression risk include tumorstage, grade, presence of CIS, recurrence pattern, multi-focality, and high-risk histologic variants.Large-scale, prospective studies have demonstrated thatTNM stage can predict progression. The risk of progressionis more than 2   greater for stage T1 versus Ta based onmultivariate analysis [21]. There are less data to correlateTNM stage with recurrence, however. Similar to stage,tumor grade portends risk of tumor progression. Large-scale,prospective studieshave demonstrateda hazardratio(HR) for progression ranging from 2.7 to 5.8 for G3 diseasecompared to lower grades [14,22,23].Recurrent tumors fare more poorly than grade- andstage-matched primary tumors, and early recurrencecarries a worse prognosis than delayed recurrence. Recur-rent tumors are about 1.5  more likely to progress to MIBCthanprimarytumors[12,22,23].Multiply-recurrenttumorsare an even worse prognostic indicator, carrying an HR of 2.3 for continued recurrence and 2.0 for progression tomuscle-invasive disease [14]. Recurrence at the first post-treatment cystoscopy is one of the worst prognosticindicators for eventual T stage progression, particularly inthesettingof otherhigh-riskfactors [21,37,24].Large serieshaveshownthat 60–80%of patients with recurrence at firstcystoscopy eventually have progression [24,39,25].DespitethefactthatCISandhigh-gradepapillarydiseasecommonly coexist, CIS is clearly an independent prognosticfactor. A large-scale meta-analysis of seven EuropeanOrganizationforResearchandTreatmentofCancer(EORTC)trialsshowedprogressionratesof10%at1yrand29%at5yrin T1G3 tumors without CIS versus 29% and 74%,respectively, with concomitant CIS. Here, multivariateanalysis showed that the presence of CIS yielded a higherHRfortumorprogression(HR:3.41)thangrade(2.67)andTcategory (2.19) [22].Several studies have shown tumor multiplicity to be asignificant predictor forrecurrence in BCG-treated patients,with an HR of approximately 1.5 [14,22,23], but only onelarge-scale study has indicated an importance in progres-sion [22]. The prognostic importance is also additive,wherein the risk of recurrence is proportional to thenumber of tumor foci [23].There are aggressive histologic features and variants inwhichBCGtreatmentshouldbeavoidedinfavorofearlyRC.These include lymphovascular invasion, which has beenassociated with overall decreased survival in cystoprosta-tectomypatients[26].Furthermore,micropapillaryvariantsofUC,squamouscellcarcinoma,andadenocarcinomaofthebladder should not be approached like non–muscle-invasive UC and are clearly not appropriate for intravesicalimmunotherapy. In one series of patients treated with BCGfor micropapillary variant, two-thirds progressed to MIBCand almost one-fourth to metastatic disease [27]. 7.2. Other risk groups for bacillus Calmette-Gue´ rin failure There are an admixture of risk factors in which the clinicianis urged to be more persistent for resistant/relapsingdisease and more creative with adjusted treatment regi-mens in cases of BCG intolerance. Furthermore, thethreshold to abandon immunotherapy for cystectomymay be somewhat higher. However, there is no substituteforcystectomyforrefractorydisease.Theriskfactors inthiscategory include prostatic urethral involvement, largetumor size, advanced age, and urinary marker findings.Within5yrofdiagnosis,theprostaticurethraandductsare secondarily involved in 10–15% of men with high-riskNMIBC [28]. Moreover, on careful pathologic analysis, itcan be observed in more than 40% of cystoprostatectomyspecimens. When CIS or multifocal BC is present, the riskfor prostatic urethral involvement is increased more than12-fold. Tumors involving the prostatic urethra have beenassociated with clinical understaging and shorter survival[29,30].However,patientswithCISoftheprostaticurethraaloneenjoya > 70%CRrateanda47–72%CRratewithbothbladder and prostate involvement [28]. Thus, there isclearly a role for BCG treatment with superficial involve-ment of the prostate. In one prospective study, there was a55% recurrence rate after CR from BCG therapy, but only28% continued to fail local therapy, and disease-specificsurvival (DSS) was nearly 90% at 7.5 yr median follow-up[31].ItisimportanttoliberallyemployTURoftheprostateduringrestagingproceduresinordertoassessforprostaticduct and stromal invasion, which are indications forcystectomy.Tumor size > 3 cm predicted recurrence and progression(HR:1.54and1.89,respectively)inthe2500-patientEORTCstudy by Sylvester et al. [22]. Based on a small, prospectivestudy, there appears to be an independent risk associatedwith tumor size in high-risk (T1G3) tumors [32]. EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) 549–555 552
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