Experimental and New Approaches for Bladder Preservation in Intermediate and High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC)

Natália D Avilez; Diego M Capibaribe; Leonardo O Reis

doi:10.2147/RRU.S452377

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Review

Experimental and New Approaches for Bladder Preservation in Intermediate and High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC)

Authors Avilez ND, Capibaribe DM, Reis LO

Received 29 November 2023

Accepted for publication 8 February 2024

Published 6 April 2024 Volume 2024:16 Pages 89—113

DOI https://doi.org/10.2147/RRU.S452377

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Panagiotis J Vlachostergios

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Natália D Avilez,¹ Diego M Capibaribe,¹ Leonardo O Reis^1,²

¹UroScience, State University of Campinas, Unicamp, Campinas, São Paulo, Brazil; ²ImmunOncology, Pontifical Catholic University of Campinas, PUC-Campinas, São Paulo, Brazil

Correspondence: Leonardo O Reis, Rua Vital Brasil, 80, Cidade Universitária Zeferino Vaz, Campinas, São Paulo, CEP 13083-888, Brasil, Tel +55 19 3521-7481, Email [email protected]

Abstract: About 75% of bladder cancers are detected as non-muscle invasive. High-risk patients have high progression risk. Although the standard is transurethral resection of bladder tumor plus full dose intravesical BCG for one to 3 years, due to the high risk of progression, radical cystectomy may be considered in specific cases. Although radical cystectomy is still the best approach for high-grade NMIBC from an oncological perspective, its high morbidity and impact on quality of life motivate studies of new strategies that may reduce the need for cystectomy. We carried out a mini-review whose objectives were: 1 - to identify bladder-sparing alternatives that are being studied as possible treatment for patients with intermediate and high-risk NMIBC; 2 - understand the evidence that exists regarding success rate, follow-up, and side effects of different strategies. Several studies have sought alternatives for bladder preservation, including immunotherapy, intravesical chemotherapy, chemo-hyperthermia, antibody-drug conjugates, viral genetic therapy, and others with promising results. The selection of an optimal therapy for high-risk NMIBC that can reduce the need for cystectomy, with low toxicity and high efficacy, is of paramount importance and remains an issue, however, several known medications are being tested as bladder-preserving alternatives in this scenario and have shown promise in studies.

Keywords: high-grade, non-muscle-invasive bladder cancer, unfavorable, bladder preservation

Introduction

Bladder cancer (BC) is the tenth most reported cancer worldwide when both sexes are considered, and the standardized death rate (per 100,000 person-years) is 3.3 for men versus 0.86 for women.¹

Approximately 75% of bladder cancers are detected as non-muscle invasive (NMIBCs).² The European Urological Association (EAU) guidelines classify NMIBCs as low, intermediate, high, and very high risk based on the World Health Organization (WHO) 2004/2016 or WHO 1973 classification systems (Table 1). Patients diagnosed with high-risk NMIBC recurred in 2.6% to 5.7% in one year and 10% to 19% in ten years, while very high-risk patients experienced recurrence in 12% to 32% and 39% to 79% in one and ten years, respectively.³

Table 1 EAU Risk Classification According to WHO 2004/2016/WHO 1973 Grading Classification Systems

Standard treatment varies by risk. Low-risk NMIBCs are treated with transurethral resection of bladder tumor (TURBT) alone, while intermediate- and high-risk NMIBCs should be treated with TURBT plus full-dose intravesical BCG for 1 to 3 years. Due to the high risk of progression, immediate radical cystectomy (RC) should be discussed with patients, mainly in the very high-risk group. Early RC is strongly recommended in patients with tumors that are not BCG-responsive and should be considered in recurrent high-grade tumors.⁴

Although RC is the best approach from an oncological point of view, its high morbidity and impact on quality of life motivate studies of new strategies that may reduce the need for cystectomy.

The only conservative alternative treatment approved by the Food and Drug Administration (FDA) for BCG-unresponsive disease is pembrolizumab, but toxicity and durability of response are concerns. Other conservative treatments are being studied and may be a future alternative to bladder preservation.

New Strategies to Reduce the Need for Cystectomy

Immunotherapy

Recent studies found that intradermal BCG priming, prior to intravesical instillations, can be a promising alternative, as it has demonstrated the ability to expedite the migration of T lymphocytes into the bladder, thereby enhancing the local immune response.⁵ Table 2 summarizes the main studies.

Table 2 Immunotherapy Studies

Another immunotherapy that also has its role proven are PD-1/PD-L1 inhibitors, which are already included in the guidelines for metastatic and locally advanced bladder cancer. Recent studies have shown the role of this immune checkpoint blockade (ICB) also in NMIBC, showing it to be an important therapeutic target in BCG-unresponsive NMIBC.

One notable breakthrough has been the approval of Pembrolizumab by the FDA for treating BCG-unresponsive Carcinoma In Situ (CIS), based on the KEYNOTE-057 study. This study evaluated the efficacy of the PD-1 inhibitor Pembrolizumab in high-risk, BCG-unresponsive NMIBC and yielded impressive results, with a complete response in 40% of patients within three months, and 42% achieving complete response. Serious treatment-related adverse events occurred in eight (8%) patients.⁸ Another study evaluated the combination of BCG and intravesical pembrolizumab, the 1-year recurrence-free rates was 22% and 5 of 9 patients had progressed to muscle invasive bladder cancer (MIBC), one death occurred from myasthenia gravis that was deemed potentially related to treatment.⁶

The SWOG S1605 study examined the use of Atezolizumab in patients with CIS unresponsive to BCG, with promising results with 37.6% of complete response at 6 months. Despite the promising results of ICB, its systemic administration presents significant adverse effects, the most frequent AEs were fatigue (49.3%) and 12.3% patients presented grade 3–5 adverse effects including one treatment-related death.⁹ Intravesical administration of Durvalumab was also studied in patients with pT1 or higher (BCG-naïve) bladder cancer with modest reported activity.⁷

CD40 is another immune checkpoint under investigation expressed by several cell types in the myeloid cell lineage, such as dendritic cells, macrophages, monocytes, and B cells, that can be targeted for agonistic antibody treatment in bladder cancer.¹¹ CD40 ligand stimulation produces a robust antitumor response, including activation of dendritic cells to engulf, process, and present tumor antigen to T cells and can initiate programmed cell death.¹² However, systemic CD40 therapy was associated with immune-related adverse events such as cytokine release syndrome, thrombocytopenia, and liver toxicity.¹⁰

Intravesical Chemotherapy

Chemotherapy is another modality that has already proven its role in metastatic and muscle invasive bladder cancer and intravesical administration has been studied for NMIBC (summarized in Table 3). Several studies have been carried out with gemcitabine as monotherapy,^13–27 as well as in association with several other medications, such as docetaxel,^28,29 cabazitaxel and cisplatin,³⁰ oral everolimus³¹ and mitomycin C (MMC).^32,33

Table 3 Intravesical Chemotherapy Studies

Hurle et al studied gemcitabine monotherapy after BGC failure or intolerance, and 68.7% of patients had negative cystoscopy and urinary cytology after induction, although the result dropped to 31.6% after 24 months; overall survival (OS) was 77.9% and cancer-specific survival (CSS) was 80.68% after 24 months.³⁴ Skinner et al had also good results with 47% of patients with negative cystoscopy, urinary cytology, and biopsy, after 3 months and 21% after 24 months.¹³

The gemcitabine’s potential has also been explored in combination with various other medications. Chevuru et al studied gemcitabine plus docetaxel with a 74% response at 3 months, and 50% and 30% high-grade recurrence-free survival (RFS) at 2 and 5 years, respectively, and 64% 5-year OS.²⁸ Studying the same drug combination Steinberg et al²⁹ and Milbar et al³⁵ found high-grade RFS of 46% and 42% at 2 years, respectively.

De Castro et al reported a few encouraging cases combining gemcitabine with cabazitaxel and cisplatin with 64% 2-year RFS.³⁰ The combination of intravesical gemcitabine and oral everolimus demonstrated 20% RFS at 12 months but was not well tolerated.³¹ Docetaxel alone showed 25% RFS at 3 years.³⁷ Other associations such as MMC,^32,33 paclitaxel, nab-paclitaxel,^16,17,36 valrubicin and doxorubicin^15,22 have been described with conflicting results.

Chemo Hyperthermia (CTH)

While hyperthermia in the temperature range of 40°C to 45°C exerts direct cytotoxic effects, disrupting metabolism, causing DNA damage, impairing cell function, and promoting apoptosis in tumor cells, chemo hyperthermia increases cell membrane permeability and modifies blood perfusion, improving drug penetration in the urothelium, with potential to increase chemotherapy effectiveness.^38–40 This is achieved through external or internal (integrated into a catheter) microwave-generated heating devices or by a conductive system that externally heats the chemotherapy solution before intravesical administration and can also be combined with radiotherapy to enhance treatment efficacy.^41,42

Colombo et al compared CHT and MMC in patients with intermediate and high-risk NMIBC with 17.1% and 57.5% recurrence rates, respectively.⁴³ An update of this study showed 15% and 53% disease-free survival (DFS) and a bladder preservation rate of 86% and 79% for thermochemotherapy and chemotherapy alone, at 10 years, respectively.⁴⁴

Another trial studying intermediate- and high-risk NMIBC patients showed 24-month RFS of 78.1% and 64.8% in the CHT with MMC and BCG group, respectively; the progression rate was <2% in both groups.⁴⁵ Nativ et al treated 111 NMBC patients that failed BCG with CHT and found 56% 24-month DFS. Recurrence rate was 61% at 2 years vs 39% in those with maintenance treatment.⁴⁶

Intravesical electromotive drug delivery is another approach involving the application of an electrical current across the urothelium to enhance drug movement. In a prospective study, Di Stasi et al evaluated patients with high-risk NMIBC, treated with conventional BCG, passive MMC, and electromotive MMC, with 64%, 31% and 58%, after 6 months, respectively, although 20 patients underwent cystectomy and 19 died of disseminated bladder cancer.⁴⁷ The main studies on CTH are in Table 4.

Table 4 Chemo Hyperthermia (CTH) Studies

Target Therapy

Table 5 shows studies on target therapy. Sunitinib acts by inhibiting the vascular endothelial growth factor receptor (VEGFR) and, thus, inhibits tumor activity. A phase II study offered Sunitinib to patients with NMIBC who progressed after BCG and found 44% remission at 12 weeks and 22% PFS after 12 months. Grades 3 and 4 toxicity was noted in 68% of patients.⁴⁸

Table 5 Target Therapy Studies

Another phase II study evaluated NMIBC patients unresponsive to BCG with altered FGFR3 expression treated with oral dovitinib and found 33% complete response in patients with FGFR3 mutation, however also with high toxicity.⁴⁹

Viral Gene Therapy

Other therapies are also being tested based on studies that show that genotypic and phenotypic alterations can favor tumor invasion and the development of tumor escape mechanisms (summarized in Table 6).

Table 6 Viral Gene Therapy Studies

Nadofaragene firadenovec (rAd-IFNα/Syn3) is a promising contender, comprises rAd-IFNα, a non-replicating recombinant adenovirus vector-based gene therapy agent, which introduces a copy of the human IFNα-2b gene into the urothelial cell wall.^55,56

Syn3, a polyamide surfactant, complements this by enhancing viral transduction of the urothelium.⁵⁷ In a phase II trial involving 40 patients with BCG-unresponsive high-grade NMIBC, the RFS after 12 months was 35%; no grade four or five adverse events occurred.⁵² Encouraged by these results, Boorjian et al conducted a multicenter phase III clinical trial in the USA, with 151 patients who did not respond to BCG and found that in patients with CIS, a complete response rate of 53.4% at 3 months and 45.5% of the response was maintained at 12 months.⁵⁰ The rAd-IFNα/Syn3 has undergone evaluation in 4 single-arm cohort trials,^50,52–54 revealing complete response rates ranging from 29% to 60% at 3 months and from 29% at 3 months to 35% at 12 months.

Complete response rate of 47% at 6 months, 30% at 12 months, with lower rates in the subgroup with concomitant CIS, was reported in a phase II study of 45 “BCG-exposed” NMIBC patients with or without CIS who refused RC and received intravesical CG0070 with n-dodecyl-BD-maltoside (a transduction enhancer).⁵¹

Other oncolytic viruses with relevance include intravesical talimogene laherparepvec, a herpes simplex 1 virus with ICP47 deletion that incorporates the human GM-CSF gene, diphtheria toxin A, and intravesical V937 (Cavatak, Coxsackievirus A21).⁵⁸

Antibody-Drug Conjugates (ADCs)

ADCs are a new therapeutic approach that combines the high specificity of monoclonal proteins with cytotoxic agents. In recent years, ADCs have emerged as an innovative therapeutic tool that can take advantage of tumor-specific molecular characteristics (the main studies are found in Table 7).

Table 7 Antibody-Drug Conjugates (ADCs)

The enfortumab vedotin is an antibody–drug conjugate directed against Nectin-4, which is highly expressed in luminal subtypes of bladder cancer.⁶⁵ It was recently approved by the FDA for the treatment of metastatic patients, and a multicenter study is evaluating the safety and response in BCG-unresponsive NMIBCs.⁶⁶

Vicinium (oportuzumab monatox) is a recombinant fusion protein that ingeniously combines a humanized single-chain anti-EpCAM (epithelial cell adhesion molecule) antibody with Pseudomonas exotoxin A. Kowalsky et al studied it in patients with NMIBC unresponsive to BCG with concomitant CIS and found a 44% response rate, and in 16% this response was maintained until the end of the follow-up period (18–25 months), with minimal adverse effects.⁶¹

A phase II trial studying a combination of BCG with interleukins achieved a 24-month OS of 94% with minimal adverse effects.⁵⁹ Other studies tested interferon (IFN)α2b action. O’Donnell et al compare INF + standard BCG and INF + reduced BCG Disease freedom at 24 months were 57% and 42%, respectively.⁶⁴ Joudi et al got promising results comparing INF in patients naïve to BCG and those having BCG failure with 59% and 45% patients disease free at 24-month median follow-up, respectively.⁶³

An immunomodulatory and antineoplastic compound derived from Mycobacterium phlei^60,62 was also tested in a phase III trial with overall disease-free survival of 19% at 2 years and few adverse events.⁶⁰

Photodynamic Therapy (PDT)

Photodynamic Therapy (PDT) involves the administration of a photosensitizing agent activated by light at a specific wavelength. PDT outcomes are based on limited patient series in the context of NMIBC and are therefore considered experimental (the main studies are found in Table 8).

Table 8 Photodynamic Therapy (PDT) Studies

Still, it is an incipient and experimental treatment, of which there are only small series described. Waidelich et al studied PDT with oral 5-aminolevulinic acid in patients with BCG-refractory NMIBC with a complete remission in 100% of patients with CIS and 79.2% patients with papillary tumors, and after 3 years 60% of CIS patients and 21% of papillary patients remained disease-free.⁶⁸

Lee et al investigated the PDT with intravenous radachlorin in 34 patients with a high-grade T1 disease, with or without concomitant CIS, and none of the patients had evidence of disease after 12 weeks. RFS was 60.1% at 30 months. Adverse events observed were mainly lower urinary tract symptoms and hematuria.⁶⁷

Discussion

In the realm of bladder cancer, Non-Muscle Invasive Bladder Cancer (NMIBC) presents a significant challenge, with a prevalence of 75%. This condition is categorized into three risk groups, with the high-risk category exhibiting a notably low recurrence-free survival (RFS) rate of just 23%. Patients with high-grade NMIBC face a substantial risk of recurrence and progression, nearly 50% in some cases, often necessitating invasive and burdensome surgical interventions.⁶⁹ Therefore, any therapeutic approach that can reduce the necessity for cystectomy while demonstrating reduced toxicity and high efficacy, is of paramount importance. Bacillus Calmette-Guérin (BCG) therapy has been the cornerstone treatment for NMIBC for decades. However, its failure rate (40%) and progression rate (15%) necessitate alternative strategies and novel treatment advancements.⁷⁰

The Food and Drug Administration (FDA) has recognized the urgency for new treatments in cases of BCG failure, as evidenced by their acceptance of single-arm studies.^71,72 However, the lack of uniformity in these studies, particularly in aspects such as tumor multifocality, size, maintenance therapy, prior recurrence rates, and cystoscopy evaluation methods, weakens the robustness of the data and complicates its interpretation.

In the context of Immune Checkpoint Blockade (ICB), only two-phase II trials have been notable. These trials have shown encouraging results in BCG-unresponsive patient cohorts with Carcinoma In Situ (CIS) or concurrent papillary tumors. The first trial, led by Balar et al,⁶ evaluated Pembrolizumab and, despite a small patient cohort, yielded promising outcomes with only 13% of patients experiencing significant treatment-related adverse events. Intravesical administration of Pembrolizumab may mitigate certain adverse events and elicit a CD4+T cell response. Interestingly, the drug was detectable in urine but not in blood samples in a small phase I study. The second trial investigated Atezolizumab but failed to meet the efficacy threshold.⁹ The success of ICB in Muscle-Invasive Bladder Cancer (MIBC) has already been incorporated into treatment guidelines and may soon extend to earlier stages of the disease. The FDA has already approved its use in the NMIBC BCG unresponsive CIS scenario, although data on toxicity and complication rates in NMIBC post-BCG failure remain limited.

Sunitinib, an early targeted agent and an endothelial growth factor receptor inhibitor, showed potential in bladder cancer (BC). However, a phase II trial by Zahoor et al involving 19 BCG-failure patients indicated that while relatively safe, Sunitinib did not improve outcomes. Dovitinib achieved biologically active concentrations in the urothelium and inhibited pFGFR3 pharmacodynamically but was associated with frequent high-grade toxicities.⁴⁹

Intravesical chemotherapy is a familiar approach in clinical practice. For BCG-naïve patients, a Randomized Controlled Trial (RCT) demonstrated that the combination of Mitomycin C (MMC) and BCG was more effective than BCG alone in terms of recurrence-free interval and progression rate reduction.⁷³ In BCG-unresponsive cases, various agents such as Valrubicin, Gemcitabine, MMC, and Docetaxel have been extensively studied, with Gemcitabine emerging as a favorable option due to its efficacy and patient acceptability, particularly in BCG-resistant cases.

Microwave-induced hyperthermia has shown to enhance the efficacy of MMC in high-risk tumors, as evidenced by a single-center study with a 10-year follow-up and an RCT indicating superior outcomes compared to BCG in intermediate and high-risk cases.⁷⁴ However, further head-to-head studies are required for a definitive conclusion.

Chemohyperthermia, combining hyperthermia with chemotherapy, has shown promise in enhancing treatment outcomes but comes with several challenges. It can increase both local and systemic toxicity, complicate treatment delivery due to the need for specialized equipment and expertise and pose risks of bladder damage. Additionally, it incurs higher costs and resource utilization, and there is a lack of long-term data on its efficacy and safety.

The exploration of immunotherapy and anti-inflammatory agents in NMIBC is an active area of research. While promising results have been observed, further validation of their safety and efficacy is necessary. Advances in immunotherapy are poised to revolutionize NMIBC treatment, but patient-specific factors must guide treatment selection.

Gene therapy, although in its nascent stages, shows great promise for NMIBC treatment. Ongoing research aims to overcome challenges in gene delivery, immune response regulation, and targeted gene expression. Current clinical trials are assessing the safety and efficacy of gene therapy for NMIBC.

Photodynamic therapy, despite being studied for decades, has a limited presence in literature with less than 30 single-arm studies. However, the outcomes have been largely positive, with most complications being mild and transient. Future high-quality research is essential to further establish its efficacy.

Enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, is currently being evaluated in a Phase 1 trial (EV-104, NCT05014139) presented by Kamat et al at ASCO 2023. This study aims to assess the safety, tolerability, and anti-tumor activity of intravesical EV in BCG-unresponsive NMIBCs and is actively recruiting participants.

Nadofaragene firadenovec has demonstrated tolerability without dose-limiting toxicity or significant treatment-related side effects. A single dose was sufficient to achieve measurable urine IFNα, indicating its potential efficacy.⁷⁴

Conclusion

The selection of an optimal therapy for intermediate and high-risk NMIBC that can reduce the need for cystectomy, with reduced toxicity and high efficacy, is of paramount importance and remains an issue; however, several bladder-preserving alternatives are being tested in this scenario and have shown promise, pending long-term oncological results and larger methodologically robust trials.

Pembrolizumab is still the only drug approved by the FDA, but other ICBs also show promise, as do intravesical chemotherapy and ADCs, recently approved by the FDA for metastatic treatment, which are also being pulled to earlier stages.

Acknowledgment

To the involved institution(s), the patients, and those that provided and cared for study patients. Heveline Roesch has helped address the reviewers’ and editors’ comments.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

Reis LO, National Council for Scientific and Technological Development – CNPq, Research Productivity: 304747/2018-1 and 310135/2022-2. The funder was not involved in study design, data collection, data analysis, manuscript preparation, and/or publication decisions.

Disclosure

The authors report no conflicts of interest.

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