Intravesical therapy for bladder cancer.

Review

Intravesical therapy for bladder cancer Sanjay G Patel†, Andrew Cohen, Adam B Weiner & Gary D Steinberg 1.

Introduction

2.

Management of non-muscle-invasive bladder

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Guelph on 03/30/15 For personal use only.

cancer 3.

Immunotherapy

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Intravesical chemotherapy

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New developments

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Expert opinion

University of Chicago Medical Center, Department of Surgery, Section of Urology, Chicago, IL, USA

Introduction: Transurethral resection of bladder tumor (TURBT) is the gold standard initial diagnostic intervention for bladder cancer and provides diagnostic, therapeutic and prognostic benefit in non-muscle-invasive bladder cancer (NMIBC). However, TURBT alone is inadequate for optimal management of NMIBC, as patients will experience recurrence or progression depending on tumor characteristics. Adjuvant intravesical therapy with either immunotherapy or chemotherapy has been shown to reduce recurrence and/or progression in appropriately selected patients through immunostimulation or direct cell ablation. Areas covered: This review will discuss risk stratification of patients with NMIBC and role of intravesical therapies in reducing recurrence and progression of disease in these patients. A Medline search was performed to identify the best available evidence available from various systematic reviews, metaanalyses, and clinical trials on various immunotherapy and chemotherapy agents. In addition, the main aspects of drug pharmacology (mechanism of action, dosing and administration) and side effects will be reviewed. Expert opinion: The selection of the appropriate intravesical agent for NMIBC is complex and is dependent on risk stratification and intravesical agent toxicity. Intravesical induction and maintenance immunotherapy with Bacillus Calmette--Guerin (BCG) is the preferred and most effective agent for patients with high-risk NMIBC (carcinoma in situ and high-grade disease) and reduces both recurrence and progression. Keywords: chemotherapy, immunotherapy, intravesical, therapeutics, urothelial neoplasms Expert Opin. Pharmacother. (2015) 16(6):889-901

1.

Introduction

In 2014, there were an estimated 74,690 new cases of bladder cancer with 15,580 bladder cancer associated deaths in the US [1]. Bladder cancer most commonly occurs during the seventh decade of life in a 3:1 male-to-female ratio. The disease is the fourth most common cancer in men and eleventh among women. Overall, it is the eighth leading cause of cancer death among men [1]. The most common histology of bladder cancer is urothelial carcinoma, which comprises 90% of bladder cancer histology [2]. The initial evaluation of bladder cancer is transurethral resection of bladder tumor (TURBT), which is diagnostic, therapeutic and prognostic. Approximately 25% of bladder cancer cases are muscle invasive at the time of diagnosis for which radical cystectomy with urinary diversion is the gold standard treatment. For the 75% of bladder cancer cases that are non-muscle invasive (non-muscle-invasive bladder cancer, NMIBC), management consists of a combination of TURBT and intravesical therapy. The choice of intravesical agents, duration and timing of administration are largely determined based on tumor characteristics, grade and stage. The current article will elaborate on the intravesical management strategies for NMIBC. 10.1517/14656566.2015.1024656 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Transurethral resection of bladder tumor is the gold standard initial diagnostic intervention for bladder cancer and provides diagnostic, therapeutic and prognostic benefit in non-muscle-invasive bladder cancer (NMIBC). Given NIMBC represents cancers with heterogeneous biologic behavior and aggressiveness, risk stratification based on tumor size, recurrence, grade and stage may inform treatment management decisions. Immediate postoperative instillation of intravesical chemotherapy in patients with low-risk tumors is controversial and may prevent tumor recurrence. Perioperative chemotherapy should not be administered in patients with suspected bladder perforation. Intermediate-risk NIMBC may be treated with up to 1 year of Bacillus Calmette--Guerin (BCG) or intravesical chemotherapy. Patients with high-risk NIMBC will benefit from BCG + maintenance therapy. There is no role for an immediate perioperative dose of intravesical chemotherapy. Current evidence suggests BCG may prevent progression and recurrence while intravesical chemotherapy reduces recurrence alone. Early cystectomy in patients with high-risk disease who develop recurrence after intravesical therapy should be strongly considered. New delivery systems or oncolytic viruses may revolutionize the future of intravesical therapy.

2. Management of non-muscle-invasive bladder cancer

Transurethral resection TURBT is the gold standard initial diagnostic intervention for bladder cancer and provides both therapeutic benefit and prognostic information to guide further management of NMIBC [3]. Clinical staging of bladder cancer is based on depth of tumor penetration from TURBT specimens according to the American Joint Committee on Cancer TumorNode-Metastases guidelines [4]. NMIBC includes tumors confined to the bladder mucosa and are frondular in appearance (Ta) or invading the lamina propria (T1). Tumors that appear as red, velvety patches and are confined to the mucosa are referred to as in situ tumors (Cis). Resection of bladder tumors should be performed to ensure complete resection of the mass with depth of resection to the muscle layer [5,6]. In T1 TURBT specimens without muscle present, > 50% of patients will have residual tumor or missed muscle-invasive disease present [7,8]. Both the American Urologic Association (AUA) and European Urologic Association (EUA) guidelines recommend repeat resection 1 -- 6 weeks after initial resection in patients with incomplete resection, high-grade Ta tumors, and all T1 tumors [9,10]. 890

Fluorescence-guided biopsies Fluorescence-guided biopsies after intravesical instillation of 5-aminolaevulinic acid or hexaminolevulinic acid have been shown to augment resection of bladder masses compared to traditional white light cystoscopy, especially with carcinoma in situ (Cis) lesions. One systematic review demonstrated fluorescence-guided biopsies compared to white light cystoscopy provided an additional 39 and 20% detection rate for CIS and all tumors, respectively [14]. While fluorescenceguided biopsies have been shown to reduce recurrence in patients with NMIBC, it has not yet been shown to affect progression or survival [15]. 2.3

Risk stratification Risk stratification in patients with NMIBC is paramount as these tumors have heterogeneous biologic behavior and aggressiveness. Sylvester et al. developed a risk stratification model to predict recurrence and progression for patients based on 2596 patients from seven European Organization for Research and Treatment of Cancer (EORTC) trials [16]. Tumors probability of recurrence and progression risk can be calculated using tumor size, prior recurrence, T stage, CIS presence and tumor grade (tool available for download: http://www.eortc.be/tools/bladdercalculator/) [16]. Different risk stratification groups have been proposed largely based on tumor size, recurrence, grade and stage by the AUA, EUA and International Bladder Cancer Group (IBCG) [9,10,17]. Theses governing bodies listed above, however, are not perfectly aligned in their risk stratification methodology. 2.4

This box summarizes key points contained in the article.

2.1

Pathologic evaluation Pathologists evaluating bladder resection specimens should report the grade, depth of invasion, and whether muscle was present in the specimen [11,12]. Care should be taken by urologists to ensure TURBT specimens have minimal electrocautery damage to allow for more accurate pathologic evaluation. Furthermore, pathologic re-evaluation of TURBT slides at another institution was shown to alter the management of one out of three patients [13]. As such, additional pathologic opinions should strongly be considered in these patients. 2.2

Article highlights.

AUA risk stratification In the AUA guidelines on NMIBC, risk is defined through ‘index patients’ reflecting commonly encountered clinical scenarios. Low risk index patients are defined as patients with solitary low-grade Ta tumors; whereas, high-risk patients are defined as patients with CIS, high-grade papillary, and or high-grade T1 tumors. Intermediate risk patients are defined as having multifocal or large-volume Ta disease or recurrent Ta disease. 2.4.1

Expert Opin. Pharmacother. (2015) 16(6)

Intravesical therapy for bladder cancer

2.4.2

EUA risk stratification

The EUA guidelines define low-risk tumors as low-grade Ta tumors < 3 cm; while, high-risk tumors are defined as any high-grade Ta/T1 tumor, CIS and or any recurrent low-grade Ta tumor > 3 cm. Intermediate risk tumors are any tumor with characteristics between low and high risk. Furthermore, risk stratification is also performed based on calculated risk of recurrence or progression scores. IBCG risk stratification The IBCG guidelines define low risk as any solitary, lowgrade Ta tumors, intermediate risk as multiple or recurrent Ta tumors, and high-risk tumors as any high-grade Ta/T1 tumor or CIS.


2.4.3

Adjuvant intravesical therapy Adjuvant intravesical therapy has become standard for most patients with NMIBC after TURBT. Adjuvant agents are easily administered to the bladder via catheterization. This allows direct contact of the agent with the bladder, minimizing systemic toxicities associated with intravenous therapies. While intravesical therapy may reduce tumor replantation, recurrence, progression and/or eradicate residual disease, it should never be viewed as an alternative to a thorough surgical resection via TURBT in patients with Ta or T1 disease. Conversely, in patients with CIS, intravesical therapy is the primary therapeutic measure as TURBT is cannot completely treat all viable disease. The nomenclature for administration of intravesical therapy is generally defined as perioperatively (within 24 h of TURBT), induction (initial course) and maintenance (subsequent courses). Various agents have been employed as adjuvant therapy and can be divided into two broad categories: immunotherapy and chemotherapy. Immunotherapeutic agents such as Bacillus Calmette--Guerin (BCG) and IFN a-2b incite a massive local immune response within the bladder. The therapeutic effects of chemotherapy agents such as mitomycin C (MMC), doxorubicin/epirubicin/valrubicin, gemcitabine and thiotepa result from bladder tumor cell cycle interference. The remainder of this review will highlight the available literature on mechanism of action, preparation, administration, indications for treatment, side effects, and impact on disease recurrence and progression of the most commonly used intravesical therapies. 2.5

3.

Immunotherapy

Bacillus Calmette--Guerin BCG was initially discovered by Albert Calmette and Camille Guerin in 1921 after attenuating a mycobacterium strain of Mycobacterium bovis [18]. This attenuated strain was later developed into a vaccine for tuberculosis. In 1976, Morales et al. demonstrated favorable recurrence patterns in nine bladder cancer patients treated with both intradermal 3.1

and intravesical administration of BCG [19]. Morales et al. administered a 120-mg dose a 6-week weekly course. Side effects from therapy generally lasted < 1 week, so a weekly frequency was selected. Moreover, a 6-week course was selected because the delayed hypersensitivity reaction on the intradermal injection sites and the bladder were not enhanced beyond 5 -- 6 treatments [18]. Brosman et al. demonstrated in 1982 similar effectiveness of BCG without the intradermal administration and the concurrent intradermal dose has since been abandoned [20]. Mechanism of action While BCG has been used for over 30 years in the treatment of NMIBC, the exact mechanism of action remains uncertain. BCG therapy requires an intact immune system and contact with bladder cancer cells. Upon instillation, BCG binds to dendritic cells and to fibronectin located in the extracellular matrix of urothelial cells [21]. The BCG is internalized by urothelial and dendritic cells and results in antigen presentation as well as release of cytokines such as IL-2, IL8, GM-CSG and TNF-a [22]. Immune cells (CD4+ and CD8+ lymphocytes, NK cells and granulocytes) are recruited and subsequently result in a local inflammatory response and cell death. Direct cytotoxic effects of the BCG therapy have been shown in in vitro studies and also may complement the immune response [23]. Approximately 40% of patients treated with intravesical BCG will have conversion of purified protein derivative skin test [24]. 3.1.1

Preparation/administration BCG is a lyophilized powder stored in a refrigerated form, which requires dissolution in 50 cc of normal saline, prior to intravesical administration. Several different strains exist, all derived from the original strain developed by Albert Calmette and Camille Guerin: Connaught, Tice, Armand Frappier, Pasteur, Tokyo and RIVM. Dosing varies from strain to strain, but there is no consensus as to whether one particular strain is superior to another. BCG is prepared in a syringe and administered via urethral catheter. Systemic absorption of BCG can occur; thus, it is recommended to wait 2 -- 4 weeks after TURBT to allow for re-epithelialization of the bladder. Similarly, it is advisable to delay therapy 1 -- 2 weeks in the setting of urinary tract infection or traumatic Foley placement. Patients are encouraged to retain the BCG for 2 h and to empty their bladder into a toilet with bleach to avoid contact infection. 3.1.2

Indications for treatment BCG is not recommended for management of low-risk patients (low-grade Ta bladder cancer) as there is general agreement that the risks of therapy outweigh the benefits. A single, immediate postoperative instillation of chemotherapy is recommended for patients with low-risk disease and will be discussed later in this review [9,10,17]. 3.1.3


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In patients with high-risk disease (any high-grade tumor or CIS), BCG induction therapy followed by maintenance therapy for 1 year is recommended [9,10,17]. BCG induction plus maintenance therapy is a first-line therapy for CIS of the bladder and is the only FDA approved agent for the management of CIS [9,10,17]. A meta-analysis of clinical trials comparing BCG to intravesical chemotherapy (MMC, epirubicin or adriamycin) in patients with CIS published by Sylvester et al. demonstrated 68% of patients on BCG therapy had a complete response. Those administered BCG had a 47% reduction in the odds of nonresponse with BCG compared to chemotherapy. Furthermore, in complete responders, BCG was shown to have a reduction of 53% in the odds of recurrence [25]. Nonetheless, recurrence rates at 10 years remain high at 70%, stressing the importance of routine surveillance in these patients [26]. There is a lack of consensus on treatment of patients with intermediate risk tumors regarding BCG therapy. In general, guidelines recommend administering either BCG induction and maintenance therapy or adjuvant intravesical chemotherapy for 6 months to 1 year [9,10,17]. Side effects Adverse effects arising from intravesical therapy with BCG manifest locally and systemically and account for about one-third of treatment discontinuations [27]. Frequent local effects include cystitis-like irritative voiding symptoms, frequency and hematuria. In most instances, these symptoms occur simultaneously [28]. Rare but more severe local symptoms include bladder contracture, ureteral obstruction, epididymo-orchitis and granulomatous prostatitis. While the former two are commonly self-limited with resolution following BCG withholding, the latter two often require further treatment. Granulomatous prostatitis occurs in 1 -- 3% of patients. About 5% of these patients will be symptomatic. Epididymo-orchitis occurs in < 1% of patients and requires treatment. Both may require rifampin, isoniazid, high-dose fluoroquinolones and corticosteroids [28,29]. Systemic effects tend to occur less frequently but with greater severity. Skin rash and arthralgia occur in < 1% of patients, are considered allergic reactions and can be managed with antihistamines and anti-inflammatory medications [29]. Minor systemic effects such as low-grade fever, malaise and other influenza-like symptoms may occur in up to onequarter of patients. These symptoms and even high-grade fever usually occur within 24 h of instillation and can be managed with antipyretics and supportively [29]. However, any high-grade fever lasting > 48 h should be evaluated for systemic nosocomial infection [30]. Granulomatous pneumonitis and hepatitis may occur in this setting and can be evaluated with a chest radiograph and measuring liver enzymes. Disseminated BCG infection is the most severe systemic side effect. Patients present with signs of sepsis, including circulatory and respiratory distress as well as disseminated intravascular coagulopathy [29]. 3.1.4

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Patients with a suspected disseminated BCG infection require immediate pan-culture, supportive care often in the intensive care unit, and subsequent administration of isoniazid 300 mg/day, rifampicin 600 mg/day, and ethambutol 1200 mg/day for 6 months in addition to fluoroquinolone and corticosteroid therapy [30]. These patients should not be exposed to BCG for further bladder cancer treatment. Strategies to minimize the more common local and systemic side effects include waiting 2 weeks post-TURBT before instillation and prophylaxis with fluoroquinolones [28]. Colombel et al. demonstrated prophylactic ofloxacin reduced several local and systemic side effects as well as treatment discontinuation without affecting 1 year recurrence or progression rates [31]. Data from the EORTC Genito-Urinary Cancers Group suggests reducing the BCG dose to one-third did not affect side effects or treatment discontinuation, even when stratified by length of treatment [27]. The trial also noted a large decrease in the number of patients discontinuing treatment over time, which the authors attribute to improved drug administration techniques among health-care providers [27,32]. This point highlights the importance of proper instructions for good techniques to reduce treatment side effects.

Impact on disease recurrence A broad volume of evidence demonstrates intravesical BCG therapy reduces risk of recurrence compared to TURBT alone. In a systematic review of six trials comparing TURBT + BCG versus TURBT alone for Ta/T1 bladder cancer, odds of recurrence were reduced by 56% in the TURBT + BCG-treated patients [33]. Similarly, Han et al. showed 36% reduction in recurrence with BCG versus TURBT alone in a review of nine trials [34]. Several meta-analyses have demonstrated the superiority of BCG over MMC with regard to tumor recurrence [35-37]. In a review of 11 studies, Bohle et al. showed superiority of BCG versus MMC in reducing tumor recurrence (odds ratio [OR]: 0.56, 95% CI: 0.38 -- 0.84) with a more pronounced reduction in six studies with patients receiving BCG maintenance therapy (OR: 0.43, 95% CI: 0.35 -- 0.53) [35]. In another meta-analysis, BCG was only superior to MMC in preventing recurrence of NMIBC if BCG was given with at least one additional series of BCG. This led to a 32% reduction in risk of recurrence [37]. Another meta-analysis demonstrated BCG’s superiority to MMC in patients with high-risk tumors (defined as having high grade, size > 3 cm, and/or prior recurrence) [36]. In one randomized controlled trial with long-term follow-up of up to 20 years, patients who underwent BCG therapy had decreased recurrence rates compared to those treated with MMC [38]. BCG also had more favorable recurrence rates in two randomized controlled trials comparing BCG to epirubicin [39] and to epirubicin plus IFN [40]. 3.1.5




3.1.6

Impact on disease progression

Current evidence suggests BCG therapy delays and in some studies prevents tumor progression. Sylvester et al. reported in a meta-analysis of 24 trials a 27% reduction in progression at 2.5 years in patients with BCG therapy versus non-BCG intravesical therapy [40]. In a meta-analysis of five clinical trials comparing BCG versus MMC, only BCG + maintenance therapy for at least 1 year was superior in preventing tumor progression [41]. However, in another meta-analysis analyzing individual patient data of 1880 patients there was no difference in progression between patients treated with BCG versus MMC [37]. In one randomized clinical trial of patients with NMIBC treated with TURBT versus TURBT + BCG therapy, there was no statistical difference in progression at 15 years follow-up with a median progression-free survival of 101 versus 90 months in the BCG versus TURBT groups [42]. The conflicting results regarding progression in patients treated with BCG may reflect the varying definitions of progression, different schedules of BCG therapy administered and the varying baseline tumor characteristics of patients included in these studies [43].

Optimizing therapy There is no consensus on the optimal schedule and duration for BCG therapy [44]. An induction course of 6 weekly doses of BCG as proposed by Morales et al. provides an immune response lasting 6 months [19]. Further maintenance courses of BCG enhance the immune response and have been shown to reduce the rates of recurrence and progression [40,41]. Various maintenance regimens have been proposed with maintenance lasting from 1 to 3 years and frequencies ranging from every 1 to 6 months [45-47]. In a SWOG trial, Lamm et al. demonstrated patients with induction BCG + maintenance (three instillations at 3, 6, 12, 18, 24, 30 and 36 months) had improved recurrence and progression-free survival; however, the toxicity of the regimen only allowed 16% to complete the full maintenance course [46]. Bohle et al. demonstrated that BCG maintenance doses of at least 1 year had improved progression and recurrence compared to MMC [41]. Dose reduction and shorter maintenance courses have been studied in efforts to reduce toxicity. In a randomized controlled trial by Oddens et al., one-third dose BCG was not inferior to full dose and 1 year was not inferior to 3 years of BCG maintenance therapy with regard to recurrence free survival. Only patients in the study arm with full-dose BCG for 3 years had improved recurrencefree survival compared to 1 year of one-third dose maintenance therapy suggesting that one-third dose therapy with 1 year of maintenance is suboptimal treatment [48]. There were no differences in progression or survival for patients treated with 1 versus 3 years of full-dose therapy [48]. 3.1.7

The Club Urolo´gico Espanõl de Tratamiento Oncolo´gico (CUETO) group studied the effects of reduction of BCG to one-third normal dose (27 mg) versus normal dose BCG (81 mg) and observed similar recurrence and progression rates with reduced toxicities suggesting reduction one-third dose is safe in scenarios where patients are unable to tolerate full-dose BCG [49]. However, in a recent prospective EORTC study there was no difference in side effects between patients treated with one-third dose versus full-dose BCG [27]. In a multicenter prospective randomized trial, comparing one-sixth dose BCG versus one-third dose BCG versus MMC in intermediate risk patient, one-third dose BCG was the minimum effective dose in preventing recurrence [50]. BCG failure Approximately 40 -- 50% of patients treated with BCG will experience BCG failure within the first year of treatment [51]. Once failure occurs, the options for management are radical cystectomy or bladder preservation therapies with alternative intravesical therapies. The decision on which treatment path to take largely depends on the patient’s ability to tolerate radical cystectomy, preference to maintain bladder, and a variety of clinical/pathologic factors associated with progression: female sex, increased age, associated CIS, disease detectable at 3 months and timing of failure [52-55]. All patients with BCG failure should have a recommendation to undergo radical cystectomy prior to further progression of their disease. If timely radical cystectomy is performed prior to muscle invasion, disease-specific survival is > 90% versus 70% in those upstaged to muscle-invasive disease [56]. In patients desiring bladder preservation, repeat BCG instillations can be administered with response rates up to 50 -- 60% provided that the tumors are not T1 [57]. The benefit of more than two BCG courses is low and should not be performed [58]. The role of BCG combined with IFN in BCG failures will be discussed in the next section. Salvage intravesical chemotherapy options will be discussed in the intravesical chemotherapy section. 3.1.8

IFN IFN exacts antitumorigenic effects through its antiproliferative and immune system enhancing activity [59]. IFN is dosed as 50 -- 100 million units (MU). IFN monotherapy in patients with NMIBC is not as effective as current standard therapies for preventing recurrence. In a randomized controlled multicenter trial, 50 MU of IFN was less effective than MMC in preventing median time to recurrence (36 versus 21 months) [60]. Furthermore, a single immediate postoperative dose of 50 MU of IFN did not reduce recurrence compared to TURBT alone [61]. BCG therapy was more effective than 54 MU IFN in patients with recurrent pT1 tumors [62]. Combination therapy with BCG and IFN has been shown to work synergistically with BCG in enhancing the immune 3.2


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response [63,64]. Furthermore, IFN may enhance tumor treatment by downregulating angiogenesis-related genes and upregulating TNF-related apoptosis [65,66]. Pharmacologically mixing BCG and IFN does not impair either agent’s biologic activity [67]. Adding IFN to BCG in BCG naı¨ve patients increases side effects without benefit. In the only randomized controlled trial comparing the BCG monotherapy versus BCG + 59 MU IFN in BCG naı¨ve patients there were no difference in recurrence between the two groups at 2-year follow-up, but there were increased side effects in the group treated with combination therapy [68]. Combination BCG + IFN therapy may have a role in patients who have failed BCG therapy. In patients with prior BCG failure two prospective single-arm studies demonstrated favorable recurrence-free survival in patients with BCG + 50 MU IFN: 60% at 22 months median follow-up [69] and 53% at 24 months [70]. In a Phase II study evaluating combination standard BCG + IFN in BCG naı¨ve patients and reduced-dose BCG + IFN in patients with prior BCG failure, combination therapy was effective in both groups with two-year recurrence-free survival of 59% in BCG naı¨ve patients and 45% in patients with prior BCG failure [71]. The side effect profile for IFN is similar to BCG but less severe, with mild-to-moderate flu-like symptoms the most common [59]. Monotherapy with IFN is inferior to standard therapy with MMC and BCG. Combination IFN and BCG therapy do not appear effective in BCG naı¨ve patients but may have a role in patients with BCG failure. Further prospective trials are needed to better define the role of combination IFN + BCG therapy. 4.

Intravesical chemotherapy

Intravesical chemotherapy’s primary role is in preventing recurrence when administered as an immediate postoperative agent. Its role in the adjuvant setting, however, is not as definitive as BCG is more efficacious particularly in higher risk patients as described in the previous section. In patients who fail BCG therapy, intravesical chemotherapy has been used with promising results; however, these patients are at high risk of progression and should undergo close surveillance with low threshold to perform radical cystectomy [72,73]. Perioperative intravesical chemotherapy Immediate intravesical chemotherapy administration is believed to eradicate tumor cells at the resection site and reduce implantation of circulating tumor cells after TURBT [74]. In two large randomized trials, one with immediate MMC instillation and the other with epirubicin instillation after TURBT, there were reductions in the recurrence of NMIBC [75,76]. Sylvester et al. showed in a meta-analysis of 1746 patients treated with intravesical chemotherapy (epirubicin doxorubicin, MMC, or thiotepa) a 12% absolute 4.1

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risk in recurrence if given within 24 h of TURBT compared to TURBT alone [77]. In two subsequent trials, the reduction of recurrence with immediate intravesical chemotherapy appears to be limited to patients with smaller and/or solitary tumors; however, these studies were underpowered to detect any recurrence benefit [78,79]. Perioperative instillation is a matter of controversy and that a new meta-analysis is needed to better define the role of intravesical chemotherapy. Guideline recommendations from the IBCG, AUA and EUA recommend immediate postoperative instillation for all patients with low-risk tumors and select patients with intermediate risk tumors for prevention of tumor recurrence. Patients with high-risk tumors do not benefit from immediate instillation of intravesical chemotherapy and should undergo BCG induction + maintenance therapy [9,10,17]. Adjuvant intravesical chemotherapy A single dose of intravesical chemotherapy is insufficient for intermediate risk tumors at higher risk for recurrence and progression. Adjuvant intravesical chemotherapy has been shown to reduce the risk of recurrence compared to TURBT alone. In a meta-analysis of 3703 patients from 11 randomized trials with Ta and T1 tumors treated with adjuvant intravesical chemotherapy for 1 --2 years, there was 44% reduction in tumor recurrence at 1 year [80]. In an AUA meta-analysis, there was an 18% reduced recurrence rate in patients treated with MMC + maintenance compared to TURBT alone [10]. Despite the available studies, there is not enough high-quality evidence to reach a consensus on the frequency, and duration of adjuvant chemotherapy [81]. It is important to note that there is no evidence to support the benefit of tumor progression from adjuvant intravesical chemotherapy. Currently guidelines suggest that patients with intermediate risk tumors undergo adjuvant intravesical therapy with either chemotherapy or BCG. While there is no consensus on the duration of intravesical chemotherapy, a maximum of 12 months has been recommended [9,10,17]. 4.2

Intravesical chemotherapy in patients with BCG failures

4.3

Valrubicin is an FDA-approved intravesical chemotherapy agent for patients with BCG refractory CIS in patients unfit for radical cystectomy [72]. Valrubicin was voluntarily removed from the market in 2002 due to manufacturing issues and was reintroduced in 2009 [82]. In its initial Phase III study, 90 patients who previously failed at least one course of BCG and had recurrent CIS were given 6 weekly instillations of 800 mg of Valrubicin. Twenty-one percent of patients had a complete response at 6 months [72]. Gemcitabine is a standard systemic chemotherapy agent used to treat patients with bladder cancer in both the neoadjuvant and adjuvant settings. It also has shown promise as an intravesical agent to treat patients who previously have failed BCG [83,84]. Di Lorenzo et al. reported lower recurrence




rates in patients treated with gemcitabine (2000 mg in 50 ml) versus BCG (87.5 vs 52.5%; p = 0.002) in a multicenter prospective randomized trial of patient who had previously failed one course of BCG therapy [73]. In a Phase III randomized clinical trial of patients with prior BCG or epirubicin failure, 6 weeks of intravesical gemcitabine therapy improved recurrence-free survival compared to 4 weeks of MMC at a median follow-up time of 36 months (72 versus 61%) [85]. A recent Phase II trial of patients who failed two prior BCG courses demonstrated no recurrence in 28% of patients at 1 year who received induction 6-week gemcitabine followed by monthly courses for up to 1 year [86]. Intravesical gemcitabine is an alternative therapy to consider in patients with BCG failure, however, further Phase III studies are need to better determine long-term durability and whether it prevents progression. 4.4

Intravesical chemotherapy agents Mitomycin C

4.4.1

The MMC is an alkylating chemotherapeutic agent derived from Streptomyces caespitosus that inhibits DNA synthesis leading to DNA degradation and cell death [87]. MMC is dosed by adding 20 mg of MMC to 40 cc of water. The agent is instilled via gravity through a urethral catheter. MMC has several common side effects including chemical cystitis (dysuria, frequency and urgency), hematuria, fatigue and a rash from direct contract of the drug with skin [88]. Suitable precautions should be taken to dispose of this agent. In patients with extravasation of MMC, pelvic pain, fibrosis and ulceration can develop and thus MMC should not be administered if perforation is suspected [89].

Gemcitabine can lead to largely minor side effects, including dysuria, hematuria, urinary retention, fatigue and headache; leukopenia is also possible [99]. Optimizing intravesical chemotherapy Thermochemotherapy is used to describe delivery of MMC in combination with radiofrequency induced bladder wall hyperthermia, which has been previously shown to improve drug effects and improved penetration into the bladder wall with minimal toxicity [100]. In patients with NMIBC the use of the Synergo thermochemotherapy system has demonstrated improved recurrence in patients who underwent MMC with thermochemotherapy versus MMC alone [101]. Most recently in 2014, Arrends et al. reported favorable 1- and 2-year recurrence-free survivals of 60 and 47%, respectively, in 160 patients with high-risk NMIBC treated with a combination of thermochemotherapy + MMC and thermochemotherapy + epirubicin [102]. Enhanced delivery of MMC can be performed by increasing the dose of MMC from 20 to 40 mg, reducing the volume of the solution from 40 to 20 cc, alkalinizing the urine to stabilize MMC, reducing residual urine in the bladder and decreasing urine production by voluntary dehydration. These efforts have been shown to improve median time to recurrence in a Phase III randomized trial [103]. Electromotive drug administration through application of electric force between intravesical drug and the bladder wall has been shown to improve transport of intravesical therapy and has been shown to be superior to passive transport [104,105]. 4.5

5. 4.4.2

Thiotepa (triethylenethiophosphoramide) is a long-studied sulfur-containing alkylating agent similar to nitrogen mustard gas used during World War I and is the only FDA-approved drug for management of papillary bladder tumors [90,91]. Thiotepa has now largely been replaced by MMC because of the more favorable toxicity profile of MMC and studies demonstrating superiority of MMC over thiotepa [92-94]. Because of its low molecular weight it is more likely to enter systemic circulation and is associated with acute and chronic myelosuppression, most commonly thrombocytopenia, as well as irritative voiding symptoms [94,95]. Doxorubicin/epirubicin/valrubicin The anthracylcines (doxorubicin/epirubicin/valrubicin) work through multiple possible mechanisms, including intercalating DNA and eventually inhibiting DNA replication [96]. Side effects consist of cystitis-like symptoms, urinary tract infection, and, rarely, thrombocytopenia and fever [72,97]. 4.4.3

Gemcitabine Gemcitabine is a pyrimidine analog that gets incorporated into DNA and subsequently inhibits DNA synthesis [98]. 4.4.4

New developments

Thiotepa

The next frontier of intravesical treatments may harness the power of the immune system. Conceptually, so-called oncolytic viruses selectively replicate in tumor cells, leading to cell lysis and release of oncolytic virions further providing targets for the immune system. CG0070 is one such cancer selective, adenovirus for the treatment of NMIBC recently assessed in Phase I safety trial. This altered virus was previously shown to preferentially replicate in retinoblastoma (Rb)-defective bladder cancer cell lines. It is estimated to be 1000 times more cytotoxic to cancer cells than normal human cells [106]. Initial results from the intravesical dose-escalation study in humans are promising. Included patients were required to fail a course of BCG and have evidence of recurrence on cystoscopy, cytology or biopsy. The complete response rate for patients receiving therapy either every 28 days or 6 consecutive weeks was 63.6% (14 of 22 patients). For those patients with evidence of Rb pathway dysregulation, there was an 81.8% complete response rate (9 of 11). Of note, most common side effects were dysuria and hematuria, but generally the treatments were well tolerated [107]. Other formulations such as AxdAdB3-F/RGD and OncoVEXGALV/ CD have inhibited bladder cancer growth in a mice and rat


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model, respectively [108,109]. Further work is needed before oncolytic viruses can become part of the armamentarium against bladder cancer. In addition to the introduction of new novel agents as intravesical therapies, delivery systems themselves may be the next breakthrough for bladder cancer treatments. The concept of intravesical devices may currently be unfamiliar to urologists but similar products have been used in other fields for decades. One such corollary is the intrauterine device, which has been increasingly adopted to deliver medications such as levonorgestrel for family planning in females for decades [110]. Intravesical devices allowing for sustained drug release have already been studied in a promising Phase I trial for interstitial cystitis (IC) treatment [111]. The lidocaine-releasing intravesical system is a dual lumen silicone device with one tube allowing urine to slowly dissolve lidocaine in the bladder. The second tube contains a nickel titanium wire, which maintains an oval shape and prevents migration of the device out of the bladder. Drug delivery was sustained over a period of 14 days. Based on preliminary data, the device was tolerated well by patients and found to be effective in reducing IC symptoms. The most common treatment-related adverse events were dysuria and microscopic hematuria. More study is required, especially in adopting the technology to less viscous media such as current intravesical treatments. Another novel device is an intravesical pressure attenuation device for treatment of female stress urinary incontinence (SUI) [112]. The device is a small polyurethane balloon of low mass and inherent buoyancy designed to float at the dome of the bladder. The treatment group received a new intravesical device every 90 days. Of note, 482 devices (89.4%) had no appreciable sediment or stone on the surface suggesting implantables in the bladder can realistically be designed for medium to long-term usage. Despite some effectiveness for SUI, the withdrawal rate in the study was higher than expected, as device insertion was somewhat uncomfortable to patients. Repeated procedures also increased the chance of urinary tract infection. Nonetheless, the implications of this work are immense. If adopted for use in bladder cancer treatment these delivery modalities may revolutionize intravesical treatment. 6.

Expert opinion

The authors recommend that patients with NMIBC undergo risk stratification to determine their risk of recurrence and most importantly progression. Several urologic organizations (AUA, EUA, IBCG) have proposed risk stratification based on the available data [9,10,16]. The type and course of intravesical chemotherapy administered should be determined based on tumor-risk stratification. Treatment recommendations are generally similar but not completely aligned among the AUA, EUA and IBCG. 896

Low-risk disease The EUA and IBCG guidelines both recommend a single immediate dose of perioperative intravesical chemotherapy for patients with low-risk disease. The AUA guidelines do not firmly recommend that recommend a single immediate dose of perioperative intravesical chemotherapy rather state that it may be administered to an index patient with lowrisk features (solitary low-grade Ta tumors). If perioperative intravesical therapy is given perioperatively, it is paramount that the bladder is carefully assessed to ensure there is no perforation as extravasation of intravesical chemotherapy can have severe side effects. Summary: There is no overall consensus on the role of perioperative intravesical therapy for low-risk tumors among the AUA, EUA and IBCG. Perioperative chemotherapy should not be administered if bladder perforation is suspected. 6.1

Intermediate risk EUA guidelines recommend immediate perioperative chemotherapy with a maximum of 1 year of intravesical chemotherapy or BCG for patients with intermediate risk disease. IBCG guidelines do not recommend immediate perioperative chemotherapy, but similar to EUA guidelines recommend up to 1 year of intravesical chemotherapy or BCG. The AUA guidelines recommend induction intravesical chemotherapy or BCG with an option for maintenance for an index patient with multifocal or large volume Ta disease or recurrent Ta disease. Summary: Among the AUA, EUA and IBCG, there is general agreement that patients with intermediate disease undergo induction intravesical chemotherapy or BCG with maintenance up to 1 year (recommendation by EUA and IBCG and an option by AUA). 6.2

High risk All guidelines (AUA, EUA, and IBCG) recommend that patients with high-risk tumors should undergo BCG therapy with maintenance. All patients with high-risk disease should be also considered for radical cystectomy. The exact duration of maintenance therapy is not specified by the AUA or IBCG guidelines while the EUA guidelines specify maintenance therapy be continued for 1 -- 3 years. In high-risk patients who fail intravesical therapy early or fail after a second cycle of therapy, there should be a low threshold to perform cystectomy. Unlike intravesical chemotherapy, only BCG therapy has been shown to delay progression and thus should be preferentially used in patients with high-risk disease. Summary: There is general agreement among the AUA, EUA and IBCG that patients with high-risk disease undergo induction BCG therapy with maintenance therapy with consideration of radical cystectomy. 6.3



Declaration of interest GD Steinberg has acted as consultant for Photocure, Heat biologics, Cold Genesys, taris Biomedical, Bioniche, Endo Pharmaceuticals, Abbott Molecular, Tengion, Genetech and Bibliography

bladder cancer (NMIBC) and provide a succinct summary of the literature used to create these guidelines.

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.


1.

2.

3.

4.

5.

6.

Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA A Cancer J Clin 2014;64:9-29 Fleshner NE, HERR HW, Stewart AK, et al. The National Cancer Data Base report on bladder carcinoma. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1996;78:1505-13 Shelfo SW, Brady JD. Transurethral resection of bladder cancer: the mainstay of treatment. Atlas Urol Clin North Am 1997;5(2):1-14 Compton CC, Byrd DR, Garcia-Aguilar J, et al. AJCC Cancer Staging Atlas. Springer Science & Business Media; 2012 Maruniak NA, Takezawa K, Murphy WM. Accurate pathological staging of urothelial neoplasms requires better cystoscopic sampling. Springer, New York. J Urol 2002;167:2404-7 Mariappan P, Zachou A, Grigor KM. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol 2010;57(1):843-9

7.

Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 1999;162(1):74-6

8.

Dutta SC, Smith JA, Shappell SB, et al. Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol 2001;166:490-3

9.

..

Babjuk M, Burger M, Zigeuner R, et al. EUA guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013;64:639-53 EUA guidelines outline management options for non-muscle invasive

Karl Storz. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

10.

..

11.

12.

Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007;178:2314-30 American Urologic Association guidelines outline management options for NMIBC and provide a succinct summary of the literature used to create these guidelines. Lopez-Beltran A, Bassi P, Pavone-Macaluso M, et al. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. Eur Urol 2004;45:257-66 Hansel DE, Amin MB, Comperat E, et al. A contemporary update on pathology standards for bladder cancer: transurethral resection and radical cystectomy specimens. Eur Urol 2013;63:321-32

13.

Lee MC, Levin HS, Jones JS. The role of pathology review of transurethral bladder tumor resection specimens in the modern era. J Urol 2010;183:921-7

14.

Kausch I, Sommerauer M, Montorsi F, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur Urol 2010;57:595-606

15.

16.

17.

Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol 2010;184:1907-13 Sylvester RJ, van der Meijden APM, 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 2006;49:466-5; discussion 475--7 Brausi M, Witjes JA, Lamm D, et al. A Review of current guidelines and best


.

practice recommendations for the management of nonmuscle invasive bladder cancer by the international bladder cancer group. J Urol 2011;186:2158-67 Manuscript details literature used to derive European Organization for Research and Treatment of Cancer recurrence and progression risk calculations for risk stratification of Ta/T1 tumors.

18.

Herr HW, Morales A. History of Bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol 2008;179:53-6

19.

Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976;116:180-3

20.

Brosman SA. Experience with Bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol 1982;128:27-30

21.

Zhao W, Schorey JS, Bong-Mastek M, et al. Role of a bacillus Calmette-Guerin fibronectin attachment protein in BCG-induced antitumor activity. Int J Cancer 2000;86:83-8

22.

Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer--a current perspective. Nat Rev Urol 2014;11:153-62

23.

Pook S-H, Rahmat JNB, Esuvaranathan K, et al. Internalization of Mycobacterium bovis, Bacillus Calmette Guerin, by bladder cancer cells is cytotoxic. Oncol Rep 2007;18:1315-20

24.

Kelley DR, Haaff EO, Becich M, et al. Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical Bacillus Calmette-Guerin. J Urol 1986;135:268-71

25.

Sylvester R, Vandermeijden A, Witjes J, et al. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of

897

S. G. Patel et al.

recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006;67:1216-23

.

35.

B€ohle A, Jocham D, Bock PR. Intravesical Bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003;169:90-5

42.

36.

Shelley MD, Wilt TJ, Court J, et al. Intravesical Bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int 2004;93:485-90

Cookson MS, Herr HW, Zhang ZF, et al. The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997;158:62-7

43.

Lamm D, Persad R, Brausi M, et al. Defining progression in nonmuscle invasive bladder cancer: it is time for a new, standard definition. J Urol 2014;191:20-7

44.

Ehdaie B, Sylvester R, Herr HW. Maintenance bacillus Calmette-Guerin treatment of non-muscle-invasive bladder cancer: a critical evaluation of the evidence. Eur Urol 2013;64:579-85

45.

Akaza H, Hinotsu S, Aso Y, et al. Bacillus Calmette-Guerin treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. Four-year results. The Bladder Cancer BCG Study Group. Cancer 1995;75:552-9

46.

Lamm DL, Blumenstein BA, Crissman JD, 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 2000;163:1124-9

47.

Palou J, Laguna P, Millań-Rodrı´guez F, et al. Control group and maintenance treatment with Bacillus Calmette-Guerin for carcinoma in situ and/or high grade bladder tumors. J Urol 2001;165:1488-91

48.

Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance Bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol 2013;63:462-72 Prospective study assessing one-third and full dose BCG for 1 and 3 years demonstrating no difference in progression among doses.

the published results of randomized clinical trials. J Urol 2005;174:86-91 26.


27.

28.

29.

30.

31.

32.

33.

34.

898

Herr HW, Wartinger DD, Fair WR, et al. Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. J Urol 1992;147:1020-3 Brausi M, Oddens J, Sylvester R, et al. Side effects of Bacillus Calmette-Guerin (BCG) in the treatment of intermediateand high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur Urol 2014;65:69-76 Witjes JA, Palou J, Soloway M, et al. Clinical practice recommendations for the prevention and management of intravesical therapy--associated adverse events. Eur Urol Suppl 2008;7:667-74 Lamm DL, van der Meijden PM, Morales A, et al. Incidence and treatment of complications of Bacillus CalmetteGuerin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596-600

37.

38.

Rischmann P, Desgrandchamps F, Malavaud B, et al. BCG intravesical instillations: recommendations for sideeffects management. Eur Urol 2000;37(Suppl 1):33-6 Colombel M, Saint F, Chopin D, et al. The effect of ofloxacin on Bacillus Calmette-Guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study. J Urol 2006;176:935-9 van der Meijden APM, Sylvester RJ, 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 2003;44:429-34 Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int 2001;88:209-16 Han RF, Pan JG. Can intravesical bacillus Calmette-Guerin reduce

39.

Malmstr€om P-U, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the longterm outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non--muscle-invasive bladder cancer. Eur Urol 2009;56:247-56 Ja¨rvinen R, Kaasinen E, Sankila A, et al. Long-term efficacy of maintenance bacillus Calmette-Guerin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol 2009;56:260-5 Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediateand high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010;57:766-73

40.

Sylvester RJ, van der Meijden APM, Lamm DL. 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 2002;168:1964-70

41.

B€ohle A, Bock PR. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal


.

meta-analysis of comparative studies on tumor progression. Urology 2004;63:682-6; discussion 686--7 Meta-analysis assessing effectiveness of Mitomycin C versus Bacillus Calmette--Guerin (BCG) for progression, which showed improved progression in patients who underwent BCG + maintenance therapy.


49.


50.

Martıńez-Pin˜eiro JA, 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-Guerin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int 2002;89:671-80 Ojea A, Nogueira JL, 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. Eur Urol 2007;52:1398-406

51.

Martin FM, Kamat AM. Definition and management of patients with bladder cancer who fail BCG therapy. Expert Rev Anticancer Ther 2009;9:815-20

52.

Fernandez-Gomez J, Solsona E, Unda M, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus CalmetteGuerin: multivariate analysis of data from four randomized CUETO trials. Eur Urol 2008;53:992-1001

53.

54.

55.

56.

57.

58.

Joudi FN, Smith BJ, O’Donnell MA, et al. The impact of age on the response of patients with superficial bladder cancer to intravesical immunotherapy. J Urol 2006;175:1634-9; discussion 1639--40 Palou J, Sylvester RJ, Faba OR, et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guerin. Eur Urol 2012;62:118-25 Solsona E, Iborra I, Dumont R, et al. The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer. J Urol 2000;164:685-9

treated with 1 or 2, 6-week courses of intravesical Bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor. J Urol 1990;144(3):652-7 59.

Belldegrun AS, Franklin JR, O’Donnell MA, et al. Superficial bladder cancer: the role of interferon-alpha. J Urol 1998;159:1793-801

60.

Boccardo F, Cannata D, Rubagotti A, et al. Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of a multicentric Italian study. J Clin Oncol 1994;12:7-13

61.

62.

63.

64.

65.

66.

Herr H, Sogani PC. Does early cystectomy improve the survival of patients with high risk superficial bladder tumors? J Urol 2001;166:1296-9 Nieder AM, Brausi M, Lamm D, et al. Management of stage T1 tumors of the bladder: International Consensus Panel. Urology 2005;66:108-25 Coplen DE, Marcus MD, Myers JA, et al. Long-term followup of patients

67.

Rajala P, Kaasinen E, Raitanen M, et al. Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study--FinnBladder III longterm results. J Urol 2002;168:981-5 Jimenez-Cruz JF, Vera-Donoso CD, Leiva O, et al. Intravesical immunoprophylaxis in recurrent superficial bladder cancer (Stage T1): multicenter trial comparing bacille Calmette-Guerin and interferon-alpha. Urology 1997;50:529-35 Luo Y, Chen X, Downs TM, et al. IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving Mycobacterium bovis bacillus Calmette-Guerin immunotherapy. J Immunol 1999;162:2399-405 Zhang Y, Khoo HE, Esuvaranathan K. Effects of bacillus Calmette-Gue`rin and interferon alpha-2B on cytokine production in human bladder cancer cell lines. J Urol 1999;161:977-83 Papageorgiou A, Dinney CPN, McConkey DJ. Interferon-alpha induces TRAIL expression and cell death via an IRF-1-dependent mechanism in human bladder cancer cells. Cancer Biol Ther 2007;6:872-9 Slaton JW, Perrotte P, Inoue K, et al. Interferon-alpha-mediated downregulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin Cancer Res 1999;5:2726-34 Downs TM, Szilvasi A, O’Donnell MA. Pharmacological biocompatibility between intravesical preparations of


BCG and interferon-alpha 2B. J Urol 1997;158:2311-15 68.

Nepple KG, Lightfoot AJ, Rosevear HM, et al. Bacillus Calmette-Guerin with or without interferon a-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol 2010;184:1915-19

69.

Lam JS, Benson MC, O’Donnell MA, et al. Bacillus calmete-guerin plus interferon-a2B intravesical therapy maintains an extended treatment plan for superficial bladder cancer with minimal toxicity. Urol Oncol 2003;21:354-60

70.

O’Donnell MA, Krohn J, DeWolf WC. 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. J Urol 2001;166:1300-4; discussion 1304--5

71.

Joudi FN, Smith BJ, O’Donnell MA, et al. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. J Urol 2006;24:344-8

72.

Steinberg G, Bahnson R, Brosman S, et al. Efficacy and safety of valrubicin for the treatment of Bacillus CalmetteGuerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol 2000;163:761-7 Study demonstrating second line option of Valrubicin for patient who failed in initial BCG therapy for CIS who were unfit for cystectomy.

.

73.

Di Lorenzo G, Perdona S, Damiano R, et al. Gemcitabine versus bacille Calmette-Guerin after initial bacille Calmette-Guerin failure in non-muscle-invasive bladder cancer. Cancer 2010;116:1893-900

74.

Pode D, Alon Y, Horowitz AT, et al. The mechanism of human bladder tumor implantation in an in vitro model. J Urol 1986;136:482-6

75.

Oosterlinck W, Kurth KH, Schr€oder F, et al. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral

899

S. G. Patel et al.

resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol 1993;149:749-52 76.


77.

78.

79.

80.

81.

82.

83.

900

Tolley DA, Parmar MK, Grigor KM, et al. The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up. J Urol 1996;155:1233-8 Sylvester RJ, Oosterlinck W, van der Meijden APM. 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 2004;171:2186-90 Berrum-Svennung I, Granfors T, Jahnson S, et al. A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences. J Urol 2008;179:101-5; discussion 105--6 Gudjońsson S, Adell L, Merdasa F, et al. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomised multicentre study. Eur Urol 2009;55:773-80 Huncharek M, Geschwind JF, Witherspoon B, et al. Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials. J Clin Epidemiol 2000;53:676-80 Sylvester RJ, Oosterlinck W, Witjes JA. The schedule and duration of intravesical chemotherapy in patients with non-muscle-invasive bladder cancer: a systematic review of the published results of randomized clinical trials. Eur Urol 2008;53:709-19 Cookson MS, Chang SS, Lihou C, et al. Use of intravesical valrubicin in clinical practice for treatment of nonmuscleinvasive bladder cancer, including carcinoma in situ of the bladder. Ther Adv Urol 2014;6:181-91 Dalbagni G, Russo P, Bochner B, et al. Phase II trial of intravesical gemcitabine in bacille calmette-guerin--refractory transitional cell carcinoma of the bladder. J Clin Oncol 2006;24(18):2729-34

84.

85.

Dalbagni G, Russo P, Sheinfeld J, et al. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol 2002;20:3193-8 Addeo R, Caraglia M, Bellini S, et al. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol 2010;28:543-8

86.

Skinner EC, Goldman B, Sakr WA, et al. SWOG S0353: phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette-Guerin. J Urol 2013;190:1200-4

87.

Crooke ST, Bradner WT. Mitomycin C: a review. Cancer Treat Rev 1976;3:121-39

88.

Lamm DL, Blumenstein BA, David Crawford E, et al. Randomized intergroup comparison of Bacillus Calmette-Guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study. Urol Oncol 1995;1:119-26

89.

Oddens JR, van der Meijden APM, Sylvester R. One immediate postoperative instillation of chemotherapy in low risk Ta, T1 bladder cancer patients. Is it always safe? Eur Urol 2004;46:336-8

90.

Bateman JC. Chemotherapy of solid tumors with triethylene thiophosphoramide. N Engl J Med 1955;252:879-87

91.

Gallagher SM. From the battlefield to the bladder: the development of thioTEPA. WJCU 2014;3:195

92.

Brassell SA, Kamat AM. Contemporary intravesical treatment options for urothelial carcinoma of the bladder. J Natl Compr Canc Netw 2006;4:1027-36

93.

Heney NM. First-line chemotherapy of superficial bladder cancer: mitomycin vs thiotepa. Urology 1985;26:27-9

94.

Heney NM, Koontz WW, Barton B, et al. Intravesical thiotepa versus mitomycin C in patients with Ta, T1 and TIS transitional cell carcinoma of the bladder: a phase III


prospective randomized study. J Urol 1988;140:1390-3 95.

Hollister D, Coleman M. Hematologic effects of intravesicular thiotepa therapy for bladder carcinoma. JAMA 1980;244:2065-7

96.

Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 1999;57:727-41

97.

Ali-El-Dein B, El-Baz M, Aly A, et al. Intravesical epirubicin versus doxorubicin for superficial bladder tumors (stages pTa and pT1): a randomized prospective study. J Urol 1997;158(1):68-73.discussion 73-4

98.

Moore MJ, Tannock IF, Ernst DS, et al. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 1997;15:3441-5

99.

Laufer M, Ramalingam S, Schoenberg MP, et al. Intravesical gemcitabine therapy for superficial transitional cell carcinoma of the bladder: a phase I and pharmacokinetic study. J Clin Oncol 2003;21:697-703

100. Paroni R, Salonia A, Lev A, et al. Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. Br J Clin Pharmacol 2001;52:273-8 101. Colombo R, Da Pozzo LF, Salonia A, et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol 2003;21:4270-6 102. Arends TJH, van der Heijden AG, Witjes JA. Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer. J Urol 2014;192:708-13 103. Au JL, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001;93:597-604 104. Di Stasi SM, Giannantoni A, Stephen RL, et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk


superficial bladder cancer: a prospective randomized study. J Urol 2003;170:777-82 105.


106.

107.

108.

Brausi M, Campo B, Pizzocaro G, et al. Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: a comparative Phase II study. Urology 1998;51:506-9 Ramesh N, Ge Y, Ennist DL, et al. CG0070, a conditionally replicating granulocyte macrophage colonystimulating factor--armed oncolytic adenovirus for the treatment of bladder cancer. Clin Cancer Res 2006;12:305-13 Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol 2012;188:2391-7 Wang H, Cai Z, Yang F, et al. Enhanced antitumor efficacy of integrin-targeted oncolytic adenovirus AxdAdB3-F/RGD on bladder cancer. Urology 2014;83:508; e13--9

109.

Simpson GR, Horvath A, Annels NE, et al. Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer. Br J Cancer 2012;106:496-507

110.

Finer LB, Jerman J, Kavanaugh ML. Changes in use of long-acting contraceptive methods in the United States, 2007-2009. Fertil Steril 2012;98:893-7

111.

Nickel JC, Jain P, Shore N, et al. Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device. Sci Transl Med 2012;4:143ra100

112.

Rovner ES, Dmochowski RR, Leach GE, et al. A randomized, controlled clinical trial of a novel intravesical pressure attenuation device for the treatment of stress urinary incontinence. J Urol 2013;190:2243-50


Affiliation

Sanjay G Patel†1 MD, Andrew Cohen2 MD, Adam B Weiner3 BS & Gary D Steinberg4 MD † Author for correspondence 1 Fellow of Urologic Oncology, University of Chicago Medical Center, Department of Surgery, Section of Urology, 5841 S. Maryland Avenue, Chicago, IL 60637, USA Tel: +1 773 702 5195; Fax: +1 773 702 1001; E-mail: [email protected] 2 Urology Resident, University of Chicago Medical Center, Department of Surgery, Section of Urology, 5841 S. Maryland Avenue, Chicago, IL 60637, USA 3 Medical Student, University of Chicago Medical Center, Department of Surgery, Section of Urology, 5841 S. Maryland Avenue, Chicago, IL 60637, USA 4 Professor of Surgery, University of Chicago Medical Center, Department of Surgery, Section of Urology, 5841 S. Maryland Avenue, Chicago, IL 60637, USA

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Adjuvant intravesical therapy for superficial bladder cancer.

Reactive arthritis induced by intravesical BCG therapy for bladder cancer.

Efficient intravesical therapy of bladder cancer with cationic doxorubicin nanoassemblies.

Intravesical chemotherapy for intermediate risk non-muscle invasive bladder cancer recurring after a first cycle of intravesical adjuvant therapy.

Mycobacterial Osteomyelitis of the Spine Following Intravesical BCG Therapy for Bladder Cancer.

Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

Clinical characteristics of Japanese patients with reactive arthritis following intravesical BCG therapy for bladder cancer.

Advances in intravesical therapy for the treatment of non-muscle invasive bladder cancer (Review).

Predictive Markers for the Recurrence of Nonmuscle Invasive Bladder Cancer Treated with Intravesical Therapy.

Long-term follow-up of intravesical Epodyl therapy for superficial bladder cancer.

Mucoadhesive polyacrylamide nanogel as a potential hydrophobic drug carrier for intravesical bladder cancer therapy.

Tuberculous Spondylitis following Intravesical Bacillus Calmette-Guerin for Bladder Cancer.

[Intravesical gemcitabine for non-muscle invasive bladder cancer].

Emerging intravesical therapies for management of nonmuscle invasive bladder cancer.

Intravesical instillation of adriamycin for bladder tumors.

Intravesical capsaicin for neurogenic bladder dysfunction.

Intravesical formalin for the control of intractable bladder haemorrhage secondary to radiation cystitis or bladder cancer.

Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer.

Local Immune Stimulation by Intravesical Instillation of Baculovirus to Enable Bladder Cancer Therapy.

High-Risk Non-Muscle-Invasive Bladder Cancer-Therapy Options During Intravesical BCG Shortage.

Management of stage T1 superficial bladder cancer with intravesical bacillus Calmette-Guerin therapy.

Clinical value of pathologic changes after intravesical BCG therapy of superficial bladder cancer.

Disseminated BCG: Complications of Intravesical Bladder Cancer Treatment.

Is intravesical Bacillus Calmette-Guérin therapy superior to chemotherapy for intermediate-risk non-muscle-invasive bladder cancer? An ongoing debate.