Indian Journal of Urology
: 2015  |  Volume : 31  |  Issue : 4  |  Page : 304--311

Intravesical immunotherapy in nonmuscle invasive bladder cancer

Jan-Friedrich Jokisch, Alexander Karl, Christian Stief 
 Department of Urology, LMU Munich, München, Germany

Correspondence Address:
Jan-Friedrich Jokisch
Department of Urology, LMU Munich, München


Introduction: Nonmuscle invasive urothelial cell carcinoma is the most frequent malignancy of the urinary bladder. The high recurrence rate (up to 80%) and risk of progression (up to 30%) reflect the need for long-term follow-up and sometimes multiple interventions. To reduce the rate of recurrences and tumor progression, intravesical immunotherapy, especially the use of Bacille Calmette-Guerin (BCG), represents the gold standard adjuvant treatment of high-risk nonmuscle invasive bladder cancer (NMIBC). This article reviews the role of BCG therapy and several promising new immunotherapeutic approaches such as mycobacterium phlei cell wall-nucleic acid complex, interleukin-10 (IL-10) antibody, vaccine-based therapy, alpha-emitter therapy, and photodynamic therapy checkpoint inhibitors. Methods: A systematic literature review was performed using the terms (immunotherapy, NMIBC, BCG, and intravesical) using PubMed and Cochrane databases. Results: BCG represents the most common intravesical immunotherapeutic agent for the adjuvant treatment of high-risk NMIBC. Its use is associated with a significant reduction of recurrence and progression. Patients with NMIBC of intermediate and high-risk benefit the most from BCG therapy. To achieve maximal efficacy, an induction therapy followed by a maintenance schedule should be used. Full-dose BCG is recommended to obtain ideal antitumoral activity and there is no evidence of a reduction of side effects in patients treated with a reduced dose. There are multiple new approaches and agents in immunotherapy with potential and promising antineoplastic effects. Conclusions: The beneficial effect of BCG is well documented and established. To reduce the tumor specific mortality, it is essential to follow guideline-based treatment. In patients with BCG-failure, there are new promising alternatives other than BCG but BCG remains the gold standard at this stage.

How to cite this article:
Jokisch JF, Karl A, Stief C. Intravesical immunotherapy in nonmuscle invasive bladder cancer.Indian J Urol 2015;31:304-311

How to cite this URL:
Jokisch JF, Karl A, Stief C. Intravesical immunotherapy in nonmuscle invasive bladder cancer. Indian J Urol [serial online] 2015 [cited 2019 Nov 21 ];31:304-311
Available from:

Full Text


Bladder cancer (BC) is the most common tumor of the urinary tract. For men, it is the fourth most common malignancy and accounts for 7% of all incident malignancies worldwide.[1] The prolonged nature of BC is similar to many chronic diseases and requires invasive and careful long-term surveillance and, in certain cases, adjuvant treatment. This results in high costs per patient ($96,000–$187,000) making BC one of the most expensive malignancies to treat.[2]

Urothelial carcinoma (UCC) represents the most common malignancy of the bladder in the Western world (90%). About 75% of patients suffering from initially diagnosed BC show a disease limited to the mucosa (pTa or carcinoma in situ [CIS]) or submucosa (pT1) and is therefore classified as nonmuscle invasive tumor (nonmuscle invasive BC [NMIBC]).

NMIBCs has progression to muscle-invasion in up to 30% patients. The WHO-classification into two groups (high- and low-grade UCC) may be associated with genetic instability as an indicator for the potential to progress. The risk group classification is based on multiple prognostic factors (European Organization of Research and Treatment of Cancer [EORTC] risk tables) and subclassifies patients into low, intermediate, and high-risk groups [Table 1].[3] Transurethral resection of the bladder tumor (TURBT) is the standard for treatment and diagnosis of BC. The aim of TURBT is to ideally remove all visible lesions within the bladder and to provide tissue for a precise histopathologic evaluation.[3] Despite complete removal, NMIBC shows a high rate of recurrence 30–85% within 2 years after initial diagnosis and stage progression in up to 30% after 5 years.[3]{Table 1}

Adjuvant therapies aim to reduce recurrence rates and ideally prevent progression. Based on the individual risk-stratification of a patient, intravesical chemotherapy or immunotherapy is recommended by different international guidelines (American Urological Association [AUA] and European association of urology [EAU]) [Table 2] and [Table 3].[3],[4] Adjuvant therapies are a complex subject as evidenced by a large number of publications (over 1605 publications in PubMed [06/2015]). Despite recommendations of international guidelines, Chamie et al. suggested that only 1 of 4545 patients receives a strictly guideline-conforming diagnosis and treatment in the US.[5] A major variation from guidelines-conforming management occurred in the use of adjuvant Bacillus Calmette-Guerin (BCG) instillation therapy.{Table 2}{Table 3}

In order to give our patients with NMIBC the best possible treatment, it is essential to guarantee evidence-based medicine in order to minimize morbidity and possibly improve survival. This article reviews the contemporary data on intravesical immunotherapy in UCC.


This review on intravesical immunotherapy of NMIBC is based on a selected electronic search on databases such as PubMed and Cochrane using following keywords: Immunotherapy, NMIBC, BCG, and intravesical. For the review on the topic, contemporary guidelines on the treatment of NMIBC were used (EAU and AUA).

 Immunotherapy With Bacillus Calmette-Guerin

In 2016, the use of BCG in patients with UCC completes 40 years (1976).[6] Today BCG-immunotherapy has proven to reduce both recurrence and progression of NMIBC and, therefore, represents an important tool in the treatment of NMIBC.[7]

Mechanism of Bacillus Calmette-Guerin

The immunomodulating effect of BCG-instillation therapy is well studied.[8] The antitumoral activity of BCG is explained by a complex interaction between a direct antineoplastic effect on malignant cells and the host's humoral immune system response provoked by local infection.[9] The effect of BCG can be summarized into three essential steps: (1) Infection of urothelium, (2) induction of an immune response, and (3) the induction of an anti-neoplastic effect. The effect is promoted not only by a direct anti-neoplastic effect through local infection of malignant lesions of the bladder but also by the activation of the host's immune response.[9]

After intravesical instillation, there is internalization of BCG into neoplastic cells, which is promoted by the attachment to extracellular proteins such as fibronectin. Thisfirst reaction reflects an infection of urothelium. Inhibiting anti-fibronectin antibodies in murine models result in a lack of antineoplastic activity of BCG and therefore the process of internalization appears to be essential for the effect of BCG.[10] Furthermore, internalization of BCG leads to an increased expression of antigen presenting cells and an enhancement of major histocompatibility complexes class I on the surface of neoplastic bladder lesions. The idea of infected bladder tissue leading to an effective immune response is supported by murine models of UCC presenting antigen to BCG-specific CD4+T-lymphocytes after intravesical instillation.[11] Infection of the urothelial tissue activates a regional immune response and usually induces an immune response promoted by both TH1-cytokines (interleukin-2 [IL-2], IL-12, tumor necrosis factor and interferon-gamma [IFN-γ]) and TH2-cytokines (IL-4, IL-5, IL-6 and IL-10). This cascade of cytokines promotes an antineoplastic activity mediated by cytotoxic T-cells, natural killer cells, macrophages, and neutrophils. Therefore, there is evidence for both TH1-response (cell-mediated acquired immune response) and TH2-response (humoral immune response) in providing antineoplastic activity.[9]

Bacillus Calmette-Guerin strains

Although the EAU-guidelines on NMIBC do not consider different BCG strains to have differences in their efficacy, literature suggests that such differences may exist.[3] Rentsch et al. investigated most common BCG strains (Connaught and Tice) in high-risk NMIBC patients and murine models. The Connaught-strain showed a significantly higher 5-year recurrence free rate of 74% versus 48% in patients treated with the Tice strain (P = 0.0108). In the murine sample, they also presented a stronger TH1-immunresponse, which eventually could lead to a clinical benefit.[12],[13] However, further clinical trials are necessary to evaluate a potential clinical impact.

Adjuvant immunotherapy with Bacillus Calmette-Guerin

The superior efficacy of BCG in the therapy of NMIBC in comparison with TURBT alone and TURBT with adjuvant chemotherapy (mitomycin C [MMC]) has been demonstrated in large studies. The 2015 EAU guidelines refer to at least 5 meta-analyses to demonstrate BCG's superiority.[3] In comparison to other agents used for instillation therapy (MMC, epirubicin, and IFN), BCG showed the best effectivity in respect to preventing recurrences.[14],[15],[16] A single BCG induction course demonstrated decreased recurrence and prevention of tumor progression.[17],[18]

Besides its well-documented ability of preventing recurrence, there is evidence for reduction of progression by BCG immunotherapy. A meta-analysis showed a reduction of 27% in the progression rate of patients following any maintenance schedule of BCG after TURBT.[19] There is data that maintenance of 3 years compared to 1 year shows a prolonged recurrence-free interval but a difference in progression could not be shown.[20] Böhle and Bock proposed in their meta-analysis that maintenance of at least 1 year is needed to provide the advantages of BCG compared to MMC.[19]

In patients with CIS, BCG instillation therapy results in significantly lower rate of recurrence. A study of patients with CIS undergoing 6-weekly BCG-courses (induction-therapy) after previous TURBT showed a complete response (CR) in 71%.[21] The rate of CR was increased to 84% by further maintenance instillations in addition to BCG induction. More than 70% of the BCG-responders remained disease free for more than 5 years.[22]

A more individualized approach was presented in 2011 in a trial including high-risk patients, undergoing a common induction course (6 weeks).[23] Patients who appear to respond after thefirst induction therapy did not get further maintenance therapy. Maintenance therapy or re-treatment was used in the event of relapse. The results showed a higher rate of recurrence but similar progression rates as outlined in previous studies. Although 32% of patients required further BCG instillations, the trial showed that approximately 7 of 10 patients who would regularly be treated with BCG did not actually need a BCG maintenance approach.[23] Concerning the potential severe side effects of BCG, its limited availability and the health economical burden of BCG, reduction of potential BCG-overtreatment makes this approach appealing. The major problem of this approach, however, is an obviously higher recurrence rate compared to a maintenance schedule.

Although there is data suggesting that only those patients who receive BCG maintenance benefit, it remains unclear what an ideal maintenance therapy is. Both frequency of instillation and duration of therapy are not uniformly defined in the literature. The different maintenance regimens are presented in the EAU-guidelines but there is no consensus on an optimal schedule.[7],[24] In order to reduce recurrence rate of high-risk patients, the EORTC proposed a 3 year maintenance regimen rather than 1 year.[20],[25] These guidelines recommend full dose BCG instillation for 1–3 years in patients presenting with high-risk tumors based on the individual risk of the patient, co-morbidities, side effects, costs, and availability of BCG.[3]

Bacillus Calmette-Guerin-dose

Considering the adverse effects of BCG there have been attempts at reducing the dose in order to achieve optimal balance between efficacy and reduction of adverse events (AE). There are several trials focusing on dose reduction (i.e., one-third) and its potential correlation of a reduction of side effects.[20],[26] Although a dose reduction of one-third of the standard dose has been shown to be adequate and efficient in intermediate-risk NMIBC patients, in the high-risk patient dose reduction was associated with a higher recurrence rate. Moreover, although a dose reduction appears to provoke less local side effects, there is no reduction in severe systemic toxicity and serious AEs with dose reduction.[27] In conclusion, most of the published data suggests that a reduction of the standard dose of BCG has little beneficial impact on serious side effects but is associated with a reduced efficiency in high-risk patients.

Bacillus Calmette-Guerin toxicity

Practical experience shows that BCG-instillation is generally well tolerated by patients but serious systemic AEs and even mortality has been reported.[3] Although most of the side effects can be treated effectively, the indication of immunotherapy with BCG has to be justified and, therefore, an individual risk evaluation should be performed.[28] There is no evidence that maintenance regimens are associated with an increased risk of side effects compared to induction therapy. Most side effects that need treatment are seen in the 1st year of BCG therapy.[29] There is no convincing evidence that local side effects correlate with efficiency of immunotherapy in terms of a better outcome.[30] Severe side effects can occur after systemic absorption. Therefore, the EAU describes visible hematuria, symptomatic urinary tract infection, previous traumatic catherisation, and status post-TURBT within 2 weeks as an absolute contraindication for BCG instillation.[3] Although EAU guidelines do not recommend the use of prophylactic antibiotics with intravesical BCG therapy, there is data suggesting an 18.5% decrease in BCG side effects with concurrent use of ofloxacin.[31] Therefore, prophylactic antibiotic use should be considered in order to reduce side effects and improve patient compliance.

Combination therapy of Bacillus Calmette-Guerin and chemotherapy

The combination of BCG with other agents such as chemotherapy may improve its efficacy. A murine model study assessing the intravesical combination of BCG and Gemcitabine suggests a decreased extent of tumor appearance rate, improved survival, and a reduction of neoplastic proliferation compared to BCG instillation alone.[32] However, a meta-analysis focusing on BCG in combination with intravesical chemotherapy detected no significant beneficial effect overall.[33] And a study assessing the combination of BCG instillation and MMC showed no superiority to BCG alone.[34]

 Intravesical Immunotherapy Other Than Bacillus Calmette-Guerin

Radical cystectomy (RC) is indicated for patients with high-risk NMIBC who experience failure of intravesical immunotherapy using BCG.[3] For patients with contraindication for major surgery, there are only a few promising local intravesical immunotherapy regimens.


IFN-α is a well known immunomodulating cytokine with antiproliferative potential with evidence of significant NMIBC tumor response through instillation-therapy. IFN-α shows a moderate response in patients with NMIBC. However, its efficacy in preventing recurrence in intermediate and high-risk NMIBC is very limited. Its utilization as a single immediate-instillation agent after TURBT could not demonstrate a reduction of recurrence risk for low-risk NMIBC.[35] In a randomized controlled trial that compared TURBT alone versus adjuvant IFN-α, the IFN-α arm showed a reduction of risk in intermediate risk patients.[36] Nevertheless in comparison with a control group of MMC over 12 months the clinical response rates were significantly lower for intermediate-risk patients.[37] In addition, IFN-α was inferior to BCG-induction in high-risk NMIBC (recurrent T1 patients).[38] Although IFN-α monotherapy shows beneficial antineoplastic responses, IFN-α-monotherapy is clearly inferior to standard installation therapies in preventing recurrence of BC.[39] IFN-α-combination with BCG in BCG-naive patients showed no benefit in recurrence or progression but is suspected to increase the risk of AE of therapy. However, dual treatment in BCG-naive high-risk patients who cannot tolerate full-dose BCG-monotherapy could help to reduce the BCG-dose and its AE.[39] Therefore, further prospective comparative studies for dual-therapy and dose reduction are needed. Contemporary IFN-α is not regarded as an efficient alternative to MMC or BCG therapy.

Mycobacterium phlei cell wall-nucleic acid complex

Mycobacterium phlei cell wall-nucleic acid complex (MCNA) (formerly Urocidin ™) is an immunomodulatory and antineoplastic substance containing mycobacterial cell wall components complexed with biologically active nucleic acids derivated from the mycobacterium phlei.[40] MCNA, like BCG, shows an indirect immunomodulatory effect that provokes antineoplastic cytokin-production through immune effector cells without pathogenic potential. In addition, there is a direct chemotherapeutic effect comparable with other cytotoxic agents.[40],[41],[42] A recent multicentered clinical trial on patients with high-risk NMIBC after BCG-refractory therapy showed an overall favorabe response of MCNA compared to other intravesical treatments in matchable populations (i.e., valrubicin or gemicitabine).[43] An overall disease-free survival (DFS) of 25% at 1 year and 19% at 2 years was found in the responding arm. MCNA resulted in a 39% DFS at 1 year in patients who had BCG-failure after maintenance (BCG-relapse) and 22.1% in patients who showed BCG-resistance after induction therapy (BCG-refractory). In the same time interval, the effectivity in patients with papillary tumors and CIS was 35.1% and 21%, respectively. The median DFS for the population was 32.7 months. In responders of MCNA, a low-risk of progression and lower RC-rates were shown. In addition, MCNA has a favorable safety profile compared to AE of BCG.[3],[25]

MCNA, therefore, appears to be a promising immunotherapy for a conservative treatment of high-risk NMIBC after BCG-failure. The limitation of the trial is reflected by the small patient population (129), the short duration of surveillance of 3 years and the patient-population “beyond treatment”without the ability of cross-comparing MCNA asfirst-line immunotherapy.

Immune checkpoint inhibitors

BC cells are capable of expressing programmed death-ligand 1 (PD-L1), a molecule that appears to block the ability of the immune system to detect and attack tumor cells.[44],[45] PD-L1 is found particularly in tumor microenvironment of invasive and metastatic stages of BC. There is evidence that PD-L1 binds to PD-1, that are found on T-lymphocytes. The binding of PD-L1 and PD-1 causes T-cell-infectivity. By blocking the PD-L1 molecules, the capability of the immune system for tumor detection and eradication is restored.[46],[47] MPDL3280A, a monoclonal antibody targeting PD-L1 was tested in 31 patients with metastatic UCC. The results were promising; besides a response rate of 50%, side effects were shown to be lower than in chemotherapy and also tolerated in patients suffering from renal failure.[46] To our knowledge there are no trials evaluating immune checkpoint inhibitors in NMIBC. Although PD-L1 was found mostly in MIBC and metastatic UCC the inhibition of PD-L1 in subtypes of superficial BC (i.e., high-risk) might represent a promising therapeutic tool in patients with BCG failure to study.

Interleukin-10 antibody

Recent data from an experimental study assesses the dual use of monoclonal antibody to IL-10 (anti-IL10R1) and concurrent BCG instillation in a murine model of BC.[48] TH1-response is known to mediate efficacy of BCG instillation; IL-10, on the other hand, is known to inhibit TH1-response and, therefore, is associated with BCG failure. The authors found a 22% regression rate in the combination arm of the trial compared to a 6% regression in a group of BCG treatment only.[48] Further, no metastases were found in the group of mice. Therefore the combination of IL-10R1 monoclonal antibody and BCG represents a new promising therapeutic tool in high-risk NMIBC combining local and systemic antineoplastic effect.

Vaccine-based therapy

Vaccine-based agents have recently been evaluated in NMIBC patients. This therapy focuses on vaccine-based proteins with the ability to direct the immune system against bladder tumor specific antigens. There are several vaccine-based agents, such as ALT-803, ALT-801, rec-MAGE-A3, PANVAC, and HS-410 currently in clinical trials.[45] The use of “tumor vaccines”is a promising novel immunotherapy approach but further clinical trials are necessary in order to translate these new modalities into clinical routine.

Intravesical treatment with α-emitter Bi-213-anti-epidermal growth factor receptor-monoclonal antibody

A recent pilot study from TUM Munich, Germany evaluated the intravesical instillation of α-emitter (Bi-213) in 5 patients with BCG-failure and presence of CIS. The α-emitter was coupled to specific antibodies (anti-epidermal growth factor receptor monoclonal antibody [EGFR-MAb]; cetuximab, Merck, Germany), which had showed effectiveness in previous murine models using intravesical human BC cells.[49],[50] Two patients with BCG-refractory CIS underwent a single-shot intravescial instillation of Bi-213-anti-EGFR-MAb. Patients showed no signs of AE and the process of instillation of the immunoradio-conjugate was monitored by single-photon emission computerized tomography/computerized tomography. Two of five patients showed no persistent CIS and 3 patients showed recurrent CIS after the surveillance-period. Bi-213-anti-EGFR-Mab-instillation may be a promising new approach in BCG-refractory patients with CIS and is hoped to be an alternative to RC. As there were no side effects reported, further instillations are theoretically possible. To evaluate the utilization of immunoradio-conjugates in a larger population, a phase-I trial is planned.

Photodynamic therapy

Although photodynamic therapy (PDT) is a device-assisted therapy, there are similarities to intravesical immunotherapy at cellular and bimolecular level.[9] PDT was shown to be an effective alternative even in BCG-refractory UCC and is a conservative option to avoid RC.[51] The effect of PDT is based on the interaction of a special light with its photosensitized target lesion. Photosensitive molecules are instilled into the bladder, internalized by tumor cells and exposed to a specific wavelength light and oxygen which causes a cytotoxic effect. The antineoplastic effect accrues by the production of free radicals, which lead to a direct damage of cells and their apoptosis. Nevertheless, besides the direct cytotoxic effect a secondary inflammatory process evokes a distinct acute inflammation leading to an infiltration of neutrophils similar to the local tissue reaction post-BCG.[52] This is supposed to lead to an increased T-cell-mediated antineoplastic effect.[53] This phase is suspected to be an important factor of successful PDT-treatment. Therefore, the mechanism of PDT shows many similarities with immunotherapy using BCG.

In thefirst generation of photosensitizers for PDT, hematoporphyrin derivates were utilized. These agents showed severe AE in up to 40% of patients.[54] Photosensitizers of the second generation are based on endogenous photoactive porphyrins that are developed intracellularly by local instillation of 5-aminolevulinic acid (5-ALA) and show no severe side effects.[55] PDT using 5-ALA or its derivates as photosensitizer presented good clinical results in several studies.[55] The application of hexaminolevulinate (HAL) showed a 2-fold increase of fluorescence intensity and dissemination in bladder tissue allowing a 20-fold lower concentration of HAL compared to 5-ALA.[56] Bader et al. proposed PDT using HAL as a photosensitizing agent might offer an alternative approach in the treatment of NMIBC.[55] Because of the small number of patients, further studies with a larger sample-size and a long-term follow-up are needed in order to interpret the effectivity of PDT.


Intravesical immunotherapy is well established and its benefits for patients suffering from NMIBC are evident. BCG still represents the gold standard of immunomodulating intravesical treatments for reduction of recurrence and progression, as well as on the improvement of tumor specific survival. However, optimal and clear instillation-schedules or protocols are still subject to debate. Despite the evident benefits of BCG and its maintenance, it is possible that a percentage of patients are over-treated. This leads not only to immense economical burden but also to potential severe side effects in patients who actually do not benefit from the therapy. Therefore, an objective predictor of success of BCG-treatment, such as biomarkers or cytokines would be useful in order to provide an optimal and efficient treatment. In patients with BCG-failure or in patients who are not able to tolerate a BCG therapy, intravesical chemotherapy is an option. However, for high-risk-patients who show BCG-refractory disease, radical cystectomy still remains the recommended treatment. The establishment and further development of alternative immunotherapies (MCNA, PTD, IFN, Bi-213-anti-EGFR-MAb) could help provide alternative treatments for patients who are not able or are not willing to undergo cystectomy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
2Sievert KD, Amend B, Nagele U, Schilling D, Bedke J, Horstmann M, et al. Economic aspects of bladder cancer: What are the benefits and costs? World J Urol 2009;27:295-300.
3Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Compérat E, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: Update 2013. Eur Urol. 2013;64:639-53.
4Witjes JA, Palou J, Soloway M, Lamm D, Kamat AM, Brausi M, et al. Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guérin (BCG): Results of an international individual patient data survey (IPDS). BJU Int 2013;112:742-50.
5Chamie K, Saigal CS, Lai J, Hanley JM, Setodji CM, Konety BR, et al. Compliance with guidelines for patients with bladder cancer: Variation in the delivery of care. Cancer 2011;117:5392-401.
6Morales A, Eidinger D, Bruce AW. Intracavitary bacillus calmette-guerin in the treatment of superficial bladder tumors. J Urol 1976;116:180-3.
7Sylvester RJ, van der Meijden AP, 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.
8Alexandroff AB, Jackson AM, O'Donnell MA, James K. BCG immunotherapy of bladder cancer: 20 years on. Lancet 1999;353:1689-94.
9Fuge O, Vasdev N, Allchorne P, Green JS. Immunotherapy for bladder cancer. Res Rep Urol 2015;7:65-79.
10Kavoussi LR, Brown EJ, Ritchey JK, Ratliff TL. Fibronectin-mediated Calmette-Guerin bacillus attachment to murine bladder mucosa. Requirement for the expression of an antitumor response. J Clin Invest 1990;85:62-7.
11Lattime EC, Gomella LG, McCue PA. Murine bladder carcinoma cells present antigen to BCG-specific CD4 T-cells. Cancer Res 1992;52:4286-90.
12Noon AP, Kulkarni GS. All bacillus Calmette-Guérin (BCG) strains are equal, but some BCG strains are more equal than others. Eur Urol 2014;66:689-91.
13Rentsch CA, Birkhäuser FD, Biot C, Gsponer JR, Bisiaux A, Wetterauer C, et al. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol 2014;66:677-88.
14Järvinen R, Kaasinen E, Sankila A, Rintala E; FinnBladder Group. Long-term efficacy of maintenance bacillus Calmette-Guérin 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.
15Duchek M, Johansson R, Jahnson S, Mestad O, Hellström P, Hellsten S, et al. Bacillus Calmette-Guérin is superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective, randomized, Nordic study. Eur Urol 2010;57:25-31.
16Shang PF, Kwong J, Wang ZP, Tian J, Jiang L, Yang K, et al. Intravesical Bacillus Calmette-Guérin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst Rev 2011;5:CD006885.
17Lamm DL. Bacillus Calmette-Guerin immunotherapy for bladder cancer. J Urol 1985;134:40-7.
18Pinsky CM, Camacho FJ, Kerr D, Geller NL, Klein FA, Herr HA, et al. Intravesical administration of bacillus Calmette-Guérin in patients with recurrent superficial carcinoma of the urinary bladder: Report of a prospective, randomized trial. Cancer Treat Rep 1985;69:47-53.
19Böhle A, Bock PR. Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: Formal meta-analysis of comparative studies on tumor progression. Urology 2004;63:682-6.
20Oddens J, Brausi M, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin 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.
21De Jager R, Guinan P, Lamm D, Khanna O, Brosman S, De Kernion J, et al. Long-term complete remission in bladder carcinoma in situ with intravesical TICE bacillus Calmette Guerin. Overview analysis of six phase II clinical trials. Urology. 1991;38:507-13.
22Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, 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.
23Herr HW, Dalbagni G, Donat SM. Bacillus Calmette-Guérin without maintenance therapy for high-risk non-muscle-invasive bladder cancer. Eur Urol 2011;60:32-6.
24Zlotta AR, van Vooren JP, Huygen K, Drowart A, Decock M, Pirson M, et al. What is the optimal regimen for BCG intravesical therapy? Are six weekly instillations necessary? Eur Urol 2000;37:470-7.
25Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and 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.
26Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, 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.
27Martínez-Piñeiro JA, Flores N, Isorna S, Solsona E, Sebastián JL, Pertusa C, et al. Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int 2002;89:671-80.
28Lamm DL. Efficacy and safety of bacille Calmette-Guérin immunotherapy in superficial bladder cancer. Clin Infect Dis 2000;31 Suppl 3:S86-90.
29van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV; EORTC Genito-Urinary Tract Cancer Group. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: Results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol 2003;44:429-34.
30Lüftenegger W, Ackermann DK, Futterlieb A, Kraft R, Minder CE, Nadelhaft P, et al. Intravesical versus intravesical plus intradermal bacillus Calmette-Guerin: A prospective randomized study in patients with recurrent superficial bladder tumors. J Urol 1996;155:483-7.
31Palou J, Angerri O, Segarra J, Caparrós J, Guirado L, Diaz JM, et al. Intravesical bacillus Calmette-Guèrin for the treatment of superficial bladder cancer in renal transplant patients. Transplantation 2003;76:1514-6.
32Horinaga M, Fukuyama R, Iida M, Yanaihara H, Nakahira Y, Nonaka S, et al. Enhanced antitumor effect of coincident intravesical gemcitabine plus BCG therapy in an orthotopic bladder cancer model. Urology 2010;76:1267.e1-6.
33Houghton BB, Chalasani V, Hayne D, Grimison P, Brown CS, Patel MI, et al. Intravesical chemotherapy plus bacille Calmette-Guérin in non-muscle invasive bladder cancer: A systematic review with meta-analysis. BJU Int 2013;111:977-83.
34Kaasinen E, Wijkström H, Malmström PU, Hellsten S, Duchek M, Mestad O, et al. Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: A nordic study. Eur Urol 2003;43:637-45.
35Rajala P, Kaasinen E, Raitanen M, Liukkonen T, Rintala E; Finnbladder Group. 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 long-term results. J Urol 2002;168:981-5.
36Giannakopoulos S, Gekas A, Alivizatos G, Sofras F, Becopoulos T, Dimopoulos C. Efficacy of escalating doses of intravesical interferon alpha-2b in reducing recurrence rate and progression in superficial transitional cell carcinoma. Br J Urol 1998;82:829-34.
37Glashan RW. A randomized controlled study of intravesical alpha-2b-interferon in carcinoma in situ of the bladder. J Urol 1990;144:658-61.
38Jimenez-Cruz JF, Vera-Donoso CD, Leiva O, Pamplona M, Rioja-Sanz LA, Martinez-Lasierra M, et al. Intravesical immunoprophylaxis in recurrent superficial bladder cancer (Stage T1): Multicenter trial comparing bacille Calmette-Guérin and interferon-alpha. Urology 1997;50:529-35.
39Lamm D, Brausi M, O'Donnell MA, Witjes JA. Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer. Urol Oncol 2014;32:35.e21-30.
40Filion MC, Phillips NC. Therapeutic potential of mycobacterial cell wall-DNA complexes. Expert Opin Investig Drugs 2001;10:2157-65.
41Filion MC, Filion B, Reader S, Ménard S, Phillips NC. Modulation of interleukin-12 synthesis by DNA lacking the CpG motif and present in a mycobacterial cell wall complex. Cancer Immunol Immunother 2000;49:325-34.
42Reader S, Ménard S, Filion B, Filion MC, Phillips NC. Pro-apoptotic and immunomodulatory activity of a mycobacterial cell wall-DNA complex towards LNCaP prostate cancer cells. Prostate 2001;49:155-65.
43Morales A, Herr H, Steinberg G, Given R, Cohen Z, Amrhein J, et al. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guérin. J Urol 2015;193:1135-43.
44LaRue H, Ayari C, Bergeron A, Fradet Y. Toll-like receptors in urothelial cells – Targets for cancer immunotherapy. Nat Rev Urol 2013;10:537-45.
45Boehm BE, Svatek RS. Novel therapeutic approaches for recurrent nonmuscle invasive bladder cancer. Urol Clin North Am 2015;42:159-68, vii.
46Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558-62.
47Carneiro BA, Meeks JJ, Kuzel TM, Scaranti M, Abdulkadir SA, Giles FJ. Emerging therapeutic targets in bladder cancer. Cancer Treat Rev 2015;41:170-8.
48Newton MR, Askeland EJ, Andresen ED, Chehval VA, Wang X, Askeland RW, et al. Anti-interleukin-10R1 monoclonal antibody in combination with bacillus Calmette – Guérin is protective against bladder cancer metastasis in a murine orthotopic tumour model and demonstrates systemic specific anti-tumour immunity. Clin Exp Immunol 2014;177:261-8.
49Scheidhauer K, Seidl C, Morgenstern A, Bruchertseifer F, Apostolidis C, Autenrieth M, et al. Treatment of bladder cancer with Bi-213-anti-EGFR-MAb - A pilot study. J Nucl Med 2014;55 Suppl 1:639. Available from: [Last accessed on 2015 Sep 19].
50Autenrieth M, Kurtz F, Horn T, Seidl C, Morgenstern A, Bruchertseifer F, et al. Intravesikale α-Strahler-Radioimmuntherapie mit Bi-213-anti-EGFR-mAb beim Carcinoma in situ-Rezidiv nach BCG-Therapie: Eine Alternative zur Zystektomie? Available from [Last accessed on 2015 Sep 19].
51Waidelich R, Stepp H, Baumgartner R, Weninger E, Hofstetter A, Kriegmair M. Clinical experience with 5-aminolevulinic acid and photodynamic therapy for refractory superficial bladder cancer. J Urol 2001;165:1904-7.
52Pinthus JH, Bogaards A, Weersink R, Wilson BC, Trachtenberg J. Photodynamic therapy for urological malignancies: Past to current approaches. J Urol 2006;175:1201-7.
53Gollnick SO, Brackett CM. Enhancement of anti-tumor immunity by photodynamic therapy. Immunol Res 2010;46:216-26.
54Nseyo 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;160:39-44.
55Bader MJ, Stepp H, Beyer W, Pongratz T, Sroka R, Kriegmair M, et al. Photodynamic therapy of bladder cancer - a phase I study using hexaminolevulinate (HAL). Urol Oncol 2013;31:1178-83.
56Lange N, Jichlinski P, Zellweger M, Forrer M, Marti A, Guillou L, et al. Photodetection of early human bladder cancer based on the fluorescence of 5-aminolaevulinic acid hexylester-induced protoporphyrin IX: A pilot study. Br J Cancer 1999;80:185-93.