The Emerging Treatment of BCG (Bacillus Calmette-Guérin)-Unresponsive Non–Muscle-Invasive Bladder Cancer

Jong Ho Park; Jong Jin Oh

doi:10.22465/juo.244800540047

J Urol Oncol > Volume 22(3); 2024 > Article

Park and Oh: The Emerging Treatment of BCG (Bacillus Calmette-Guérin)-Unresponsive Non-Muscle-Invasive Bladder Cancer

Invited Review

Bladder Cancer

Journal of Urologic Oncology 2024; 22(3): 246-255.

Published online: November 30, 2024

DOI: https://doi.org/10.22465/juo.244800540047

The Emerging Treatment of BCG (Bacillus Calmette-Guérin)-Unresponsive Non-Muscle-Invasive Bladder Cancer

Jong Ho Park¹

, Jong Jin Oh^1,²

¹Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea

²Department of Urology, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Jong Jin Oh Department of Urology, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea Email: urojj@snubh.org

Received September 12, 2024 Revised November 11, 2024 Accepted November 23, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Bacillus Calmette-Guérin (BCG) remains the cornerstone in the treatment of high-risk non-muscle-invasive bladder cancer (NMIBC), effectively preventing recurrence and progression. Unfortunately, a significant proportion of patients are classified as BCG-unresponsive, and there have been no definite alternative treatments for these disease group except for radical cystectomy, which is still challenging and sometimes not applicable. Therefore, there has been a need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. Intravesical therapies, such as gemcitabine, mitomycin C and docetaxel, are mostly studied approaches, showing some promising results. However, no definitive conclusion has be drawn because of the heterogeneity of the studies and protocols and the limited number of patients enrolled in most of these studies. Immunotherapy and anti-inflammatory agents, though promising, require further validation through ongoing clinical trials to ensure their safety and efficacy. Gene therapy is also being explored, though it is in its early stages, with challenges in gene delivery and immune regulation still to be addressed. Photodynamic therapy and hyperthermia, particularly in combination with other treatments like intravesical chemotherapy, have shown potential in improving outcomes for BCG-unresponsive patients, though they are not yet considered first-line treatments. While these novel approaches hold promise, more robust data and clinical trial results are necessary to guide treatment protocols. In conclusion, ongoing research and clinical trials will continue to shape the future of NMIBC management, with the aim of providing more effective and bladder-preserving options for patients.

Key Words: Non-muscle-invasive bladder cancer, BCG vaccine, Genetic therapy, Immunotherapy, Photochemotherapy

HIGH-RISK NMIBC AND BCG UNRESPONSIVENESS

Bladder cancer is the ninth most common malignancy worldwide and the tenth most diagnosed malignancy in South Korea [1,2]. It is a highly heterogeneous disease that includes both non-muscle-invasive bladder carcinoma (NMIBC) and muscle-invasive bladder carcinoma (MIBC), which have distinct prognoses and treatment strategies. About 80% of bladder cancers are initially diagnosed as NMIBC after initial transurethral resection of bladder tumor (TURBT). While low-risk NMIBC patients are mainly treated with TURBT alone, intermediate- and high-risk patients usually require additional adjuvant therapies to reduce the risk of recurrence and progression [3-6].

Current standard treatment after TURBT for high-risk NMIBC patients, according to National Comprehensive Cancer Network (NCCN) guideline, involves intravesical bacillus Calmette-Guérin (BCG) therapy, which has been proven to be effective in reducing tumor recurrence and progression [7]. However, approximately 30% to 40% of patients receiving BCG treatment will experience failure, resulting in an elevated risk of recurrence and progression [8,9]

BCG failure has been broadly defined as any recurrence or progression during therapy. However, the term is heterogeneous, encompassing a number of differing clinical scenarios. Kamat et al. [10] classifies BCG failure into the following 4 types, the classification of which NCCN cites for its guideline; BCG refractory, BCG relapsing, BCG intolerant, and BCG unresponsive. For clinical trials, adequate BCG therapy is when a patient has received at least 5 of 6 induction instillations and at least 2 of 3 maintenance instillations in a 6-month period. BCG refractory means a persistent high-grade (HG) disease at 6 months despite adequate BCG treatment. This category also includes any stage or grade progression by 3 months after the first BCG cycle. BCG relapsing means a recurrence of HG disease after achieving a disease-free state at 6 months after adequate BCG. BCG intolerant means a disease persistence as a result of inability to receive adequate BCG because of toxicity. Lastly, BCG unresponsive comprehends both BCG refractory and BCG relapsing disease. The European Association of Urology guidelines currently define “BCG-unresponsive” as all BCG-refractory tumors and those that develop T1/Ta HG recurrence within 6 months of completion of adequate BCG exposure or develop carcinoma in situ (CIS) within 12 months of completion of adequate BCG exposure [11]. Patients with BCG-unresponsive NMIBC are very unlikely to benefit from further BCG administration and their needs for new treatment options are urgent and therapeutically challenging [11,12].

In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.

RADICAL CYSTECTOMY

According to the NCCN guidelines, the recommended treatment for BCG-unresponsive disease remains radical cystectomy (RC), offering a reasonable quality of life outcome and improved disease-specific survival (DSS) if performed within 2 years of the initial BCG therapy. [7,13-15]

Moreover, the study by Herr and Sogani [14] shows significant difference (92% vs. 56% during 15-to 20-year follow-up) of DSS between early cystectomy and delayed cystectomy among 35 BCG-unresponsive patients. Also, the study by Denzinger et al. [15] shows that the 10-year cancer-specific survival rate was 78% in early RC and 51% in deferred RC among total of 105 BCG-unresponsive patients.

These studies suggest the superiority of early RC over deferred RC for BCG-unresponsive NMIBC patients.

BLADDER-SPARING TREATMENT

Despite that RC is the most efficient and recommended treatment for BCG-unresponsive patients, surgical treatment may not be feasible for patients with significant comorbidities, those who prefer bladder preservation, or those who are reluctant to undergo major surgery [16]. Yet, nonsurgical options for BCG-unresponsive patients are limited [11]. By 2020, the only U.S. Food and Drug Administration (FDA)-approved bladder-sparing treatment for BCG-unresponsive patients was intravesical valrubicin, with a complete response (CR) rate of about 18%, which might be an unsatisfactory efficacy profile [17]. Nowadays, multiple new therapeutic options have been suggested and could lead to a breakthrough in the treatment of BCG-unresponsive patients. The NCCN guideline currently presents a number of bladder-sparing treatments; intravesical chemotherapy (Gemcitabine, Mitomycin C), Pembrolizumab, Nadofaragene firadenovec and Nogapendekin alfa-inbakicept (NAI) [7]. Besides the FDA-approved treatment that guideline suggests, there are a few others that have been investigated, such as intravesical photodynamic therapy (PDT) or chemohyperthemia [11,16].

1. Intravesical Chemotherapy

For decades, various chemotherapeutic agents have been investigated for intravesical administration in BCG-unresponsive NMIBC. Among the chemotherapeutic agents studied, gemcitabine may be the one that receives most attention [18]. Gemcitabine administration regimens are quite heterogeneous among the published literature, with some studies suggesting a single agent, while others recommending commbinations with various other drugs such as docetaxel [19-22], cabazitaxel and cisplatin [23], oral everolimus [24], and mitomycin C [25,26]. No clear and standardized regimen can be found in either single agent or drug combination studies.

1) Gemcitabine monotherapy

Hurle et al. [27] reported disease-free survival (DFS) rates of 44.44% at 12 months and 31.66% at 24 months. Progression-free survival (PFS) was 80.13% at 12 months and 69.55% at 24 months.

Skinner et al. [28] found that 47% of patients achieved CR rate after 3 months of treatment with gemcitabine alone, with a median recurrence-free survival (RFS) of 6.1 months and 21% RFS at 24 months.

In the study of Sternberg et al. [29], the 5-year progression to MIBC was 19% in BCG-unresponsive patients. The study also recorded 27 patients who achieved CR, with a cancer-specific death rate of 12% among complete responders.

2) Gemcitabine combinations

Chevuru et al. [19] suggested gemcitabine plus docetaxel regimen and reported RFS rates of 57% at 12 months and 44% at 24 months, with slightly poorer outcomes in CIS patients compared to those with papillary disease. Similar results were found in the retrospective study by Steinberg et al. [20] published in 2020.

Regimen of gemcitabine plus cabazitaxel and cisplatin has been suggested by DeCastro et al. [23]. The study of DeCastro et al. [23] achieved a CR rate in 89% of patients with a median RFS of 27 months. The study also reported 94% RC-free survival at 1 year and 81% at 2 years.

Dalbagni et al. [24] suggested gemcitabine plus oral everolimus regimen, and reported a RFS of 58% at 3 months, 27% at 6 and 9 months, and 20% at 12 months.

As for gemcitabine plus mitomycin C regimen, Cockerill et al. [25] found a 63% recurrence rate with a median RFS of 15.2 months, while Lightfoot reported a CR rate of 68%, with 1-year and 2-year RFS rates of 48% and 38%, respectively.

3) Others

Other drugs such as docetaxel [30,31], paclitaxel, nab-paclitaxel [31-33], and doxorubicin [34] also have been studied, unfortunately showing conflicting results.

In summary, despite some notable results, no definitive conclusion has been drawn regarding intravesical chemotherapy for BCG unresponsiveness, due to the heterogeneity of the studies and regimens and the limited number of patients enrollment.

2. Immunotherapy: Immune Checkpoint Blockade

1) Pembrolizumab

In the field of immunotherapy for both MIBC and upper tract urothelial carcinoma, pembrolizumab (programmed cell death protein 1 [PD-1] inhibitor) has played an increasingly important role in recent years [8,35]. Up to date, some studies have attempted to evaluate the efficacy of pembrolizumab in BCG-unresponsive NMIBC. In these studies, pembrolizumab has been administered in combination with BCG by both intravesical and intravenous, or as a single agent [12,36-38].

In a study by Meghani et al. [36], 9 patients were treated with a combination of BCG and intravesical pembrolizumab. RFS rates at 3-, 6-, and 12-month was 100%, 67%, and 22%, respectively, and PFS rates at 6 and 12 months was 100% and 56%, respectively, with MIBC occurrence being reported in 5 patients. Alanee et al. [37] found a CR rate of 69% in 18 patients with BCG in combination with intravenous pembrolizumab, with 1 patient progressing to MIBC.

The KEYNOTE-057 (NCT02625961) trial is an open-label, single-arm, multicenter, phase 2 study that evaluated pembrolizumab monotherapy as a treatment for patients with BCG-unresponsive NMIBC, focusing on 2 cohorts; cohort A with CIS +/- papillary tumors and cohort B with papillary tumors without CIS. Cohort A shows CR rates of 41%, 31%, and 19% at 3, 6, and 12 months of treatment respectively [12]. Cohort B shows a DFS rate of 43.5% at 12 months of treatment [38]. The study is ongoing, with further follow-ups and detailed data expected in the future.

2) Atezolizumab

The SWOG-S1605 (NCT02844816) phase II trial was a single-arm study that tested the efficacy of atezolizumab (PD-L1 inhibitor), in patients with BCG-unresponsive NMIBC who were either ineligible for or declined RC. Participants were grouped into 2 cohorts: those with CIS and those with Ta/T1 HG tumors. Results showed a CR rate of 27% (20 of 74) in the CIS cohort at 6 months, with these responses lasting a median of 15.4 months. The 18-month DFS rates varied, recorded at 47.1% in the Ta/T1 HG cohort, 17% in the CIS cohort, and 29% across all participants. Notably, 3 individuals progressed to MIBC, 2 at 3 months and 1 at 22 months. Additionally, 2 patients developed metastatic disease without any recurrence in the bladder at 17 and 31 months, respectively [39].

3) Tar-200 +/- cetrelimab

The SunRISe-1 trial (NCT04640623) is a pivotal phase 2b study evaluating TAR-200, a novel drug delivery system for sustained release of gemcitabine, in BCG-unresponsive NMIBC patients who are ineligible for or refusing RC [40,41].

The study enrolled patients across several cohorts. Cohort 1 included patients who received Tar-200 plus cetrelimab (PD-1 inhibitor), while cohort 2 and 3 received TAR-200 monotherapy and cetrelimab monotherapy, respectively [41].

Results from cohort 2 showed a CR rate of 83.5%, with 82% of those responses maintained after a median follow-up of 9 months, and an estimated 12-month CR rate was 57.4% based on the Kaplan-Meier curve. Importantly, TAR-200 was well tolerated, with only 6% of patients discontinuing due to adverse effects [41]. Results from cohort 1 and 3 showed a 67.9% and 46.4% of CR rate, respectively. The cetrelimab monotherapy CR rate is numerically similar to previously published CR rates from this class of therapies [42].

3. Immunotherapy: Inflammatory Marker Targeting Agents

The relationship between inflammation and tumor development has always been an important field of translational research [43]. Moreover, targeting inflammation in cancer treatment, including cytokines, and/or chemokines and their receptors, is a crucial point in inhibiting tumor invasion and progression [44].

NAI, known as N-803, an interleukin (IL)-15 super agonist, is a fused protein from a human IL-15 variant bound to a dimeric human IL-15Ra domain/human IgG1 Fc. This IL-15-based immunostimulatory complex plays a crucial role in the activation and proliferation of natural killer (NK) cells as well as effector and memory T cells [45]. Hypothesizing that NAI may synergistically enhance the efficacy of BCG by activating NK and T cells in an above-mentioned mechanism, Chamie et al. [46] conducted an open-label, multi-institutional study in 3 cohorts of BCG-unresponsive patients. Cohort A comprised patients with CIS +/- other NMIBC papillary diseases, treated with intravesical NAI plus BCG. Cohort B included patients with Ta/T1 HG NMIBC, also receiving NAI plus BCG. Cohort C consisted of patients treated solely with NAI. The primary endpoints were the CR rates at 3, 6, and 12 months for cohorts A and C, and the DFS rate at 12 months for cohort B. Results showed a 71% CR rate in cohort A, with specific rates of 55%, 56%, and 45% at 3, 6, and 12 months respectively, and a median duration of response (DOR) of 26.6 months. Cohort B showed a 12-month DFS rate of 55.4%, with a median DFS of 19.3 months. In contrast, cohort C achieved only a 20% CR rate at 3 months, leading to its early termination based on predefined protocol rules. Treatment-related adverse events, mainly minor and related to bladder instillation, were also documented.

4. Viral Gene Therapy

Interferon alfa-2b (IFNα-2b) protein has been believed to be inducing tumor regression in BCG-unresponsive patient with good tolerance, while in vitro studies have shown that intravesical administration of recombinant IFNα gene facilitates the local production of IFNα-2b [47-49]. Nadofaragene firadenovec (rAd-IFNα/Syn3) is a novel viral gene therapy agent, that consists of 2 functional components. rAd-IFNα is a nonreplicating recombinant adenovirus vector-based genetic agent that delivers a copy of the human IFNα-2b gene into the urothelial cell wall [48,49]. The other part is Syn3 which is a polyamide surfactant that enhances viral transduction of the urothelium [50]. In a phase II trial involving 40 BCG-unresponsive NMIBC patients, 35% were free of HG recurrence after 12 months [51]. Motivated by these promising results, Boorjian et al. [52] conducted a more extensive phase III study across 33 U.S. institutions, involving 151 BCG-unresponsive patients. The primary endpoint of this multicenter, single-arm, open-label, repeat-dose (administered at 3, 6, and 9 months) trial was CR at any time in patients with CIS, +/- concurrent Ta/T1 HG NMIBC. The observed CR rates were 53.4% at 3 months, 40.8% at 6 months, and 24.3% at 12 months. The treatment was generally well tolerated with no significant side effects reported.

Cretostimogene grenadenorepvec, also known as CG0070, is a replication-competent oncolytic adenovirus that targets bladder cancer cells through their defective retinoblastoma signaling pathway [11]. In a phase II, single-arm, multicenter BOND-2 trial (NCT02365818), Packiam et al. [53] studied 45 BCG-responsive patients who received intravesical CG0070. Overall, administration of CG0070 resulted in a CR rate of 47% at 6 months for all patients and 50% for patients with pure CIS. Currently a phase III, single-arm, open-label, BOND-3 trial (NCT04452591) of intravesical administration of CG0070 monotherapy for patients with pathologically confirmed BCG-unresponsive NMIBC with CIS +/- Ta/ T1, is ongoing and Tyson et al. reported promising results at SUO 2023. Of the 66 patients who received intravesical administration of CG0070 monotherapy, a CR rate was 75.7% at any time, and 74.4% (32 of 43) of responders maintained a response for more than 6 months [54].

The combination of CG0070 + pembrolizumab is under investigation in a single-arm, phase-2 CORE-001 trial (NCT04387461). Thirty-five patients were included, and 5 patients discontinued prior to the 12-month time point. The CR rate at 12 months, 24 months, and any time, was 57%, 46%, and 83%, respectively. Median DOR has not been reached but exceeds 21 months [55].

5. Intravesical PDT

Recent studies have explored efficacy and safety of PDT in BCG-unresponsive NMIBC, which uses an interaction between absorbed light and a retained photosensitizing agent to destroy tissue [56].

Kulkarni et al. [57] examined the use of the photosensitizer TLD-1433 in a small cohort of BCG-unresponsive patients. In this open-label, single-arm study, 6 patients received escalating doses of the therapy. Of the 3 patients who were administered the therapeutic dose, 2 achieved CR at 180 days, which was later confirmed at 18 months. The other patient developed metastatic disease approximately 4 months after treatment. Therapy was generally well tolerated, with all patients experiencing at least one grade ≤2 adverse events.

Lee et al. [58] conducted a more extensive investigation involving 34 patients with HG NMIBC who were either unresponsive to or intolerant of BCG. In this study, patients were treated with photosensitizer Radachlorin-mediated PDT. The RFS rate was 90.9% at 12 months, 64.4% at 24 months, and 60.1% at 30 months. Survival analysis did not show significant differences related to lesion size, the presence of CIS, or the number of previous BCG cycles.

In 2023, Kulkarni et al. [59] published interim findings from a phase II clinical trial assessing the efficacy of TLD-1433-mediated PDT in BCG-unresponsive CIS patients. Total of 45 patients were included, along with 3 patients from an earlier phase Ib study. The interim clinical data demonstrates a 90 days CR of 50% and a DOR at 360 and 450 days of 35% and 21%, respectively. There have been 8 serious adverse events identified, but none of them were deemed to be directly related to the PDT.

6. Chemohyperthermia

The effects of hyperthermia on tumor cells have been studied up to date, and several therapeutic effects have been discovered. First, when tumor cells are exposed to temperatures above 40.5℃, critical cellular processes like RNA and DNA synthesis are reduced, and DNA repair mechanisms are impaired. [60]. Hyperthermia also impacts tumor blood flow. Up to 43℃, vasodilation occurs, which can enhance the delivery of chemotherapeutic agents. Moreover, direct damage to the endothelial cell lining of the tumor vessels results in decreased blood flow to the cancer cells. In turn, the cancer microenvironment becomes gradually hypoxic, and cancer cells become more vulnerable to hyperthermia or chemotherapeutic agents, while angiogenesis is inhibited via the upregulation of the plasminogen activator inhibitor-1 pathway in endothelial cells of the tumor vasculature [61]. In addition, hyperthermia can stimulate the immune system by mimicking the body’s natural fever response. It activates CD8 and CD4 immune cells, promotes the infiltration of NK cells, and triggers the production of heat shock proteins and cytokines, which collectively enhance immune responses against tumors [62].

In practice, an intravesical temperature ranging between 40℃-45℃ can be achieved either by using microwaves from radiofrequency emitters in a catheter or external conductive systems that heat chemotherapeutic solutions before delivery. Locoregional hyperthermia, which uses external devices to generate localized heat, is another approach [63].

Despite some variations in study designs and protocols across studies, DFS rates peaked at 85% in some cases, with around 50% of patients achieving a CR at 1 or 2 years [64-66]. In a randomized clinical trial by Tan et al. [67], no significant differences in oncological outcomes were observed between radiofrequency-induced thermo-chemotherapy with MMC and BCG retreatment. Additionally, a retrospective, multicenter, single-arm study tested the efficacy of a hyperthermic intravesical chemotherapy system that reheats and circulates hot mitomycin C in the bladder; the 2-year RFS rate was 19.9% and 43.7% in patients with or without CIS respectively, with no significant differences in progression to MIBC between the 2 groups [68].

In conclusion, although there have been some promising results with chemohyperthermia, the data remain inconsistent across different studies and patient populations, and is needed to be confirmed by further studies.

CONCLUSIONS

Nowadays, BCG continues to play a central role in the treatment of high-risk NMIBC. It is highly effective in preventing the recurrence and progression of NMIBC and remains the treatment of choice today. However, there is a significant proportion of patients who are classified as BCG-unresponsive. As RC remains the gold standard for patients with BCG-unresponsive NMIBC, there is growing interest in establishing novel bladder-preserving therapeutic methods.

Intravesical therapies with gemcitabine, docetaxel, and other agents, have shown a potential role in the treatment of BCG-unresponsive NMIBC, despite of the heterogeneity of the studies and protocols and the limited number of patients enrolled in most of these studies.

The use of immunotherapy and anti-inflammatory agents in NMIBC is an area of active research and ongoing clinical trials. Although some of these agents have shown promising results, further demonstration of their safety and efficacy in the treatment of NMIBC is needed.

Gene therapy offers a promising avenue for treating NMIBC, but it is still in the early stages of development. There are several challenges that need to be overcome, including improving gene delivery methods, managing immune responses, and ensuring targeted gene expression. Ongoing clinical trials are assessing the safety and effectiveness of this therapy and as research progresses, it could potentially provide new treatment options for patients with this type of bladder cancer.

PDT is showing promise as an alternative treatment for BCG-unresponsive NMIBC patients. Studies on TLD-1433 and Radachlorin-mediated PDT have reported encouraging outcomes, with high RFS rates and manageable safety profiles. However, long-term data and further clinical trials are necessary to fully understand the potential benefits and risks.

Hyperthermia, especially in combination with other therapies such as intravesical chemotherapy, has shown quite promising results in clinical trials in improving treatment outcomes in NMIBC patients, particularly those with high-risk or recurrent tumors. However, further studies are still needed to determine the optimal protocols, safety, and long-term benefits of hyperthermia in combination with other treatments for NMIBC.

In conclusion, whilst more robust data is required to develop guidelines, available treatment options should be discussed with patients, and recruitment for clinical trials needs to continue. Results from ongoing trials will provide us with more insight into many of the existing regimens, and potentially new treatment options will soon be available for BCG-unresponsive NMIBC patients.

NOTES

Grant/Fund Support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of Interest

The authors have nothing to disclose.

Author Contribution

Conceptualization: JJO, JHP; Data curation: JHP, JJO; Formal analysis: JHP, JJO; Methodology: JHP, JJO; Project administration: JJO; Visualization: not applicable; Writing - original draft: JHP; Writing - review & editing: JJO, JHP.

REFERENCES

1. Pettenati C, Ingersoll MA. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol 2018;15:615-25.

2. Park EH, Jung KW, Park NJ, Kang MJ, Yun EH, Kim HJ, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2021. Cancer Res Treat 2024;56:357-71.

3. Beijert IJ, Hentschel AE, Bründl J, Compérat EM, Plass K, Rodríguez O, et al. Prognosis of primary papillary Ta grade 3 bladder cancer in the non-muscle-invasive spectrum. Eur Urol Oncol 2023;6:214-21.

4. Claps F, van de Kamp MW, Mayr R, Bostrom PJ, Boormans JL, Eckstein M, et al. Risk factors associated with positive surgical margins’ location at radical cystectomy and their impact on bladder cancer survival. World J Urol 2021;39:4363-71.

5. Claps F, van de Kamp MW, Mayr R, Bostrom PJ, Shariat SF, Hippe K, et al. Prognostic impact of variant histologies in urothelial bladder cancer treated with radical cystectomy. BJU Int 2023;132:170-80.

6. Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur Urol 2022;81:75-94.

7. National Comprehensive Cancer Network. NCCN guideline for bladder cancer. Version 4.2024 [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; [cited 2024 Oct 12]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.

8. Witjes JA. Management of BCG failures in superficial bladder cancer: a review. Eur Urol 2006;49:790-7.

9. Barmoshe S, Zlotta AR. Prognosis of T1G3 tumors: clinical factors. Eur Urol Suppl 2004;3:73-8.

10. Kamat AM, Sylvester RJ, Böhle A, Palou J, Lamm DL, Brausi M, et al. Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the international bladder cancer group. J Clin Oncol 2016;34:1935-44.

11. Claps F, Pavan N, Ongaro L, Tierno D, Grassi G, Trombetta C, et al. BCG-unresponsive non-muscle-invasive bladder cancer: current treatment landscape and novel emerging molecular targets. Int J Mol Sci 2023;24:12596.

12. Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguié M, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an openlabel, single-arm, multicentre, phase 2 study. Lancet Oncol 2021;22:919-30.

13. Esrig D, Freeman JA, Stein JP, Skinner DG. Early cystectomy for clinical stage T1 transitional cell carcinoma of the bladder. Semin Urol Oncol 1997;15:154-60.

14. Herr HW, Sogani PC. Does early cystectomy improve the survival of patients with high-risk superficial bladder tumors? J Urol 2001;166:1296-9.

15. Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53:146-52.

16. Kodera A, Mohammed M, Lim P, Abdalla O, Elhadi M. The management of bacillus Calmette-Guérin (BCG) failure in high-risk non-muscle invasive bladder cancer: a review article. Cureus 2023;15:e40962.

17. Soria F, Gontero P. Re: Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Eur Urol 2021;79:891-2.

18. Yoshida T, Kates M, Fujita K, Bivalacqua TJ, McConkey DJ. Predictive biomarkers for drug response in bladder cancer. Int J Urol 2019;26:1044-53.

19. Chevuru PT, McElree IM, Mott SL, Steinberg RL, O’Donnell MA, Packiam VT. Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for nonmuscle invasive bladder cancer. Urol Oncol 2023;41:148.e1-148.e7.

20. Steinberg RL, Thomas LJ, Brooks N, Mott SL, Vitale A, Crump T, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol 2020;203:902-8.

21. Milbar N, Kates M, Chappidi MR, Pederzoli F, Yoshida T, Sankin A, et al. Oncological outcomes of sequential intravesical gemcitabine and docetaxel in patients with nonmuscle invasive bladder cancer. Bladder Cancer 2017;3:293-303.

22. Steinberg RL, 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;1:65-72.

23. DeCastro GJ, Sui W, Pak JS, Lee SM, Holder D, Kates MM, et al. A phase I trial of intravesical cabazitaxel, gemcitabine and cisplatin for the treatment of nonmuscle invasive bacillus Calmette-Guérin unresponsive or recurrent/relapsing urothelial carcinoma of the bladder. J Urol 2020;204:247-53.

24. Dalbagni G, Benfante N, Sjoberg DD, Bochner BH, Machele Donat S, Herr HW, et al. Single arm phase I/II study of everolimus and intravesical gemcitabine in patients with primary or secondary carcinoma in situ of the bladder who failed bacillus Calmette Guerin (NCT01259063). Bladder Cancer 2017;3:113-9.

25. Cockerill PA, Knoedler JJ, Frank I, Tarrell R, Karnes RJ. Intravesical gemcitabine in combination with mitomycin C as salvage treatment in recurrent non-muscle-invasive bladder cancer. BJU Int 2016;117:456-62.

26. Lightfoot AJ, Breyer BN, Rosevear HM, Erickson BA, Konety BR, O’Donnell MA. Multi-institutional analysis of sequential intravesical gemcitabine and mitomycin C chemotherapy for non-muscle invasive bladder cancer. Urol Oncol 2014;32:35.e15-35.e19.

27. Hurle R, Casale P, Morenghi E, Saita A, Buffi N, Lughezzani G, et al. Intravesical gemcitabine as bladder-preserving treatment for BCG unresponsive non-muscle-invasive bladder cancer. results from a single-arm, open-label study. BJUI Compass 2020;1:126-32.

28. Skinner EC, Goldman B, Sakr WA, Petrylak DP, Lenz HJ, Lee CT, 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-Guérin. J Urol 2013;190:1200-4.

29. Sternberg IA, Dalbagni G, Chen LY, Donat SM, Bochner BH, Herr HW. Intravesical gemcitabine for high risk, nonmuscle invasive bladder cancer after bacillus CalmetteGuérin treatment failure. J Urol 2013;190:1686-91.

30. Barlow LJ, McKiernan JM, Benson MC. Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus CalmetteGuérin Therapy. J Urol 2013;189:834-9.

31. McKiernan JM, Barlow LJ, Laudano MA, Mann MJ, Petrylak DP, Benson MC. A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. J Urol 2011;186:448-51.

32. Robins DJ, Sui W, Matulay JT, Ghandour R, Anderson CB, DeCastro GJ, et al. Long-term survival outcomes with intravesical nanoparticle albumin-bound paclitaxel for recurrent non-muscle-invasive bladder cancer after previous bacillus Calmette-Guérin Therapy. Urology 2017;103:149-53.

33. Bassi PF, Volpe A, D’Agostino D, Palermo G, Renier D, Franchini S, et al. Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder: results of a phase I study. J Urol 2011;185:445-9.

34. Ignatoff JM, Chen YH, Greenberg RE, Pow-Sang JM, Messing EM, Wilding G. Phase II study of intravesical therapy with AD32 in patients with papillary urothelial carcinoma or carcinoma in situ (CIS) refractory to prior therapy with bacillus Calmette-Guerin (E3897): a trial of the Eastern Cooperative Oncology Group. Urol Oncol 2009;27:496-501.

35. Rouprêt M, Seisen T, Birtle AJ, Capoun O, Compérat EM, Dominguez-Escrig JL, et al. European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2023 update. Eur Urol 2023;84:49-64.

36. Meghani K, Cooley LF, Choy B, Kocherginsky M, Swaminathan S, Munir SS, et al. First-in-human intravesical delivery of pembrolizumab identifies immune activation in bladder cancer unresponsive to bacillus Calmette-Guérin. Eur Urol 2022;82:602-10.

37. Alanee S, Sana S, El-Zawahry A, Peabody J, Pearce T, Adams N, et al. Phase I trial of intravesical bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous bacillus Calmette-Guérin Treatment. World J Urol 2021;39:3807-13.

38. Necchi A, Daneshmand S, Simone G, Xylinas E, Morris DS, Zainfeld D, et al. Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2025;25:720-30.

39. Black PC, Tangen C, Singh P, McConkey DJ, Lucia S, Lowrance WT, et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). J Clin Oncol 2020;25:5022.

40. Tyson MD, Morris D, Palou J, Rodriguez O, Mir MC, Dickstein RJ, et al. Safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who refused or were unfit for curative-intent therapy: a phase 1 study. J Urol 2023;209:890-900.

41. Necchi A, Daneshmand S, Simone G, Xylinas E, Morris DS, Zainfeld D, et al. TAR-200 in patients with bacillus Calmette-Guérin-unresponsive high-risk non-muscle-invasive bladder cancer: results from SUNRISE-1 study. J Urol 2024;211(5S2):e1.

42. van der Heijden MS, Simone G, Boegemann M, Xylinas E, Roumiguié M, Guerrero-Ramos F, et al. TAR-200 +/- cetrelimab and cetrelimab alone in patients with bacillus Calmette-Guérin-unresponsive high-risk non-muscle-invasive bladder cancer: updated results from SUNRISE-1. Ann Oncol 2024;35(suppl_2):1-72.

43. Zappavigna S, Cossu AM, Grimaldi A, Bocchetti M, Ferraro GA, Nicoletti GF, et al. Anti-inflammatory drugs as anticancer agents. Int J Mol Sci 2020;21:2605.

44. Catalano M, Roviello G, Santi R, Villari D, Spatafora P, Galli IC, et al. Inflammation in urological malignancies: the silent killer. Int J Mol Sci 2023;24:866.

45. Han KP, Zhu X, Liu B, Jeng E, Kong L, Yovandich JL, et al. IL-15 receptor alpha superagonist complex: high-level coexpression in recombinant mammalian cells, purification and characterization. Cytokine 2011;56:804-10.

46. Chamie K, Chang SS, Kramolowsky E, Gonzalgo ML, Agarwal PK, Bassett JC, et al. IL-15 superagonist NAI in BCG-unresponsive non-muscle-invasive bladder cancer. NEJM Evid 2023;2:EVIDoa2200167.

47. Lamm 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.e21-35.e30.

48. Benedict WF, Tao Z, Kim CS, Zhang X, Zhou JH, Adam L, et al. Intravesical Ad-IFNalpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-alpha protein. Mol Ther 2004;10:525-32.

49. Connor RJ, Anderson JM, Machemer T, Maneval DC, Engler H. Sustained intravesical interferon protein exposure is achieved using an adenoviral-mediated gene delivery system: a study in rats evaluating dosing regimens. Urology 2005;66:224-9.

50. Yamashita M, Rosser CJ, Zhou JH, Zhang XQ, Connor RJ, Engler H, et al. Syn3 provides high levels of intravesical adenoviral-mediated gene transfer for gene therapy of genetically altered urothelium and superficial bladder cancer. Cancer Gene Ther 2002;9:687-91.

51. Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, et al. Intravesical RAd-IFNα/Syn3 for patients with high-grade, Bacillus Calmette-Guérin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study. J Clin Oncol 2017;35:3410-6.

52. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol 2021;22:107-17.

53. Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL 3rd, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive nonmuscle-invasive bladder cancer: interim results. Urol Oncol 2018;36:440-7.

54. UroToday. SUO 2023 late-breaking abstract: first results from BOND-003, a phase 3 study of intravesical Cretostimogene Grenadenorepvec monotherapy for patients with high-risk BCG-unresponsive NMIBC [Internet]. UroToday; 2023 [cited 2024 Oct 12]. Available from: https://www.urotoday.com/conference-highlights/suo-2023/suo-2023-bladder-cancer/148306-suo-2023-late-breaking-abstract-first-results-from-bond-003-a-phase-3-study-of-intravesical-cretostimogene-grenadenorepvec-monotherapy-for-patients-with-high-risk-bcg-unresponsive-nmibc.html.

55. Li R, Shah PH, Stewart TF, Bivalacqua T, Lamm DL, Geynisman DM, et al. Final results of CORE-001: a phase-2, single arm study of cretostimogene grenadenorepvec in combination with pembrolizumab in patients with BCG-unresponsive, non-muscle invasive bladder cancer with carcinoma in situ. J Clin Oncol 2024;42(16_suppl):4601.

56. Moussa M, Papatsoris AG, Dellis A, Abou Chakra M, Saad W. Novel anticancer therapy in BCG unresponsive non-muscle-invasive bladder cancer. Expert Rev Anticancer Ther 2020;20:965-83.

57. Kulkarni GS, Lilge L, Nesbitt M, Dumoulin-White R, Mandel A, Jewett MAS. A phase 1b clinical study of intravesical photodynamic therapy in patients with bacillus Calmette-Guérinunresponsive non-muscle-invasive bladder cancer. Eur Urol Open Sci 2022;41:105-11.

58. Lee JY, Diaz RR, Cho KS, Lim MS, Chung JS, Kim WT, et al. Efficacy and safety of photodynamic therapy for recurrent, high grade nonmuscle invasive bladder cancer refractory or intolerant to bacille Calmette-Guérin immunotherapy. J Urol 2013;190:1192-9.

59. Kulkarni GS, Richards KA, Black PC, Rendon RA, Chin J, Shore ND, et al. A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis). J Clin Oncol 2023;41(6_suppl):528.

60. Rampersaud EN, Vujaskovic Z, Inman BA. Hyperthermia as a treatment for bladder cancer. Oncology (Williston Park) 2010;24:1149-55.

61. Seynhaeve ALB, Amin M, Haemmerich D, van Rhoon GC, Ten Hagen TLM. Hyperthermia and smart drug delivery systems for solid tumor therapy. Adv Drug Deliv Rev 2020;163-164:125-44.

62. Peer AJ, Grimm MJ, Zynda ER, Repasky EA. Diverse immune mechanisms may contribute to the survival benefit seen in cancer patients receiving hyperthermia. Immunol Res 2010;46:137-54.

63. Liem EIML, Crezee H, de la Rosette JJ, de Reijke TM. Chemohyperthermia in non-muscle-invasive bladder cancer: an overview of the literature and recommendations. Int J Hyperth 2016;32:363-73.

64. Nativ O, Witjes JA, Hendricksen K, Cohen M, Kedar D, Sidi A, et al. Combined thermo-chemotherapy for recurrent bladder cancer after Bacillus Calmette-Guérin. J Urol 2009;182:1313-7.

65. Witjes JA, Hendricksen K, Gofrit O, Risi O, Nativ O. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo working party. World J Urol 2009;27:319-24.

66. De Jong JJ, Hendricksen K, Rosier M, Mostafid H, Boormans JL. Hyperthermic intravesical chemotherapy for BCG unresponsive non-muscle invasive bladder cancer patients. Bladder Cancer 2018;4:395-401.

67. Tan WS, Panchal A, Buckley L, Devall AJ, Loubière LS, Pope AM, et al. Radiofrequency-induced thermo-chemotherapy effect versus a second course of bacillus Calmette-Guérin or institutional standard in patients with recurrence of non-muscle-invasive bladder cancer following induction or maintenance Bacillus Calmette-Guérin therapy (HYMN): a phase III, open-label, randomised controlled trial. Eur Urol 2019;75:63-71.

68. Anastay V, Baboudjian M, Masson-Lecomte A, Lebacle C, Chamouni A, Irani J, et al. Is CIS a contraindication to hyperthermic intravesical chemotherapy (HIVEC) after BCG-failure? Cancers (Basel) 2023;15:1455.