Intravesical bacillus Calmette Guerin instillation in non-muscle-invasive bladder cancer: A review

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1 International Journal of Urology (2018) 25, doi: /iju Review Article Intravesical bacillus Calmette Guerin instillation in non-muscle-invasive bladder cancer: A review Manmeet Saluja 1 and Peter Gilling 2 1 Department of Urology, Auckland City Hospital, Auckland, and 2 Department of Urology, Tauranga Hospital, Tauranga, New Zealand Abbreviations & Acronyms BCG = bacillus Calmette Guerin CIS = carcinoma in situ EAU = European Association of Urology EORTC = European Organization for Research and Treatment of Cancer FDA = US Food and Drug Administration IL = interleukin LUTS = lower urinary tract symptoms NMIBC = non-muscleinvasive bladder cancer SWOG = Southwest Oncology Group TURBT = transurethral resection of bladder tumor UTI = urinary tract infection Correspondence: Manmeet Saluja M.B.Ch.B., Department of Urology, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand. manmeet.saluja@gmail.com Received 14 March 2017; accepted 2 June Online publication 25 July 2017 Abstract: Intravesical bacillus Calmette Guerin has been the standard of care for highrisk non-muscle-invasive bladder cancer for 40 years. It remains one of the most successful immunotherapies ever used. Bacillus Calmette Guerin shows superior efficacy to alternative intravesical treatments, and has an established role in reducing both recurrence and progression in non-muscle-invasive bladder cancer. It remains relatively safe, and has acceptable tolerability of both local and systemic side-effects. The present review provides insights into the role of bacillus Calmette Guerin compared with alternative treatments both in primary and refractory settings. Key words: adjuvant treatment, bacillus Calmette Guerin, immunotherapy, non-muscleinvasive bladder cancer, urinary bladder neoplasms. Introduction Intravesical BCG is the gold standard treatment for intermediate- and high-risk NMIBC, and has stood the test of time for >40 years. Its role as a bladder preserving treatment is backed up with robust evidence, as it delays recurrence and progression of NMIBC. More recently, a worldwide shortage of BCG as a result of decreased supply has made us closely reflect on it use. Questions regarding appropriate patient selection, duration and dosing regimens, cost-effectiveness, and superiority over other intravesical agents have been raised. Furthermore, definitions of BCG failure and subsequent management options have been evaluated. The present review addresses and summarizes these issues, and introduces future direction and novel treatment strategies in NMIBC. History of BCG It has been nearly 100 years since the development of the BCG vaccine by Calmette and Guerin. 1 Immunotherapy was realized soon after as a cancer treatment, and BCG was investigated for many different cancer subtypes. 2 In 1976, BCG was tested as an intravesical treatment for superficial bladder cancer by Morales. 3 His initial work was promising in showing a decrease in recurrence rates. Subsequent studies confirmed the role of BCG in reducing recurrences, delaying progression and improving survival in patients with highrisk NMIBC. 4 6 After toxicity studies were carried out, it was finally approved by the FDA as an intravesical treatment in 1990 and now remains the standard of care in highrisk NMIBC. Mechanism of action Despite its clinical use for >40 years, the mechanism is not completely understood. BCG is a live attenuated form of Mycobacterium bovis, and needs an intact immune system to be effective. 7 BCG works through two mechanisms: a direct tumor response and immune response. 8 BCG attaches to urothelial cells through fibronectin, and becomes internalized by bladder cancers cell through macropinocytosis (Fig. 1). 7 BCG itself can induce cell death by apoptosis or necrosis. Bladder cancer cells activate the immune system by upregulating antigen-presenting cells (major histocompatibility complex-ii and intercellular adhesion molecule-1) and are presented to CD4 T cells. Cytokines (such as IL-1, IL-2, IL-6, IL-8, IL-10, 1L-12, tumor necrosis The Japanese Urological Association

2 Intravesical BCG in superficial bladder cancer BCG Attachment to urothelial cells Fibronectin Integrin α5β1 Processing by dendritic cells Direct cytotoxicity Internalization by bladder cancer cells Constitutive activation of macropinocytosis (PTEN, RAS, other oncogenes) Antigen presentation and cytokine release by bladder cancer cells MHC II upregulation ICAM-1 Secretion of IL-6, IL-8, GM-CSF, TNF-α Immune cell recruitment Granulocytes CD4 + Iymphocytes CD8 + Iymphocytes NK cells Macrophages Cytokine production IL-1, IL-2, IL-5, IL-6, IL-8, IL-12, IL-18, TNF-α, IFN-γ, GM-CSF Killing of cancer cells Immune-mediated cytotoxicity NK cells CD8 + Iymphocytes Macrophages TRAIL (granulocytes) Fig. 1 Mechanism of BCG. Reprinted with permission from Macmillan Publishers Ltd, Redelman-Sidi et al. 7 factor-alpha, interferon) are secreted, which recruit cytotoxic cells natural killer cells, cytotoxic T cells, neutrophils and macrophages that specifically target the tumor cells. 9 Recommended administration BCG is indicated for high-risk and intermediate non-muscleinvasive transitional cell carcinoma of the bladder (Table 1). Contraindications must be avoided to prevent local and systemic toxicity. Induction course Patients who are scheduled for BCG need to have a complete transurethral resection of tumor. Morales originally described intravesical treatment with once-weekly BCG for 6 weeks. BCG was instilled for a maximum of 2 h due to the dilution effect of urine. Once-weekly intervals were chosen, as the local side-effects last for less than a week. 3 A total of 6 weeks was chosen, as it was estimated to take that length Table 1 Indications and contraindications for BCG for NMIBC Indications High-risk NMIBC: CIS T1 High grade Multiple and recurrent and large (>3 cm) Ta low grade tumors Intermediate-risk NMIBC: One year of full dose BCG or intravesical chemotherapy Contraindications Absolute: <2 weeks post-turbt Macroscopic hematuria After traumatic catheterization Symptomatic UTI Pregnancy/lactation Active Tb Hypersensitivity to BCG Relative: Immunosuppression (Lamm, 1992) 36 Previous radiotherapy to bladder (EAU) 11 All factors must be present. Adapted from the EAU and American Urology Association guidelines. 11,18 of time for delayed hypersensitivity to take effect. This regime has been used in subsequent trials, and has persisted into routine clinical practice worldwide The Japanese Urological Association 19

3 M SALUJA AND P GILLING Maintenance course The SWOG trial had used an induction course for 6 weeks followed by three instillations weekly at 3 and 6 months, and every 6 months thereafter for 3 years. 10 Cystoscopy and cytology was initially carried out 3-monthly for the first 2 years followed by 6-monthly surveillance. This protocol has been adopted by the EAU guidelines. 11 Multiple other protocols have been described; however, a meta-analysis was unable to note any differences in outcome between the protocols. 12 Maintenance versus induction therapy alone Maintenance therapy is required to maximize the benefits of BCG compared with induction alone. 10,13 15 The SWOG trial concluded that 3-year maintenance therapy was better than induction alone in reducing both recurrence (from 59% to 41%) and progression (from 30% to 24%) at 5 years. At least 1 year of maintenance therapy is required to have superior efficacy over mitomycin therapy. 16 The EORTC trial showed that a 3-year maintenance course at full dose reduced the risk of recurrence from 52% to 25% compared with 1 year for the high-risk group. 15 However, no differences in progression or overall and disease-free survival were noted. For the intermediate risk group, a 1-year maintenance course was adequate. Maintenance therapy can lead to higher toxicity than induction alone, and there might be a dropout rate of up to 48% after 1 year. 10,17 There appears to be no increase in toxicity between 1 and 3 years. 10 Therefore, maintenance therapy is now the standard recommendation for the high-risk group. However, the duration of 1 year versus 3 years needs to be weighed against the cost and tolerability for the patient. 11 Method of administration Before instillation, patients have their urine analyzed and temperature measured. Contact precautions need to be maintained, and BCG is instilled through a urinary catheter and retained in the bladder for approximately 2 h. Patients are advised to bleach toilets after urinating for up to 6 h after the procedure and wear a condom during sexual intercourse during the entire treatment course. 18 Low dose versus standard dose Low-dose BCG was trialed in order to reduce toxicity. Some prospective studies and reviews 19 suggest that one-third dose has equivalent efficacy to full dose in high-risk patients with lesser toxicity. 20 Conflicting evidence from the EORTC study and a recent meta-analysis suggest that one-third dose is associated with a higher recurrence rate, but has no difference in toxicity, progression or survival. 13,15 One-sixth dose appears to be inferior, even in intermediate-risk disease, with no reduction of side-effects and therefore is not recommended. 21 Dose reduction could be considered in patients who cannot tolerate a full dose of BCG. 22 Therefore, the guidelines vary in recommending the optimal dosing, as current evidence is inconclusive. 11,18 Strain of BCG A meta-analysis could not decipher a difference between the different BCG strains. 12 A recent randomized control trial has inferred that the Connaught strain might be superior to Tice in reducing recurrences; however, further trials are necessary. 23 This is particularly relevant because of the worldwide shortage of BCG, where limited strains are available. Efficacy of BCG Risk of recurrence Adjuvant BCG reduces the risk of recurrence of high-grade NMIBC by 70% compared with transurethral resection alone. 24,25 For CIS, BCG has been shown to generate a complete response in up to 70 90% of cases. 10,14,26 However, recurrence in the long term might be as high as 50% with risk of progression. For multiple, large or recurrent Ta low-grade tumors (intermediate risk), BCG induction and maintenance can reduce recurrences by 24% and 31%, respectively. 27 Risk of progression Maintenance BCG is the only intravesical therapy that has level 1 evidence to show a reduction of tumor progression. 22 The EORTC meta-analysis showed a reduction of progression by 27% for intermediate- and high-risk groups including CIS and Ta tumors. 12 BCG versus intravesical chemotherapy For high-risk NMIBC, there is considerable evidence showing that maintenance BCG (of greater than 1 year duration) is superior to intravesical chemotherapy. 14,16,20 BCG decreases both recurrences by 32% and progression by 34% compared with chemotherapy. 16,24 For CIS alone, BCG reduces recurrence by 59% and progression by 26%. 14 The benefit is also noted in patients who have previously undergone intravesical chemotherapy. 28 Adding chemotherapy to BCG is not associated with superior outcomes and is therefore not recommended. 29 However, BCG has more toxicity compared with chemotherapy. 16 Therefore, for intermediate risk, maintenance intravesical chemotherapy might be a preferred option, especially if the patient is intolerant to BCG. 11,18 BCG versus early cystectomy in highgrade T1 No randomized trials have been carried out comparing intravesical BCG and early cystectomy. Trials that show early cystectomy is superior to late cystectomy have an inherent bias, as patients that have failed intravesical treatment are more likely to have aggressive tumors. It is known that 30% are pathologically upstaged after cystectomy. 30 Patients who are highest risk (i.e. T1G3 with CIS, multiple or large T1G3, The Japanese Urological Association

4 Intravesical BCG in superficial bladder cancer T1G3 in prostatic urethra, unusual histology or lymphovascular invasion) have a poorer prognosis. 11 Therefore, early cystectomy is likely to have a superior outcome and should be offered. Other risk factors that would support an early cystectomy include a young age (<60 years), incomplete resection and high-grade T1 in a bladder diverticulum. 31 Radical cystectomy is associated with significant treatment morbidity and potential mortality; therefore, benefits should be outweighed against the risks. Side-effects/complications Complications can either be local or systemic (Table 2). Minor local reactions are common and usually non-preventable. However, they are usually mild, transient and easily managed. 32 LUTS are the most common, occur due to the generated inflammatory response and usually respond to symptomatic management. Low-grade fever is associated with flu-like symptoms, and usually lasts for h. Urinary tract infection needs to be excluded or treated before administering subsequent doses of BCG. A single-dose quinolone 6 h after instillation might decrease side-effects and improve tolerability. 33 Severe systemic complications occur in <5% of patients, and can be potentially life threatening. These occur as a result of systemic absorption, and can be prevented by careful patient selection and safe administration practices. They require involvement of infectious disease physicians and require antituberculous medications for 3 6 months. 32,34 BCG sepsis is a rare event, but carries up to 50% mortality. 35 Patients might have a persistent high-grade fever or show signs of septic shock. Patients require urgent resuscitation, tuberculosis triple therapy, high-dose steroids and broad-spectrum antibiotics. 36 Table 2 Local and systemic complications of BCG Incidence rate (%) Management Local LUTS Rule out UTI. Treat symptoms Hematuria 1 40 Rule out UTI and recurrence UTI 5 Antibiotics Ureteric obstruction 0.3 Withhold BCG. De-obstruct ureter Contracted bladder <1 Withhold BCG. Hydrodistension Systemic Low grade fever <38.3 C High grade fever >39.4 C Granulomatous prostatitis (1%) 30 Rule out UTI. Treat symptoms 2.9 Withhold BCG. Treat symptoms 1 Antibiotics anti Tb therapy 3 6 months Epididymitis 0.2 Anti Tb therapy 3 6 months Granulomatous <1 Anti Tb therapy steroids hepatitis/ pneumonitis BCG sepsis 0.4 Antibiotics/anti Tb therapy/steroids Allergy/skin rash 0.5 Withhold BCG, antihistamines Adapted from Koya et al., 32 Lamm, 36 Rischmann et al. 34 and EAU Guidelines. 11 BCG failure Rate of BCG failure is as high as 50% in the long term. 37 BCG failure has multiple definitions described by different panels (Table 3). 11,37 Patients who have the highest risk are more likely to have BCG failure and are recommended to have early cystectomy. Women and patients aged older than 70 years also appear to be less responsive to BCG. 38,39 FISH or UroVysion assays of urine samples have been proposed to predict BCG failure, but are yet to be tested in a randomized fashion. 37 Similarly, analysis of patient s inflammatory response, immunohistochemistry or genomics might help in predicting failure. The CUETO group has formulated a predictive model for risk of recurrence and progression after BCG; however, their model has limitations that make it less applicable. 18 Management of BCG failure It has been recognized that high-grade tumor recurrence despite BCG infers a poor prognosis; and further, BCG is associated with an additional response in up to 20% of cases and an increased risk of progression. 40,41 Radical cystectomy is therefore the gold standard recommendation in patients with BCG refractory disease of patients with high-grade recurrence, with long-term survival rates exceeding >90% at 10 years. 42 In recurrent CIS, an additional BCG course can achieve a response in 30 50% of cases; however, it is rarely durable, therefore radical cystectomy remains the optimal treatment. 14 Persistent low-grade tumor recurrences are not classified as BCG failure, and can be treated by re-resection and further intravesical therapy. 11 Multiple intravesical agents have been used in a BCG refractory setting, where radical cystectomy is not an option or not preferred by the patient. These might be in the form of monotherapies with immunotherapy or chemotherapy, combination therapy or device-assisted therapies (Table 4). Valrubicin is the only FDA-approved intravesical therapy that can be used in this context. Gemcitabine has been extensively studied in the salvage setting with variable results. Addition of interferon to BCG might have a limited role, as it appears to have similar efficacy rates to BCG alone. 58 In general, chemotherapy appears to be superior to immunotherapy in a refractory setting, as they have a different mechanism of action. Combination therapies tend to be more efficacious than monotherapy. However, these studies are limited by small patient numbers and poor evidence. Even at best, these therapies yield modest responses, which are not Table 3 BCG failure: international consultation on bladder tumour definition 37 Category Intolerance Resistance Relapse Refractory Definition Intolerant of at least one induction course Recurrence or persistence of lesser stage or grade after initial course which then resolves with further BCG Recurrence after initial resolution Persistance or progression despite BCG 2017 The Japanese Urological Association 21

5 M SALUJA AND P GILLING durable and have not been shown to prevent progression or survival. 43 Future of BCG Various methods have been developed in order to improve the efficacy of BCG, through applying basic science. 61 These range from improving BCG absorption and augmenting the immune response through toll-like receptor agonists. These have had promising results in vitro, and animal studies and clinical trials are pending. Recombinant BCG strains expressing IL-2 and interferon-alpha are also currently being researched and validated. 56,57 Immune check-point inhibitors, such as actezolizumab, have proven to be effective in metastatic bladder cancer, and there is optimism on its role in the NMIBC setting. 57,58 Multiple phase I/II trials are currently underway to explore various immunotherapy agents mainly in the BCG refractory settings. This includes oncolytic viruses, such as recombinant adenovirus (CG00700), immune-modulators (ALT-801, HS- 410, ALT-803), cancer vaccines (PANVAC) and targeted kinase inhibitors (sunitinib, dovitinib, erlotinib). 18 Multiple novel strategies have been used both in primary and BCG refractory settings in order to improve outcomes (Table 4). 58 Electromotive therapy allows a chemotherapy agent to be transported across the bladder urothelium through a process called iontophoresis and aids in improved penetration. Thermochemotherapy can potentiate the effect of chemotherapeutic agents using radiofrequency hyperthermia. Photodynamic therapy uses specific wavelengths of light to activate a topical administration of a photosensitizer agent into the bladder. Device-assisted therapy allows various intravesical drug delivery devices to be implanted in the bladder. These increase the dwell time of intravesical drugs, as they are left in for an extended period of time. 60 These strategies are still in their experimental stages with limited evidence, but might become more applicable in the future. 11 Radiotherapy has historically not been shown to be effective in the management of NMIBC. However, one non-randomized trial has shown good response rates (70% progression free survival at 10 years), and chemoradiation could be a viable alternative for patients with T1 NMIBC instead of intravesical treatments. 59 Two different chemoradiotherapy regimes are currently being evaluated as part of the RTOG 0926 trial to evaluate efficacy in T1 patients who have failed BCG treatment. Additionally, compliance with BCG needs to be improved within institutions through regional audits and education. Improved tumor detection and resection strategies, and optimal surveillance regimes are currently being studied to complement BCG treatment. 18 The worldwide shortage of BCG needs to be addressed with increased production and research into new strains. Finally, the optimal dosing and duration of BCG needs to be identified in order for it to remain costeffective. Table 4 Intravesical treatment options for BCG failure Author No. patients (n) Recurrence free survival Monotherapies Gemcitabine Dalbagni et al % at 1 year Skinner et al % 1 year 21% 2 years Di Lorenzo et al % 2 years Docetaxel Barlow et al % at 1 year 25% at 3 years Valrubicin Steinberg et al % 6 months 8% 30 months Combination therapy BCG and interferon Joudi et al % 2 years Gemcitabine/ mitomycin Gemcitabine/ docetaxel Cockerill et al % at 22 months Lightfoot et al % at 1 year 38% at 2 years Steinberg et al % at 1 year 34% at 2 years Novel strategies Thermochemotherapy Nativ et al % at 2 years Photodynamic therapy Electromotive therapy Nseyo et al % at 1 year Lee et al % 1 year 64.4% 2 years Di Stasi et al % at 1 year Only FDA approved therapy for BCG refractory CIS. Conflict of interest None declared. References 1 Calmette A, Guerin C. La vaccination preventive contre la tuberculose par le BCG. Paris Masson 1927; 73: Pearl R. Cancer and tuberculosis. Am. J. 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7 M SALUJA AND P GILLING 52 Steinberg R, Thomas LJ, O Donnell MA, Nepple KG. Sequential intravesical gemcitabine and docetaxel for the salvage treatment of non- muscle invasive bladder cancer. Bladder Cancer 2015; 1: Nativ O, Witjes JA, Hendricksen K et al. Combined thermo-chemotherapy for recurrent bladder cancer after Bacillus Calmette-Guerin. J. Urol. 2009; 182: Nseyo UO, Shumaker B, Klein EA, Sutherland K. Photodynamic therapy using porfimer sodium as an alternative to cystectomy in patients with refractory transitional cell carcinoma in situ of the bladder. Bladder Photofrin Study Group. J. Urol. 1998; 160: Lee JY, Diaz RR, Cho KS et al. Efficacy and safety of photodynamic therapy for recurrent, high grade nonmuscle invasive bladder cancer refractory or intolerant to bacille Calmette-Guerin immunotherapy. J. Urol. 2013; 190: LaRue H, Ayari C, Bergeron A et al. Toll-like receptors in urothelial cells targets for cancer immunotherapy. Nat. Rev. Urol. 2013; 10: Donin NM, Lenis AT, Holden S et al. Immunotherapy for the treatment of urothelial carcinoma. J. Urol. 2017; 197: 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: Kamat AM, Colombel M, Sundi D et al. BCG-unresponsive non-muscleinvasive bladder cancer: recommendations from the IBCG. Nat. Rev. Urol. 2017; 14: Weiss C, Wolze C, Engehausen DG et al. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: an alternative to intravesical therapy or early cystectomy? J. Clin. Oncol. 2016; 24: Douglass L, Schoenberg M. The future of intravesical drug delivery for nonmuscle invasive bladder cancer. Bladder Cancer 2016; 2: The Japanese Urological Association