Global insights into the management of BCG-unresponsive non-muscle invasive bladder cancer: a narrative review of provider surveys

Introduction

The current standard of care for high-risk (HR) non-muscle invasive bladder cancer (NMIBC) remains transurethral resection followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG) therapy, typically administered over 1 to 3 years (1,2). Although BCG is considered effective in managing HR NMIBC, up to 40% of patients eventually develop BCG-unresponsive disease (3). This condition is particularly concerning due to its elevated risk of progression to muscle-invasive disease and distant metastasis, both of which significantly compromise patient survival (4). For BCG-unresponsive disease, radical cystectomy (RC) continues to be the guideline-recommended treatment (1,2). However, many patients are either medically unfit for surgery or decline it due to its substantial morbidity, reported in up to 90% of cases, with a mortality rate approaching 5% (5).

In light of these challenges, further compounded by global BCG shortages since 2012, a wide range of therapeutic strategies has been proposed for the management of BCG-unresponsive NMIBC, including both intravesical and systemic approaches. However, only a limited number of these treatments have received FDA approval, and their indications are typically narrow, most often restricted to cases with carcinoma in situ (CIS). To date, only four agents have been approved for BCG-unresponsive disease: intravesical valrubicin (1998), systemic pembrolizumab (2020), intravesical nadofaragene firadenovec (adstiladrin; a gene therapy, 2022), and intravesical nogapendekin alfa inbakicept-pmln (anktiva, 2024) (6-8).

Interestingly, several intravesical chemotherapy regimens have been introduced for the same indication and are increasingly used in clinical practice, even though they lack formal regulatory approval. These include single-agent treatments like gemcitabine (Gem) and mitomycin C (MMC), as well as sequential combination regimens such as gemcitabine/docetaxel (Gem/Doce) and Gem/MMC. Among these, Gem/Doce has gained notable popularity due to its perceived effectiveness, favorable safety profile, and wide availability (9).

Major clinical guidelines recognize intravesical chemotherapy as a viable therapeutic option for patients with BCG-unresponsive NMIBC. The European Association of Urology (EAU) guidelines specifically mention Gem/Doce as an example of this approach. Similarly, the American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN) guidelines endorse the use of Gem/Doce in this clinical setting. The International Bladder Cancer Group (IBCG) also supports bladder-sparing strategies in carefully selected patients, recommending both single-agent therapies (Gem or MMC) and combination intravesical chemotherapy regimens (Gem/Doce). Despite these developments, RC remains the preferred and most definitive treatment across all major guidelines for BCG-unresponsive NMIBC (1,2,10,11). Furthermore, while newly approved agents show promise, they are limited by several practical concerns, including dependence on BCG co-administration, unfavorable side effect profiles, and high treatment costs. Additionally, complete response rates for CIS at 24 months remain below 40% for these agents, preventing them from being considered true alternatives to RC at this time (6-8,12).

A recent real-world study revealed an unexpectedly high reliance on BCG rechallenge as a bladder-sparing strategy for BCG-unresponsive disease, with more than 60% of the 129 patients included in the study receiving this approach (13). Given the expanding array of therapeutic options for BCG-unresponsive disease, including both approved and investigational treatments, it is crucial to understand how urologists manage this condition in routine clinical practice. Such insights are essential not only for evaluating the dissemination of medical knowledge but also for fostering a more consistent and evidence-based consensus on potential treatment strategies. This review aims to explore global treatment patterns among urologists by analyzing published surveys that detail regional approaches to managing BCG-unresponsive disease. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-661/rc).

Methods

Search strategies and data organization

To conduct a comprehensive review of published surveys on treatment practices for BCG-unresponsive HR NMIBC, we performed a structured literature search using PubMed. We used the following keywords in PubMed: “BCG-unresponsive”, “BCG failure”, “non-muscle invasive bladder cancer”, “survey”, “practice patterns”, and “treatment patterns”. These were automatically combined using ‘AND’ by default. The search was limited to articles published in English between 2005 and 2025, and studies available only in abstract form were excluded. After screening for clinical relevance and alignment with the review’s objectives, 5 studies were selected. These studies specifically reported provider-level treatment decisions for BCG-unresponsive cases by country, rather than presenting aggregated global data. All extracted data were organized according to key survey questions, and responses were compiled accordingly. Although not all surveys included identical questions, missing responses in one section were supplemented with available data from other sections whenever possible. Two authors (M.A.C., I.D.) screened and selected articles retrieved from PubMed for inclusion in this review. Discrepancies were resolved through discussion and consensus. A summary of our search strategy is presented in Table 1.

Statistical analysis

Descriptive statistics were used to summarize responses from all participants. Categorical variables were reported as frequencies and percentages, and all calculations were performed using Microsoft Excel. Because most of the online surveys included in our review were designed with mandatory-response logic, participants were required to answer each question to proceed, resulting in a dataset with no missing values. Inferential statistics were not applied, as the objective of the review was to describe global practice patterns in the treatment of BCG-unresponsive disease rather than to test specific hypotheses.

Results

Participant demographics and guideline preferences

To inform the analysis of clinical practices among physicians managing BCG-unresponsive NMIBC, data were drawn and analyzed from multiple regional surveys. Between 2005 and 2025, only four relevant surveys were identified, originating from the U.S., Europe, Arab countries, Saudi Arabia. An additional provider-based survey examining practice patterns in the management of BCG-unresponsive disease was conducted by our team in collaboration with colleagues in Romania and completed in June 2025. Although the results of this survey were unpublished at the time of this review, they have been included to provide a more comprehensive overview of current clinical practices. Table 2 summarizes the key characteristics of the five provider-based surveys included in our analysis (14-18). All surveys were conducted using an online format.

In the U.S., a national survey conducted in 2022 captured responses from 259 urologists. In the Arab countries survey, data were collected between October 17 and November 17, 2023, with 106 urologists participating from 14 countries, including Algeria (n=5), Bahrain (n=14), Egypt (n=12), Iraq (n=10), Jordan (n=4), Kuwait (n=5), Lebanon (n=16), Morocco (n=4), Oman (n=9), Qatar (n=6), Saudi Arabia (n=5), Tunisia (n=4), the United Arab Emirates (n=7), and Yemen (n=5). The European cohort was based on a multicenter, retrospective survey conducted between January and May 2019, involving physicians from France (n=39), Germany (n=39), Italy (n=39), Spain (n=49), and the UK (n=36). In Asia, a comparable survey conducted during the same period included 91 physicians from Japan and 35 from China. Additional national surveys were conducted in Saudi Arabia (n=19; April 28 to May 9, 2024) and Romania (n=216; May 15 to June 30, 2025). All surveys were completed by urologists, except in France, Germany, Italy, Spain, the United Kingdom, Japan, and China, where both urologists and medical oncologists contributed.

Guideline preferences for managing BCG-unresponsive disease varied by region. Urologists in the U.S. and Saudi Arabia predominantly followed the AUA/Society of Urologic Oncology (SUO) guidelines. In Romania, the EAU guidelines were most used. In Arab countries, preferences were more distributed, with the EAU, AUA/SUO, and NCCN guidelines being the most followed. No data on which guidelines were used in this setting were available for the remaining European countries, Japan, and China (Figure 1).

Figure 1 Distribution of provider-adopted guidelines for BCG-unresponsive NMIBC across regions. European, Japanese, and Chinese surveys did not report data on the guidelines used to manage BCG-unresponsive disease. AUA, American Urological Association; BCG, Bacillus Calmette-Guérin; EAU, European Association of Urology; KSA, Kingdom of Saudi Arabia; NCCN, National Comprehensive Cancer Network; NMIBC, non-muscle invasive bladder cancer; SUO, Society of Urologic Oncology.

Management options for BCG-unresponsive disease

Treatment preferences for BCG-unresponsive NMIBC varied across global regions. In the United States, intravesical chemotherapy was the most frequently employed option (53%), followed by RC (27%) and systemic therapy, including checkpoint inhibitors (14%). A minority of respondents (6%) reported using repeat BCG, re-resection, or enrolling patients in clinical trials. In the Arab region, RC was the predominant choice (50%), followed by intravesical chemotherapy (30%) and repeat BCG (12%), with 8% opting for re-resection and surveillance.

In China, treatment choices for BCG-unresponsive disease most commonly included intravesical chemotherapy (64%), biopsy ad fulguration (36%), watchful waiting (39%), systemic therapy such as checkpoint inhibitors (23%), and resection followed by continued surveillance (21%). In the same clinical context, Japanese respondents most frequently selected watchful waiting (49%), resection with surveillance (35%), and biopsy with fulguration (16%). Use of RC was relatively limited in both countries, reported by only 7% of respondents in China and 13% in Japan.

Across surveyed European countries, including Germany, France, Spain, Italy, the United Kingdom, and Romania, the most frequently selected treatments for BCG-unresponsive NMIBC included RC (ranging from 15% to 67%), resection with surveillance (24% to 46%), and watchful waiting (42% to 60%).

Figure 2 summarizes treatment choices for patients with BCG-unresponsive disease, as reported across global regions.

Figure 2 Treatment choices for patients with BCG-unresponsive disease. In surveys conducted across the U.S., Arab countries, Romania, and KSA, the most commonly chosen treatment options were highlighted. In one survey conducted across European countries, Japan, and China, treatments administered to patients at any point after BCG therapy were recorded. Since some patients received more than one treatment, the total percentage could exceed 100%. Other options reported in the U.S. survey included repeat BCG, repeat resection, participation in clinical trials, and observation. BCG, Bacillus Calmette-Guérin; KSA, Kingdom of Saudi Arabia.

Intravesical chemotherapy used in BCG-unresponsive disease

Intravesical chemotherapy preferences for BCG-unresponsive disease varied significantly by region. In the U.S, Gem was the most frequently administered agent (43%), followed by MMC (26%), valrubicin (16%), and sequential Gem/Doce (11%). In the Arab region, Gem remained predominant (60%), with additional use of MMC (19%), sequential Gem/Doce (8%), Doce (8%), Gem/MMC (4%), and valrubicin (1%). In Saudi Arabia, Gem was again the leading agent (60%), followed by MMC (20%), and both Doce and Gem/Doce (10% each). In Romania, Gem was preferred by most respondents (85%), with limited use of MMC (5%), Gem/Doce (4%), Gem/MMC (3%), and other agents (3%). In contrast, treatment patterns in China differed substantially, with Epirubicin being the most utilized agent (37%), followed by doxorubicin (34%) and Gem (26%). A small proportion (3%) reported using other agents. Notably, MMC was the most frequently used agent in the European survey. Figure 3 illustrates the regional distribution of the top three intravesical chemotherapy agents used in the treatment of BCG-unresponsive disease.

Figure 3 Top intravesical chemotherapy agents for BCG-unresponsive disease by region. In one survey conducted across several European countries, mitomycin C was reported as the most commonly used intravesical chemotherapy, although the percentage of use was not provided. BCG, Bacillus Calmette-Guérin; KSA, Kingdom of Saudi Arabia.

Regional surveys have highlighted several key obstacles to the use of intravesical chemotherapy in patients with BCG-unresponsive NMIBC. In Arab countries, the most commonly cited barrier was the absence of clear recommendations in clinical guidelines (41%). This was followed by concerns about oncological safety and the risk of disease progression (23%), as well as limited familiarity with available intravesical chemotherapy options (18%). In Saudi Arabia, the issue of guideline limitations was even more pronounced, reported by 58% of respondents. Additional challenges included patient hesitancy toward chemotherapy (21%) and equal concerns about safety and lack of awareness of available agents (10.5% each). In Romania, the primary concern was oncologic safety concerns and risk of progression, noted by 56% of participants. Other contributing factors included insufficient guideline support (14%) and limited access to chemotherapeutic agents (12%), which have hindered broader adoption of this treatment approach (Figure 4).

Figure 4 Factors limiting the use of intravesical chemotherapy in BCG-unresponsive cases. BCG, Bacillus Calmette-Guérin; KSA, Kingdom of Saudi Arabia.

Use of newly FDA-approved therapies for BCG-unresponsive NMIBC

As of October 2025, four agents have received FDA approval for the treatment of BCG-unresponsive NMIBC: systemic pembrolizumab (approved in 2020), intravesical nadofaragene firadenovec (2022), intravesical nogapendekin alfa inbakicept-pmln (2024), and TAR-200, a pretzel-shaped intravesical drug delivery device for Gem, approved in September 2025.

When interpreting the survey data included in our review regarding the use of these therapies, it is important to consider the timing of their regulatory approvals. Most agents were only recently authorized, and at the time the surveys were conducted, some had not yet received regulatory approval in certain countries. Consequently, respondents often reported limited use and low familiarity with these treatments.

Discussion

Current guidelines offer limited direction for BCG-unresponsive NMIBC cases in which patients either decline RC or are medically unfit for the procedure (1,2). The absence of randomized trials comparing available bladder-sparing therapies (BSTs) further complicates clinical decision-making. Such trials are inherently difficult to conduct due to the lack of a universally accepted comparator among BSTs and the ethical and logistical challenges of randomizing patients to RC (11). As previously noted, the EAU and AUA guidelines offer open-ended recommendations regarding BSTs. In contrast, the NCCN and IBCG guidelines provide more specific guidance based on tumor type (CIS vs. papillary tumors). These guidelines also stress the importance of counseling patients on the frequency of intravesical therapy administration, guiding them through treatment options, and involving them in shared decision-making. RC is emphasized as a recommended option at each tier of therapy (1,2,10,11). In light of the open-ended nature of the guidelines, our review highlighted substantial regional variation in clinical practice for the management of BCG-unresponsive disease. In certain regions, such as the Arab world and Romania, RC remains the preferred approach. In contrast, countries including the U.S., Japan, China, and various European nations tend to favor BSTs. Even within BST strategies, notable differences exist. While intravesical chemotherapy is commonly employed by urologists in the U.S. and China, practitioners in France, Germany, Italy, the UK, Spain, and Japan more frequently opt for resection and surveillance. Notably, a “watch-and-wait” strategy is also utilized by some urologists in Europe, China, and Japan.

Recent data showed no significant difference in overall survival [hazard ratio (HR): 1.40; 95% confidence interval (CI): 0.68–2.89; P=0.4] or cancer-specific survival (HR: 0.88; 95% CI: 0.22–3.55; P=0.9) between patients with BCG-unresponsive disease treated with BSTs and those undergoing early RC, over a median follow-up of 71 months (n=114). BSTs included intravesical Gem/Doce, repeat BCG, and BCG combined with interferon-α (19), suggesting that these approaches may offer a safe “window of opportunity” before RC. A multi-country chart review (n=129) from 15 academic centers in Canada, France, Germany, Korea, the Netherlands, and the U.S. found that BCG rechallenge, with or without interferon, was commonly used in this patient population, though over 25% progressed to muscle-invasive or metastatic disease within the first 3 years of therapy (13). In another cohort of patients with BCG-unresponsive NMIBC (n=36; 20 with T1, 7 with Ta, 9 with CIS only, and 8 with concomitant CIS), rescue BCG therapy resulted in 24-month disease-free and progression-free survival rates of 63% and 86%, respectively (20). These findings underscore the variability in outcomes of BSTs using rescue BCG, likely attributable to differences in treatment regimens (e.g., duration of therapy), patient population characteristics, and varying definitions of BCG-unresponsive disease. In our review, repeat BCG was used by only 12% of urologists in the Arab world and 14% in Romania, underscoring the gap between real-world practice and data from controlled studies.

Our review revealed significant regional variation in the selection of intravesical therapies for BCG-unresponsive disease. Single-agent Gem is the most commonly used option in the U.S., Arab countries, and Romania, while epirubicin is preferred in China, and MMC is widely used across Europe. Sequential Gem/Doce is also utilized in the U.S. and Arab countries, though by fewer than 15% of urologists, with no reported use in Europe, China, or Japan. The choice of intravesical chemotherapy appears to be driven more by drug availability than by efficacy or cost. This trend may be influenced by the open-ended nature of current guidelines regarding the selection of intravesical agents when BSTs are used for BCG-unresponsive disease. Among major guidelines, only the IBCG provides specific recommendations: sequential Gem/Doce is favored for CIS, while both single-agent chemotherapy (e.g., Gem or MMC) and Gem/Doce are considered appropriate for papillary tumor (11). A recent meta-analysis underscores the limited efficacy of intravesical Gem in BCG-unresponsive NMIBC. The 24-month recurrence-free survival (RFS) rate is approximately 40% in patients with high-grade papillary-only disease but drops to around 20% in those with CIS. In contrast, sequential regimens such as Gem/Doce and Gem/MMC show improved outcomes, with 24-month RFS rates exceeding 40%, even in CIS-containing cohorts (21,22). A recent U.S. survey on therapies for BCG-unresponsive disease found that many urologists tend to use the same treatment approach for both CIS and papillary tumors, underscoring the need for clearer guidance on outcome differences between these tumor types when BSTs are employed (16).

Our review found that two therapies recently approved by the FDA for BCG-unresponsive NMIBC-nadofaragene firadenovec and pembrolizumab-had not yet been widely adopted by urologists at the time most surveys were conducted, which was prior to the approvals of intravesical nogapendekin alfa inbakicept and TAR-200 in 2024 and 2025, respectively. This suggests a gap between regulatory approval and clinical practice, potentially due to limited global access or availability of these agents. Another possible reason for the slow uptake may be the high cost of these therapies, with annual treatment expenses exceeding $200,000. In comparison, Gem/Doce therapy is significantly more affordable, with an annual cost of approximately $3,300, and even less for single-agent Gem (23). This substantial cost difference likely contributes to the broader adoption of intravesical chemotherapy among urologists. Notably, the majority of surveys were conducted prior to 2024 or within a few years following the approval of recently FDA-approved agents for BCG-unresponsive disease. Consequently, further time may be required before these therapies are fully integrated into routine urologic practice.

Notably, one of the included surveys was administered by the Arab Association of Urology (AAU), which comprises 22 Arabic-speaking countries across Asia and Africa (15). This classification reflects shared linguistic and professional affiliations rather than geographic proximity. While such grouping may suggest similarities in clinical practice, this cannot be confirmed from the available data and warrants further investigation to better understand the factors influencing regional practice patterns.

One of the key insights from our review is the urgent need for clearer and more consistent clinical guidelines to address the complexity of managing BCG-unresponsive disease. With several therapies recently approved or pending approval, a knowledge gap has emerged among urologists regarding optimal treatment strategies. More comprehensive guidance is needed to support the selection of appropriate BSTs, improve patient education on their effectiveness, and expand access to intravesical chemotherapy. In addition to the limited number of clinical trials and the inconsistent definitions of BCG-unresponsive disease, the lack of patient-centered approaches that consider quality of life during treatment decisions remains a major barrier to the integration of BSTs into routine clinical practice.

Strengths and limitations

This review has several strengths. It is the first to explore real-world treatment patterns for BCG-unresponsive disease across multiple continents using data from diverse surveys. It also highlights current challenges in clinical practice and offers insight into physicians’ concerns regarding the use of BSTs. Moreover, it may contribute to the design of future clinical trials by deepening our understanding of how clinicians and patients perceive the safety and effectiveness of BSTs.

However, several limitations should be acknowledged. While a meta-analysis could have provided pooled estimates, the variability in survey methodologies and outcome measures precluded meaningful quantitative synthesis. Our literature search was limited to PubMed and restricted to English-language publications. As a result, studies indexed in other databases or published in other languages may have been excluded. The integration of survey data from multiple countries, each using different questionnaire formats, may have introduced selection bias. Additionally, the reliance on retrospective, self-reported data from physicians raises concerns about recall bias. Most surveys focused solely on urologists, even though medical oncologists play a key role in treatment decisions for BCG-unresponsive disease in certain regions. The limited number of physician respondents per country also restricts the generalizability of findings to national practice patterns. Unlike a multicenter retrospective cohort study, our review captures what urologists report as their preferred management strategies for BCG-unresponsive disease, which may not reflect actual clinical practice. Moreover, the findings of this study are based on survey data, which may not fully reflect actual clinical practice patterns due to potential sources of bias, such as recall bias, as previously noted, and variability across individual practice settings. Future research incorporating objective clinical data or observational audits may help validate and enrich these results. Lastly, only one of the reviewed surveys included both urologists and medical oncologists among respondents (17). However, the results were not stratified by specialty, limiting our ability to compare treatment approaches across disciplines. This highlights the need for future studies to report specialty-specific data to better understand interdisciplinary variation in the management of BCG-unresponsive disease.

Conclusions

This review highlights the significant global variation in the management of BCG-unresponsive NMIBC, which could be attributable to the open-ended nature of current clinical guidelines. In Romania and many Arab countries, RC remains the primary treatment option, largely due to limited access to BSTs and concerns about their oncological safety. In contrast, urologists in the U.S. and China tend to favor intravesical chemotherapy, with single-agent Gem being the most commonly used in the U.S., and Epirubicin in China. Physicians in European countries and Japan generally prefer more conservative approaches, such as resection followed by surveillance or watchful waiting. Despite growing evidence supporting the use of BSTs in patients with BCG-unresponsive disease, their adoption remains limited. Major barriers include the high cost of newly FDA-approved agents, limited drug availability, unclear and fragmented guidelines on optimal therapy sequencing when RC is not feasible, and ongoing oncological safety concerns among urologists. Addressing these disparities through stronger clinical guidance, broader access to effective treatments, and a greater emphasis on patient-centered care is essential to improving outcomes and treatment adherence for BCG-unresponsive NMIBC patients worldwide.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-661/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-661/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-661/coif). M.A.C. serves as an unpaid editorial board member of Translational Andrology and Urology from August 2025 to June 2027. M.A.O. has received consulting fees from Fidia Farmaceuticals, Theralase, and Urogen; received honoraria from Merck; and serves on the data safety monitoring board for Combat Medical. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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