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Review Article| Volume 8, ISSUE 7, P549-555, September 2009

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Intravesical Instillation Treatment of Non–muscle-invasive Bladder Cancer

      Abstract

      Bacillus Calmette-Guérin (BCG) is a proven and valuable adjunct to transurethral resection (TUR) for decreasing recurrence and progression of non–muscle-invasive bladder cancer (NMIBC). The European Association of Urology (EAU) and American Urological Association (AUA) have similar recommendations for induction and maintenance treatment in patients based on clinical and pathologic risk factors. To most effectively treat this disease, clinicians must be aware of the risk factors for treatment failure, strategies to deal with failures and BCG intolerance, and the appropriate threshold to proceed with radical cystectomy (RC). Combination, alternative, and multimodal intravesical treatments for patients with BCG failure have arisen in recent years, and the outcomes data are reviewed here.

      Keywords

      1. Introduction

      Various forms of non–muscle-invasive bladder cancer (NMIBC) comprise >70% of all new bladder cancer (BC) diagnoses [
      • Jones J.S.
      • Campbell S.C.
      Non-muscle-invasive bladder cancer (Ta, T1, CIS).
      ]. About half of these are low-grade, Ta tumors with low risk (<5%) of progression. The others represent more worrisome lesions with higher risk of progression [
      • Sylvester R.J.
      • van der Meijden A.P.
      • 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.
      ].
      Standard treatment consists of transurethral resection of bladder tumors (TURBT), with the addition of intravesical adjuvant therapy when indicated. The most widely used agents include the immunotherapy drugs bacillus Calmette-Guérin (BCG), interferon-α (IFN-α), and the chemotherapy agent mitomycin C (MMC), among others. BCG represents the only agent known to reduce progression into muscle-invasive bladder cancer (MIBC) [
      • Sylvester R.J.
      • van der Meijden A.P.
      • 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.
      ].

      2. Recommendations for treatment-naïve patients

      In patients who have not previously been treated with intravesical agents, induction therapy should be preceded by adequate and safe transurethral resection (TUR) of all visible tumors. Intravesical therapy should never be considered an alternative to satisfactory extirpation. In cases of high-grade T1 disease, it is strongly advised that repeat TURBT be considered 4–6 wk after the original resection, primarily because of frequent clinical understaging and the presence of unresected residual disease. Muscle invasion has been found on re-resection in up to 49% of cases when no muscularis propria was present and in up to 14% of cases when muscle was present in an original T1 tumor [
      • Jakse G.
      • Algaba F.
      • Malmström P.-U.
      • Oosterlinck W.
      A second-look TUR in T1 transitional cell carcinoma: why?.
      ]. Residual disease has been found in 20–40% of cases [
      • 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.
      ]. The European Association of Urology (EAU) has recommended re-resection for all TaT1, high-grade tumors [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ].
      The optimal schedule for BCG remains unknown. Typical induction treatment for BCG-naïve patients begins 2–4 wk after TURBT and consists of six weekly instillations of a full vial of BCG suspension. Using a linear regression model, a dose-response relationship was found wherein at least 12 BCG doses were needed to show superiority over MMC in preventing recurrence [
      • Böhle 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.
      ]. Currently, the general consensus calls for at least 1 yr [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ] and even up to 3 yr of maintenance therapy [
      • 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.
      ], if tolerated.
      The 2007 update to the American Urological Association (AUA) BC guidelines [
      • 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.
      ] and the 2008 EAU guidelines on NMIBC [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ] generally agree on the recommendations for adjuvant immunotherapy in low-, intermediate-, and high-risk NMIBC. A summary of the general recommendations is provided below.

      2.1 Low-risk disease (small volume, primary, low grade, stage Ta)

      Neither the AUA nor the EAU have made BCG therapy a practice standard for this category, which generally includes patients with low to moderate risk of recurrence (≤15%) and very low risk of progression (≤0.2%) at 1 yr [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ]. Surgical eradication of all visible tumors is a standard. The EAU advocates a single dose of intravesical chemotherapy (primarily MMC) postoperatively, but the AUA considers this 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 the intermediate-risk category as defined by the EAU guidelines, with low to moderate risk of progression (≤1% at 1 yr, ≤6% at 5 yr), and recurrence risk of 46–62% at 5 yr [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ]. In general, this would include patients with multifocal, recurrent, and/or large-volume, low-grade Ta (and sometimes T1) disease without carcinoma in situ (CIS) in both the EAU and AUA risk-stratification schemes.
      Both organizations recommend an induction course of either BCG or intravesical cytotoxic chemotherapy (usually MMC), as there is a paucity of data to confirm a distinct advantage of BCG over chemotherapy for this cohort. In addition, the EAU more confidently recommends 1 yr of BCG maintenance or 6–12 mo of maintenance chemotherapy. The AUA considers maintenance therapy with either agent optional but acknowledges the superiority of maintenance over non-maintenance for MMC.

      2.3 High-risk disease (high-grade Ta or T1 and/or carcinoma in situ)

      Little controversy exists about the adequate treatment of high risk tumors, which generally include high-grade T1 tumors, CIS, or a combination of high-grade Ta disease and CIS. In general, this group has a ≤17% risk of progression to MIBC at 1 yr and 45% risk at 5 yr [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ]. Both the EAU and the AUA recommend TURBT (with possible re-resection), followed by induction BCG, and then at least 1 yr of maintenance intravesical therapy. If cytotoxic chemotherapy is chosen instead, induction treatment should be followed by at least 6–12 mo of maintenance therapy. The AUA, although falling short of declaring BCG maintenance the standard of care, emphasizes that there is still a lack of data showing a clear progression advantage over MMC, with maintenance, potential side effects of treatment, and financial burdens that may outweigh the benefits in some patients.
      It is also important to consider the risks and benefits of early radical cystectomy (RC) in this patient cohort. This decision weighs heavily on issues of BCG failure risk and treatment side effects in high-risk patients. These are perhaps the most difficult and disputed treatment dilemmas regarding immunotherapy.

      3. Effectiveness of intravesical treatment in preventing 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 [
      • van der Meijden A.P.M.
      • Sylvester R.
      • Oosterlinck W.
      • et al.
      EAU guidelines on the diagnosis and treatment of urothelial carcinoma in situ.
      ]. Several meta-analyses have shown the superiority of BCG over intravesical cytotoxic chemotherapy (primarily MMC) in preventing tumor recurrence and progression. However, it is essential to institute regular maintenance therapy in order to achieve a significant advantage with BCG therapy [
      • Sylvester R.J.
      • van der Meijden A.P.
      • 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.
      ,
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ]. In a meta-analysis of more than 2700 patients with a median follow-up of 26 mo, the relative risk of recurrence was 0.75 with BCG compared to MMC, which decreased further to 0.64 in subgroups treated with BCG maintenance therapy [
      • Böhle 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.
      ].

      3.2 Carcinoma in situ

      A similar treatment effect is seen in patients with CIS, where BCG remains the treatment of choice. Approximately 5–10% of all NMIBC patients harbor this high-grade and often multifocal form of urothelial carcinoma (UC) [
      • van der Meijden A.P.M.
      • Sylvester R.
      • Oosterlinck W.
      • et al.
      EAU guidelines on the diagnosis and treatment of urothelial carcinoma in situ.
      ]. A meta-analysis of more than 700 patients showed complete response (CR) rates of 68% and 52% and disease-free rates (at 3.6 yr) of 47% and 26% for BCG versus chemotherapy, respectively [
      • Sylvester R.J.
      • van der Meijden A.P.
      • Witjes J.A.
      • Kurth K.
      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.
      ].
      Justification for BCG maintenance treatment can reasonably be extrapolated from papillary carcinoma data. However, it was demonstrated in the Southwest Oncology Group (SWOG) 8507 study that the addition of even one 3-wk maintenance cycle could improve the 6-mo CR rate from 68% to 84% [
      • 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.
      ].

      4. BCG failure

      The decision to employ intravesical immunotherapy, or alternatively, when to abandon treatment, is typically more complex than simply inserting an index patient into the EAU 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 other variables (eg, recurrence patterns, histologic variants, and molecular characteristics) that cannot easily be applied to straightforward algorithms. To fully understand and manage this complex issue, one must be versed on the types of BCG failure and strategies to manage BCG intolerance.

      4.1 Types of bacillus Calmette-Guérin failure

      Traditionally, the term BCG failure has been applied generically in the literature, usually referring to patients who have recurrent disease any time after initiation of therapy. In fact, failure patients can roughly be divided into the categories of BCG intolerant, refractory, resistant, and relapsing disease.
      BCG intolerance is defined as recurrence after an inadequate treatment course, halted prematurely because of symptomatic intolerance or serious adverse events. In contrast, BCG-refractory patients fail to achieve disease-free status by 6 mo after induction with either maintenance or re-induction at 3 mo. This group also includes patients with progression in grade or stage by 3 mo after the first induction cycle. BCG-resistant patients have recurrent or persistent disease (of lesser degree, stage, or grade) after initial induction but then have complete response at 6 mo after TURBT. In essence, the disease initially improves, and then resolves with BCG. In contrast, BCG relapsing patients achieve disease-free status before 6 mo post-TURBT but then have early (within 12 mo), intermediate (12–24 mo), or late (>24 mo) recurrence [
      • O’Donnell M.A.
      • Böhle A.
      Treatment options for BCG failures.
      ].

      5. BCG intolerance

      Serious side effects occur in <5% of all patients undergoing BCG treatment, and a vast majority of these can be effectively treated [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ]. Although a slightly higher rate of side effects has been associated with BCG over MMC, it is estimated that only 5–10% of patients fail to complete induction treatment, and about 5–11% have interruption but eventual completion [
      • Böhle 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.
      ,
      • Ojea A.
      • Nogueira J.L.
      • Solsona E.
      • et al.
      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.
      ]. However, 84% of patients on full-dose BCG using the rigorous SWOG 3-yr maintenance plan did not receive all of their planned doses [
      • 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.
      ].
      BCG toxicity can be divided into local and systemic side effects. Local toxicities are generally more frequent and less severe than systemic toxicity, but they are more often the cause of treatment stoppage [
      • van der Meijden A.P.M.
      • Sylvester R.J.
      • Oosterlinck W.
      • Hoeltl W.
      • Bono A.V.
      for the EORTC Genito-Urinary Tract Cancer Group
      Maintenance bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial.
      ]. However, most local side effects are brief [
      • O’Donnell M.A.
      • Böhle A.
      Treatment options for BCG failures.
      ,
      • Losa A.
      • Hurle R.
      • Lembo A.
      Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results.
      ]. The incidence of local side effects is similar with or without maintenance therapy. For patients who receive or do not receive maintenance therapy, respectively, these include lower urinary tract symptoms (57–71%, 38–59%), hematuria (20%, 29%), and bladder contracture (3%, 1%) [
      • 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.
      ].
      Similarly, others have found no difference in systemic side effects between maintenance and non-maintenance groups [
      • Böhle 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.
      ] and even reduced toxicity in the period after the first 6 mo of treatment [
      • van der Meijden A.P.M.
      • Sylvester R.J.
      • Oosterlinck W.
      • Hoeltl W.
      • Bono A.V.
      for the EORTC Genito-Urinary Tract Cancer Group
      Maintenance bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial.
      ]. Systemic side effects can be divided 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 2007 AUA guidelines update [
      • 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.
      ] include fevers, chills, and flu symptoms (22–30%, 19–26%); epididymitis, prostatitis, and urethral infections (4%, 4%); and systemic infection (7%, 1%) for patients treated with maintenance versus no maintenance, respectively. Less severe systemic toxicities such as fever (>39.5 °C), skin rash, arthralgias, and BCGitis (established BCG infection with organ manifestation [epididymal-orchitis, pneumonitis, hepatitis]) occur at a rate of 2–6% [
      • O’Donnell M.A.
      • Böhle A.
      Treatment options for BCG failures.
      ,
      • Lamm D.L.
      • Stogdill V.D.
      • Stogdill B.J.
      • Crispen R.G.
      Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer.
      ].

      6. Treatment strategies for bacillus Calmette-Guérin intolerance

      6.1 Dose adjustment

      Dose adjustment remains one of the most common methods to manage BCG intolerance and is frequently employed to reduce dropout during maintenance treatments. A one-third dose of BCG showed similar efficacy in preventing recurrence and progression with significantly less toxicity, but there has been some concern about applying this strategy routinely in multifocal and high -risk tumors [
      • Martínez-Piñeiro J.A.
      • Flores N.
      • Isorna S.
      • et al.
      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.
      ,
      • Martínez-Piñeiro J.A.
      • Martínez-Piñeiro 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.
      ]. In one randomized, prospective trial, a one-third dose of BCG was more effective than MMC in preventing recurrence in intermediate-risk disease. However, a 1/6 dose of BCG was less effective without the benefit of decreased toxicity in these patients [
      • Ojea A.
      • Nogueira J.L.
      • Solsona E.
      • et al.
      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.
      ]. Further dose reduction (1/10, 1/30, and even 1/100 of BCG) in combination with IFN-α in patients with severe toxicity may also be efficacious 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 improve tolerance is increasing the instillation interval during induction or maintenance (eg, doubling from 1 to 2 wk). Unfortunately, there is little data on the efficacy of this tactic. One small phase 2 trial showed decreased rates of mild to moderate side effects in the slow-rate group compared to standard rate. Twenty-five percent of patients in the standard rate cohort experienced severe side effects requiring delay of instillation, and 6% required treatment interruption, but no patient required delay or interruption in the slow-rate cohort [
      • Bassi P.
      • Spinadin R.
      • Carando R.
      • Balta G.
      • Pagano F.
      Modified induction course: a solution to side-effects?.
      ].

      6.3 Dwell time

      In patients with significant side effects, Andius et al showed improvement in fevers, chills, dysuria, and overall time to recovery by reducing BCG dwell time from 2 hr to ≤30 min [
      • Andius P.
      • Fehrling M.
      • Holmäng S.
      Intravesical bacillus Calmette-Guérin therapy: experience with a reduced dwell-time in patients with pronounced side-effects.
      ]. Compared to a control group with normal dwell time, these patients had similar tumor-free results. Although this may represent a treatment alternative for patients with BCG intolerance, long-term efficacy data are currently lacking.

      6.4 Pharmacologic

      Most BCG-associated cystitis symptoms can be effectively managed with aspirin, nonsteroidal anti-inflammatory drugs, urinary analgesics, and antispasmodics [
      • O’Donnell M.A.
      • Böhle A.
      Treatment options for BCG failures.
      ]. In addition, 200 mg ofloxacin given 6 and 18 hr after treatment has shown promise in a prospective, placebo-controlled, randomized, controlled trial [
      • 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.
      ]. There was a significant reduction in moderate to severe adverse events during the second half of the BCG induction cycle and severe events throughout the induction and maintenance periods. Despite being tuberculostatic, more patients in the ofloxacin group completed all treatments without an obvious detriment to BCG efficacy. A newer fluoroquinolone antibiotic—prulifloxacin—significantly decreased moderate to severe adverse events and treatment interruption without affecting 6-mo recurrence rates in a prospective, randomized, controlled trial [

      Damiano R, De Sio M, Quarto G, et al. Short-term administration of prulifloxacin in patients with nonmuscle-invasive bladder cancer: an effective option for the prevention of bacillus Calmette-Guerin-induced toxicity? BJU Int. In press.

      ]. Here again, long-term data are lacking.

      7. Refractory, resistant, and relapsing disease in bacillus Calmette-Guérin–naïve patients

      High-risk NMIBC patients undergoing BCG treatment require diligent monitoring, as they face a rather grim fate with disease progression and fare as poorly as, or even worse than, patients who present with primary muscle-invasive disease. A clinician must be mindful of the risk categories for BCG failure when guiding intravesical treatment decisions.

      7.1 Groups at highest risk for bacillus Calmette-Guérin failure

      For patients in the highest risk group, it is suggested that a clinician more strongly consider radical therapy if a patient demonstrates significant BCG intolerance, resistance, or a concerning relapse pattern—particularly in patients with fewer comorbidities. The risk factors most clearly associated with recurrence and progression risk include tumor stage, grade, presence of CIS, recurrence pattern, multifocality, and high-risk histologic variants.
      Large-scale, prospective studies have demonstrated that TNM stage can predict progression. The risk of progression is more than 2× greater for stage T1 versus Ta based on multivariate analysis [
      • Herr H.W.
      • Badalament R.A.
      • Amato D.A.
      • Laudone V.P.
      • Fair W.R.
      • Whitmore Jr., W.F.
      Superficial bladder cancer treated with bacillus Calmette-Guerin: a multivariate analysis of factors affecting tumor progression.
      ]. There are less data to correlate TNM stage with recurrence, however. Similar to stage, tumor grade portends risk of tumor progression. Large-scale, prospective studies have demonstrated a hazard ratio (HR) for progression ranging from 2.7 to 5.8 for G3 disease compared to lower grades [
      • Martínez-Piñeiro J.A.
      • Flores N.
      • Isorna S.
      • et al.
      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.
      ,
      • Sylvester R.J.
      • van der Meijden A.P.M.
      • 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.
      ,
      • Fernandez-Gomez J.
      • Solsona E.
      • Unda M.
      • et al.
      Prognostic factors in patients with non–muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials.
      ].
      Recurrent tumors fare more poorly than grade- and stage-matched primary tumors, and early recurrence carries a worse prognosis than delayed recurrence. Recurrent tumors are about 1.5× more likely to progress to MIBC than primary tumors [
      • Losa A.
      • Hurle R.
      • Lembo A.
      Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder: long-term results.
      ,
      • Sylvester R.J.
      • van der Meijden A.P.M.
      • 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.
      ,
      • Fernandez-Gomez J.
      • Solsona E.
      • Unda M.
      • et al.
      Prognostic factors in patients with non–muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials.
      ]. Multiply-recurrent tumors are an even worse prognostic indicator, carrying an HR of 2.3 for continued recurrence and 2.0 for progression to muscle-invasive disease [
      • Martínez-Piñeiro J.A.
      • Flores N.
      • Isorna S.
      • et al.
      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.
      ]. Recurrence at the first post-treatment cystoscopy is one of the worst prognostic indicators for eventual T stage progression, particularly in the setting of other high-risk factors [
      • Herr H.W.
      • Badalament R.A.
      • Amato D.A.
      • Laudone V.P.
      • Fair W.R.
      • Whitmore Jr., W.F.
      Superficial bladder cancer treated with bacillus Calmette-Guerin: a multivariate analysis of factors affecting tumor progression.
      ,
      • Thalmann G.N.
      • Markwalder R.
      • Shahin O.
      • Burkhard F.C.
      • Hochreiter W.W.
      • Studer U.E.
      Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy?.
      ,
      • Solsona E.
      • Iborra I.
      • Dumont R.
      • Rubio-Briones J.
      • Casanova J.
      Almenar S. The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer.
      ]. Large series have shown that 60–80% of patients with recurrence at first cystoscopy eventually have progression [
      • Solsona E.
      • Iborra I.
      • Dumont R.
      • Rubio-Briones J.
      • Casanova J.
      Almenar S. The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer.
      ,
      • Luo Y.
      • Chen X.
      • Downs T.M.
      • DeWolf W.C.
      • O’Donnell M.A.
      IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving mycobacterium bovis bacillus Calmette-Guérin immunotherapy.
      ,
      • Lockyer C.R.W.
      • Sedgwick J.E.C.
      • Gillatt D.A.
      Beware the BCG failures: a review of one institution's results.
      ].
      Despite the fact that CIS and high-grade papillary disease commonly coexist, CIS is clearly an independent prognostic factor. A large-scale meta-analysis of seven European Organization for Research and Treatment of Cancer (EORTC) trials showed progression rates of 10% at 1 yr and 29% at 5 yr in T1G3 tumors without CIS versus 29% and 74%, respectively, with concomitant CIS. Here, multivariate analysis showed that the presence of CIS yielded a higher HR for tumor progression (HR: 3.41) than grade (2.67) and T category (2.19) [
      • Sylvester R.J.
      • van der Meijden A.P.M.
      • 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.
      ].
      Several studies have shown tumor multiplicity to be a significant predictor for recurrence in BCG-treated patients, with an HR of approximately 1.5 [
      • Martínez-Piñeiro J.A.
      • Flores N.
      • Isorna S.
      • et al.
      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.
      ,
      • Sylvester R.J.
      • van der Meijden A.P.M.
      • 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.
      ,
      • Fernandez-Gomez J.
      • Solsona E.
      • Unda M.
      • et al.
      Prognostic factors in patients with non–muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials.
      ], but only one large-scale study has indicated an importance in progression [
      • Sylvester R.J.
      • van der Meijden A.P.M.
      • 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.
      ]. The prognostic importance is also additive, wherein the risk of recurrence is proportional to the number of tumor foci [
      • Fernandez-Gomez J.
      • Solsona E.
      • Unda M.
      • et al.
      Prognostic factors in patients with non–muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials.
      ].
      There are aggressive histologic features and variants in which BCG treatment should be avoided in favor of early RC. These include lymphovascular invasion, which has been associated with overall decreased survival in cystoprostatectomy patients [
      • Quek M.L.
      • Stein J.P.
      • Nichols P.W.
      • et al.
      Prognostic significance of lymphovascular invasion of bladder cancer treated with radical cystectomy.
      ]. Furthermore, micropapillary variants of UC, squamous cell carcinoma, and adenocarcinoma of the bladder should not be approached like non–muscle-invasive UC and are clearly not appropriate for intravesical immunotherapy. In one series of patients treated with BCG for micropapillary variant, two-thirds progressed to MIBC and almost one-fourth to metastatic disease [
      • Kamat A.M.
      • Dinney C.P.
      • Gee J.R.
      • et al.
      Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson Cancer Center experience with 100 consecutive patients.
      ].

      7.2 Other risk groups for bacillus Calmette-Guérin failure

      There are an admixture of risk factors in which the clinician is urged to be more persistent for resistant/relapsing disease and more creative with adjusted treatment regimens in cases of BCG intolerance. Furthermore, the threshold to abandon immunotherapy for cystectomy may be somewhat higher. However, there is no substitute for cystectomy for refractory disease. The risk factors in this category include prostatic urethral involvement, large tumor size, advanced age, and urinary marker findings.
      Within 5 yr of diagnosis, the prostatic urethra and ducts are secondarily involved in 10–15% of men with high-risk NMIBC [
      • Palou J.
      • Baniel J.
      • Klotz L.
      • et al.
      Urothelial carcinoma of the prostate.
      ]. Moreover, on careful pathologic analysis, it can be observed in more than 40% of cystoprostatectomy specimens. When CIS or multifocal BC is present, the risk for prostatic urethral involvement is increased more than 12-fold. Tumors involving the prostatic urethra have been associated with clinical understaging and shorter survival [
      • Shen S.S.
      • Lerner S.P.
      • Muezzinoglu B.
      • Truong L.D.
      • Amiel G.
      • Wheeler T.M.
      Prostatic involvement by transitional cell carcinoma in patients with bladder cancer and its prognostic significance.
      ,
      • Huguet J.
      • Crego M.
      • Sabaté S.
      • Salvador J.
      • Palou J.
      • Villavicencio H.
      Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor.
      ]. However, patients with CIS of the prostatic urethra alone enjoy a >70% CR rate and a 47–72% CR rate with both bladder and prostate involvement [
      • Palou J.
      • Baniel J.
      • Klotz L.
      • et al.
      Urothelial carcinoma of the prostate.
      ]. Thus, there is clearly a role for BCG treatment with superficial involvement of the prostate. In one prospective study, there was a 55% recurrence rate after CR from BCG therapy, but only 28% continued to fail local therapy, and disease-specific survival (DSS) was nearly 90% at 7.5 yr median follow-up [
      • Taylor J.H.
      • Davis J.
      • Schellhammer P.
      Long-term follow-up of intravesical bacillus Calmette-Guérin treatment for superficial transitional-cell carcinoma of the bladder involving the prostatic urethra.
      ]. It is important to liberally employ TUR of the prostate during restaging procedures in order to assess for prostatic duct and stromal invasion, which are indications for cystectomy.
      Tumor size >3 cm predicted recurrence and progression (HR: 1.54 and 1.89, respectively) in the 2500-patient EORTC study by Sylvester et al. [
      • Sylvester R.J.
      • van der Meijden A.P.M.
      • 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.
      ]. Based on a small, prospective study, there appears to be an independent risk associated with tumor size in high-risk (T1G3) tumors [
      • Hurle R.
      • Losa A.
      • Manzetti A.
      • Lembo A.
      Intravesical bacille Calmette-Guérin in Stage T1 grade 3 bladder cancer therapy: a 7-year follow-up.
      ].
      Like many other cancers (breast, ovarian, thyroid), BC is largely a disease of the elderly. BCG relies heavily on cell-mediated immunity, putting immune-suppressed individuals at higher risk for failure. With BCG monotherapy, Fernandez-Gomez et al showed a negative impact of age on progression to muscle-invasive disease by multivariate analysis (age >60 yr, HR: 1.57; age >70 yr, HR: 1.74) [
      • Fernandez-Gomez J.
      • Solsona E.
      • Unda M.
      • et al.
      Prognostic factors in patients with non–muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials.
      ]. In a large, multicenter, phase 2 trial using combination intravesical BCG plus INF-α, patients over 80 yr of age had statistically lower cancer-free survival at 24-mo follow-up [
      • Joudi F.N.
      • Smith B.J.
      • O’Donnell M.A.
      National BCG-Interferon Phase 2 Investigator Group. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer.
      ]. However, no specific treatment strategies or surveillance protocols have been advised by the AUA or the EAU that differ from those for younger patients.
      Fluorescent in situ hybridization (FISH) is widely available and may be helpful for predicting relapse and progression. One study showed 100% relapse in patients with positive FISH shortly after BCG induction compared to 50% relapse with negative FISH (HR: 4.6) [
      • Kipp B.R.
      • Karnes R.J.
      • Brankley S.M.
      • et al.
      Monitoring intravesical therapy for superficial bladder cancer using fluorescence in situ hybridization.
      ]. Over half of the patients with positive FISH had muscle-invasive disease at relapse. However, another study showed that although the recurrence rate was clearly increased (∼3-fold) by a post-TURBT positive FISH result, the progression rate was not affected [
      • Mengual L.
      • Marín-Aguilera M.
      • Ribal M.J.
      • et al.
      Clinical utility of fluorescent in situ hybridization for the surveillance of bladder cancer patients treated with bacillus Calmette-Guérin therapy.
      ]. Further studies in this area are needed.

      8. Treatment of bacillus Calmette-Guérin–failure patients

      Approximately 30–50% of patients will not respond to BCG treatment or have recurrence within 5 yr, and up to 90% will relapse by 15 yr [
      • Lamm D.L.
      • Griffith J.G.
      Intravesical therapy: does it affect the natural history of superficial bladder cancer?.
      ]. Treatment strategies will depend heavily on the recurrence interval and other risk factors, as previously discussed. The following section is meant to guide the clinician through further treatment options after BCG failure—in particular, when to use and when not to use alternative immunotherapy regimens and intravesical chemotherapy.

      8.1 Radical therapy

      Foremost, the clinician must realize when to abandon immunotherapy in high-risk patients. The decision to proceed with RC for BCG failure is sometimes straightforward, such as in the case of dysfunctional bladder, progression in grade or stage, early recurrence pattern, or when it becomes impossible to cystoscopically control the tumor. At other times, the decision is not so clear, particularly when caring for suboptimal surgical candidates.
      According to the EAU [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ] and AUA guidelines [
      • 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.
      ], cystectomy can be offered to all high-risk patients at initial diagnosis but must be emphasized for BCG-refractory patients. There does not appear to be an overall survival or DSS advantage for early cystectomy over BCG therapy for primary NMIBC, even for high-risk (T1G3) disease [
      • Thalmann G.N.
      • Markwalder R.
      • Shahin O.
      • Burkhard F.C.
      • Hochreiter W.W.
      • Studer U.E.
      Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy?.
      ], though this has not been formally tested in randomized clinical trials. In other words, careful and appropriate use of BCG can always be considered a first-line treatment for primary NMIBC when confirmed by re-TUR and no residual T1 disease.

      8.2 Second induction bacillus Calmette-Guérin

      Patients who recur with the same or lower T stage and grade at 3 mo after induction are not considered treatment failures, as 35% will respond to a second 6-wk BCG induction. Treatment beyond two courses is not recommended and is associated with <20% success and increased chance of disease progression [
      • O’Donnell M.A.
      • Böhle A.
      Treatment options for BCG failures.
      ]. The appearance of higher grade or stage or new diagnosis of CIS during therapy is considered a treatment failure and should prompt discussion about cystectomy [
      • Babjuk M.
      • Oosterlinck W.
      • Sylvester R.
      • Kaasinen E.
      • Böhle A.
      • Palou-Redorta J
      EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.
      ]. However, when recurrence is late (>2 yr after CR), these patients fare nearly as well with re-treatment as with initial BCG [
      • Bui T.T.
      • Schellhammer P.F.
      Additional bacillus Calmette-Guérin therapy for recurrent transitional cell carcinoma after an initial complete response.
      ].

      8.3 Combination bacillus Calmette-Guérin–interferon

      Other intravesical agents, particularly combination BCG–IFN-α or sequential chemotherapy regimens, have arisen as viable treatment options for BCG-resistant and relapsing disease, principally in high-risk cystectomy patients who fail primary therapy. However, they cannot be advocated for true BCG-refractory disease. Noting that BCG owes part of its activity to a T-helper type 1 (TH1) immune response in the bladder, in vitro studies have shown that IFN-α potentiates the TH1 response by inhibiting interleukin-10 (IL-10: a TH1 inhibitory cytokine) [
      • Luo Y.
      • Chen X.
      • Downs T.M.
      • DeWolf W.C.
      • O’Donnell M.A.
      IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving mycobacterium bovis bacillus Calmette-Guérin immunotherapy.
      ]. IFN-α monotherapy has a favorable toxicity profile, but the high cost and reduced efficacy compared to BCG make it an inferior choice for monotherapy [
      • Belldegrun A.S.
      • Franklin J.R.
      • O’Donnell M.A.
      • et al.
      Superficial bladder cancer: the role of interferon-alpha.
      ].
      Combination BCG plus IFN-α has shown promise for treatment of recurrent UC in BCG-resistant and BCG-relapsing patients. A large, multicenter, phase 2 trial demonstrated that 45% of BCG-failure patients were disease free at a median 24-mo follow-up after combination low-dose BCG plus IFN-α (50 million units [MU]) [
      • Joudi F.N.
      • Smith B.J.
      • O’Donnell M.A.
      National BCG-Interferon Phase 2 Investigator Group. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer.
      ]. This compared favorably to the response rate in BCG-naïve patients, where 59% were disease free at 24 mo. Several other studies have shown a 50–60% disease-free rate (12–30-mo follow-up) for BCG plus IFN-α after BCG failure, even in recurrent T1 disease [
      • Punnen S.P.
      • Chin J.L.
      • Jewett M.A.
      Management of bacillus Calmette-Guerin (BCG) refractory superficial bladder cancer: results with intravesical BCG and Interferon combination therapy.
      ,
      • O’Donnell M.A.
      • Krohn J.
      • DeWolf W.C.
      Salvage intravesical therapy with interferon-alpha 2b plus low dose bacillus Calmette-Guerin is effective in patients with superficial bladder cancer in whom bacillus Calmette-Guerin alone previously failed.
      ,
      • Lam J.S.
      • Benson M.C.
      • O’Donnell M.A.
      • et al.
      Bacillus Calmette-Guérin plus interferon-alpha2B intravesical therapy maintains an extended treatment plan for superficial bladder cancer with minimal toxicity.
      ]. For patients with CIS, the 24-mo disease-free rate after BCG plus IFN-α compared favorably between patients failing one previous course of BCG (57%) and BCG-naïve patients (60%) [
      • Maymí J.L.
      • O’Donnell M.A.
      for the National BCG/Interferon Investigator Group. Factors affecting response to BCG plus interferon in patients with urothelial carcinoma in situ.
      ].
      The early reports from a large, multicenter, randomized, controlled trial do not find a clear advantage for combination BCG plus IFN-α therapy in treatment of NMIBC in BCG-naïve patients. The unpublished results were presented at the 2008 AUA National Meeting [
      • Lamm D.L.
      • O’Donnell M.A.
      Multicenter randomized comparison of BCG with or without alfa 2b interferon (IFN) and Oncovite (Onc) versus recommended daily allowance (RDA) vitamins during induction and extended 3-week maintenance.
      ]. The study randomized more than 600 individuals to recommended daily allowance or high-dose antioxidant vitamins and also to induction plus 3 yr of maintenance using either BCG monotherapy or BCG plus IFN-α (50 MU). The results showed no significant difference in tumor recurrence with the addition of IFN-α versus supplementation with high-dose antioxidant vitamins for BCG monotherapy patients. Further investigation in this area is needed.
      BCG plus IFN-α therapy is well tolerated and compares favorably to BCG monotherapy. In one study, serious side effects were reported in 6.2% and 4.8% of BCG-naïve and BCG-failure patients, respectively [
      • O’Donnell M.A.
      • Lilli K.
      • Leopold C
      National Bacillus Calmette-Guerin/Interferon Phase 2 Investigator Group. Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer.
      ]. Severe symptoms occurred in <2% of patients during maintenance therapy in both groups. In all, ≤10% patients reported moderate to severe symptoms, and ≤36% reported moderate symptoms, even through the duration of three maintenance cycles. Less than 5% of BCG-failure patients had permanent termination of therapy resulting from toxicity, and <5% required dose reduction.

      8.4 Intravesical chemotherapy

      Several chemotherapeutic agents (MMC, valrubicin, gemcitabine) have shown durable response rates of ≤21% when used as monotherapy after BCG failure [
      • Malmström P.U.
      • Wijkström H.
      • Lundholm C.
      • Wester K.
      • Busch C.
      • Norlén B.J.
      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.
      ,
      • Steinberg G.
      • Bahnson R.
      • Brosman S.
      • Middleton R.
      • Wajsman Z.
      • Wehle M.
      Efficacy and safety of valrubicin for the treatment of bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group.
      ,
      • Dalbagni G.
      • Russo P.
      • Bochner B.
      • et al.
      Phase II trial of intravesical gemcitabine in bacille Calmette-Guérin-refractory transitional cell carcinoma of the bladder.
      ]. Better results have been observed with sequential gemcitabine-MMC regimens [
      • Maymí J.L.
      • Saltsgaver N.
      • O’Donnell M.A.
      Intravesical sequential gemcitabine-mitomycin chemotherapy as salvage treatment for patients with refractory superficial bladder cancer.
      ] but have not been substantiated by large prospective trials. In addition, a recent prospective trial using docetaxel induction along with nine monthly maintenance treatments in BCG-failure patients showed a 46% disease-free rate at 13 mo follow-up [

      Barlow L, McKiernan J, Sawczuk I, Benson M. A single-institution experience with induction and maintenance intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to bacille Calmette-Guérin therapy. BJU Int. In press.

      ]. Again, large-scale and long-term studies on treatment durability are needed. Finally, device-assisted therapies such as thermochemotherapy, electromotive drug administration, and photodynamic therapy have shown promise but await randomized, controlled trials before they will be used large scale [

      Barlow L, McKiernan J, Sawczuk I, Benson M. A single-institution experience with induction and maintenance intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to bacille Calmette-Guérin therapy. BJU Int. In press.

      ].

      9. Conclusions

      NMIBC is a heterogeneous disease encompassing a number of treatment variables. In the case of intermediate- and high-risk cases, the current standard of care is adjuvant BCG after adequate TUR. However, this treatment carries an inherent toxicity profile that limits the ability to deliver the necessary treatment to some individuals. In addition, there are certain risk factors for tumor progression and recurrence despite therapy. It is important for practitioners to grasp alternative treatment strategies to circumvent side effects and to firmly understand risk categories for treatment failure.

      Conflicts of interest

      The authors have nothing to disclose.

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