New Bladder Preservation Strategies in Urothelial Carcinoma of the Bladder

Background: 17 500 persons receive a new diagnosis of urothelial carcinoma of the bladder in Germany each year. Radical cystectomy is performed for muscle-invasive and for non-muscle-invasive, recurrent, high-risk tumors. Because this procedure carries a perioperative complication rate of 30–40% and impairs the patients’ quality of life, options have been developed for intravesical and systemic bladder-preserving treatment.

Methods: This review is based on pertinent publications (up to July 2024) on bladder-preserving treatment methods that were retrieved by a selective search in the PubMed, Web of Science, and Cochrane Library databases.

Results: Multiple clinical phase II–III trials and observational studies are available. Carefully selected patients with recurrent, non–muscle-invasive, high-risk urothelial carcinoma received bladder-preserving treatment of the following kinds: intravesical chemotherapy with or without hyperthermia (52–65% progression-free at 2–3 years); drug-coated carrier systems (complete remission, 50–83%); viral gene therapy (complete remission, 53%); systemic immunotherapy with checkpoint inhibitors (19–44% recurrence-free at 1 year). The rate of bladder preservation was 49–100%. No worsening of overall survival was observed. Treatments for muscle-invasive urothelial carcinoma included neoadjuvant chemotherapy followed by frequent follow-up, radical transurethral tumor resection, partial cystectomy, and trimodal radiochemotherapy (TMRT). Only TMRT yielded comparable long-term oncological results to those of cystectomy, with a 74% rate of freedom from metastases and an overall survival rate of 73%. Any type of bladder-preserving treatment requires meticulous long-term uro-oncological follow-up, with repeated cystoscopies, bladder biopsies, urine cytologies, and multiparametric bladder MRI.

Conclusion: Bladder-preserving treatments should be considered part of the therapeutic armamentarium and should be critically discussed in an interdisciplinary setting.

Cite this as: Heidenreich A, Böhmer D, Bolenz C, Borkowetz A, Rieger C, De Santis M: New bladder preservation strategies in urothelial carcinoma of the bladder. Dtsch Arztebl Int 2025; 122: 211–8. DOI: 10.3238/arztebl.m2025.0014

In Germany, about 17 500 persons are diagnosed with urothelial carcinoma (UCa) of the bladder each year, with a peak between age 65 and 74 (1). Risk factors include nicotine abuse as well as exposure to aromatic amines, chronic inflammation of the bladder lining, prior radiation therapy, and a family history of bladder cancer. In more than 90% of case, the histological diagnosis is that of urothelial carcinoma of the bladder (2). Less common variants include squamous cell and adenocarcinomas as well as subtypes of UCa (e1). Painless macrohematuria, persistent microhematuria and persistent irritative voiding symptoms are typical initial symptoms of UCa and should be investigated using flexible urethrocystoscopy (3).

Approximately 70–75% of the newly diagnosed cases of bladder cancer are non-muscle-invasive carcinomas with invasion into the urothelium or lamina propria. The primary treatment of non-muscle-invasive variants is transurethral resection of bladder tumor (TURBT) and, as a recurrence prophylaxis, intravesical instillation of mitomycin C or intravesical Bacillus Calmette-Guérin (BCG) immunotherapy (Figure 1, [3]).High-risk tumors and early recurrent urothelial carcinomas are treated with BCG as an immunotherapeutic activator of cytotoxic T cells (six-week induction therapy plus a 1– to 3-year maintenance therapy), resulting in a reduction in recurrence risk of up to 56% compared to TURBT alone (e2) and a 30% reduction in progression risk (e3). In 20–30% of cases, muscle invasion or a locally advanced tumor stage (pT2–pT4) is present at the time of first diagnosis; these patients are treated with neoadjuvant systemic chemotherapy followed by radical cystectomy with pelvic lymph node dissection (PLND). Five to 10% of patients are diagnosed with locoregional and/or systemic metastases and treated with primary systemic chemotherapy with or without immunotherapy (Figure 1), (4, 5). The stage-specific recurrence and survival rates are listed in eTable 1.

Figure 1

Guideline-based treatment recommendations

eTable 1

Oncological recurrence and survival rates by stage at first diagnosis

Indication for radical cystectomy

Radical cystectomy is guideline-recommended with curative intention for any of the following clinical constellations:

• Primary non-muscle-invasive high-risk tumor
• Recurrent disease after intravesical BCG instillation therapy with high risk of progression, or
• Muscle-invasive urothelial carcinoma (Table 1, Figure 1).

Table 1

Guideline-based indications for radical cystectomy

In this article, our focus is on treatment alternatives to radical cystectomy for recurrent and muscle-invasive bladder cancer.

Early radical cystectomy is recommended for non-muscle-invasive primary high-risk tumors or high-risk tumors after intravesical BCG therapy based on the observation that muscle-invasive progression often has a clinically indolent course and is diagnosed at too late a stage. In addition, it has been observed that muscle-invasive progression leads to an about 40–50% less favorable overall survival in patients with primary muscle-invasive urothelial carcinoma (6, e5). Primary non-muscle-invasive high-risk tumors are all papillary high-grade tumors with one to three of the following risk factors:

• Age >70 years,
• Multiple papillary tumors and
• Tumor size >3 cm (eTable 2) (3).

eTable 2

Definition of very high-risk urothelial carcinoma of the bladder

Controversies surrounding radical cystectomy

Radical cystectomy is associated with a perioperative 30-day complication rate of approximately 30% and with a reduction in quality of life (e5, e6). Recent studies have shown that the quality of life in the first postoperative year after radical cystectomy is equal to that of metastatic urothelial carcinoma and that the majority of patients desire alternative treatment options to radical cystectomy (e7).

Furthermore, it is important to take into account when deciding on the treatment strategy that, depending on the type of neoadjuvant systemic therapy, a pathological complete response (ypT0 ypN0) can be achieved in 30–50% of patients (e8, e9, e10, e11). In this situation, abstaining from radical cystectomy is associated with a cancer-specific 5-year survival rate of 80–90% (7). The above information illustrates the challenges and controversies surrounding radical cystectomy in the context of modern and innovative, perioperative pharmacological strategies. In this article, we present the alternatives to radical cystectomy for the various clinical scenarios based on the available evidence.

Methods

Our review is based on pertinent publications that were retrieved by a selective search in the PubMed, Web of Science, and Cochrane Library databases (see eBox for details). We included the most relevant, high-quality (prospective randomized clinical phase II–III trials, prospective and retrospective cohort studies) and the most recent studies with the highest available level of evidence.

eBox

Search strategy

Organ-sparing treatment of recurrent, BCG-refractory/non-responding NMI urothelial carcinomas

For the prevention of disease recurrence or muscle-invasive progression, various intravesical and systemic therapies have been developed and studied (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, Table 2). It should be noted, however, that these studies are often single-armed and in some cases retrospective; in addition, most of the randomized clinical trials are small. Some of these treatment options have not (yet) been approved in Germany or are currently not reimbursed.

Table 2

The outcomes achieved with the various bladder-preserving treatment modalities for BCG-refractory non-muscle-invasive urothelial carcinoma of the bladder

Drug-coated carrier systems

TAR-200 is a gemcitabine-releasing, intravesical tube system that is placed into the bladder cystoscopically; with the continuous release of the cytostatic agent, high intravesical drug concentrations are achieved. The interim analysis of the Sunrise-1 study found that with TAR-200 monotherapy complete remission was achieved in 83% of the 58 evaluable patients (85 patients were recruited) after a median of 30 weeks (Table 2) (8). Sunrise-1 is a three-arm randomized phase 2b study, comparing the efficacy of TAR-200 treatment alone versus TAR-200 in combination with the PD-1 inhibitor cetrelimab versus cetrelimab alone. A total of 200 patients with BCG-refractory bladder cancer and bladder preservation were included in the study. The primary endpoint of the study is complete response at any point in time, confirmed by cystoscopy, urine cytology and bladder biopsy at weeks 24 and 48. The most common side effects (>10%) were pollakiuria, dysuria, urinary urgency, and urinary tract infections.

The intravesically placed TAR-210 system is indicated for patients with FGFR-3 mutation to ensure sustained release of the FGFR inhibitor erdafitinib with high local concentrations and low systemic toxicity (e12). First data from a dose-finding study in patients with BCG-refractory, papillary, high-risk urothelial carcinomas were promising with a complete response rate of approximately 82%. The most common adverse events (>grade 3) were stomatitis (10%), nail dystrophy (4%) and glossitis (4%).

Hyperthermia and intravesical chemotherapy

The rationale for the use of hyperthermia plus intravesical chemotherapy is to improve remission rates by increasing the intravesical temperature to about 40–42 ° Celsius so that the penetration depth of the cytostatic agents also increases. A small prospective study reported promising data for the combination of ElectroMotifDrugAdminstration (EMDA) plus mitomycin C (MMC), showing a muscle-invasive progression-free survival of 85% (9).

For a combination of hyperthermia with intravesical MMC application (HIVEC), recurrence rates at year 1 and year 2 of 33% and 60%, respectively, have been reported; the progression rate in a muscle-invasive tumor is 2–16% (10). In 97–100% of patients, the bladder could be preserved. Low recurrence rates can only be achieved with a combination of induction and maintenance therapy, an MMC dose of 80 mg/application, transurethral bladder biopsies at multiple sites after the induction and maintenance periods, and annual multiparametric magnetic resonance imaging (mpMRI) of the bladder (11, 12). Bladder mpMRI has a diagnostic accuracy of 89% in the detection of muscle-invasive recurrence and is more accurate than cystoscopy or bladder mapping (e13). The lack of a control group is a limitation for HIVEC; in Germany, however, no approved pharmacological alternatives are available for the treatment of BCG-refractory NMI bladder cancer.

Intravesical cancer therapy

Intravesical chemotherapy with gemcitabine or the combination of gemcitabine and docetaxel (Gem/Doc) have become an established practice in recent years (13, 14, 15, 16, 17, 18, 19). For treatment with gemcitabine monotherapy, a progression-free survival rate of 65% at month 36 has been reported (13, 14, 15). Data from the largest cohort with 276 patients show for Gem/Doc treatment a recurrence-free survival in patients with high-risk tumors of 65% and 52% at year 1 and year 2, respectively (16). Progression to muscle-invasive urothelial carcinoma was observed in 8% of patients and it was possible to preserve the bladder in 85% of cases. This treatment approach is supported by additional larger patient series, showing progression-free and cystectomy-free survival rates of 82% and 75%, respectively, after a median follow-up duration of 18 to 49 months (17, 18, 19).

A viral gene therapy, nadofaragene firadenovec, was approved by the US Food and Drug Administration (FDA) (20). The primary endpoint of the single-arm phase III trial was complete remission of carcinoma in situ (CIS) within the first 12 months after initial application. In 55 of 103 (53.4%) patients with CIS of the bladder (pTis), a complete response was achieved; of these, 25 (45.5%) had not experienced a high grade recurrence after 12 months. During the median follow-up of 19,7 (IQR = 16.0–24.8) months, 73 of the 103 study participants (71%) developed non-muscle-invasive, high-grade recurrence and 5 (5%) muscle-invasive progression.

Systemic immunotherapy

The FDA approved pembrolizumab for the treatment of BCG-refractory NMI urothelial carcinoma based on the findings of the single-arm phase II KEYNOTE-057 trial. With a dosing regimen of 200 mg every 3 weeks for up to 24 months (21), a complete response at 3 months (primary endpoint) was achieved in 39 of the 96 patients (41%). At 12 months, 18 of the 39 cases (46%) were still recurrence-free, corresponding to a recurrence-free survival rate of 18.7% in the total cohort. In another cohort of the KEYNOTE-057 trial, 132 patients with only papillary, BCG-refractory NMI urothelial carcinomas without CIS were treated (22). The primary endpoint was recurrence-free (high-risk NMI urothelial carcinoma) and progression-free survival at 12 months, which was reached by 43.5% of patients.

The rationale for organ-sparing treatment in muscle-invasive urothelial carcinoma of the bladder

Taking an organ-preserving approach aims at reducing the morbidity associated with radical cystectomy, preserving the function of the bladder and improving the patient’s quality of life. The primary treatment options after neoadjuvant chemotherapy are:

• Frequent follow-up without or with transurethral resection of bladder tumor
• Partial resection of the bladder
• Trimodal radiochemotherapy.

Frequent follow-up and/or transurethral resection of bladder tumor after neoadjuvant systemic therapy

Treatment with TURBT alone should only be considered in a highly selected patient population, if

• a solitary tumor <3 cm in size with invasion only into the superficial muscle layer is present
• radical cystectomy is refused by the patients, or
• the patients are not eligible for surgery due to their poor physical condition (4, 5).

The largest prospective study to date on the subject evaluated 133 patients after tumor-free resection and a minimum follow-up of 15 years (23). Of the study participants, 30% developed a non-muscle-invasive urothelial carcinoma and received intravesical instillation therapy. Forty patients (30%) developed muscle invasion and 27 patients (20%) died of urothelial carcinoma. At 5, 10 and 15 years, the tumor-specific survival rates were 81.9%, 79.5% and 76.7%, respectively, and the progression-free survival with bladder preservation was 75.5%, 64.9% and 57.8%, respectively.

Neoadjuvant systemic chemotherapy alone without radical cystectomy but with radical TURBT rarely achieves long-term freedom from recurrence, even in patients with complete clinical response. An analysis of 1538 patients in the US National Cancer Database as well as the findings of other studies revealed that in cT2 patients the survival rates at 2 and 5 years were only 52.6% and 36.2%, respectively (24, 25, 26).

Treatment with immune checkpoint inhibitors

New treatment approaches employing immune checkpoint inhibitors (CPIs) have been used prior to radical cystectomy in the neoadjuvant situation to improve the rates of complete pathological response (ypT0). CPIs are used to activate the tumor defense by interrupting inhibitory interactions between antigen-presenting cells and T lymphocytes at the checkpoints (e.g., anti-PD-1/PD-L1, anti-CTLA-4) or by stimulating activating checkpoints (e14, e15, e16). In the single-arm PURE-01 trial, a ypT0 was observed in 39.8% of patients after the use of pembrolizumab prior to radical cystectomy (27), with atezolizumab the ypT0 rate was 31% (28). Neoadjuvant therapy with pembrolizumab appears to improve event-free survival at 3 years compared to neoadjuvant chemotherapy (86.6% vs 63.5%, p<0.001) (29). The data of the prospective randomized clinical phase III NIAGARA trial show complete response rates of 37.5% and 27.5% with and without durvalumab, respectively (30). Event-free survival at 2 years also differs only slightly with 67.8% versus 59.8%.

The findings of a clinical phase II trial (31) indicate that combinations of a neoadjuvant chemotherapy with nivolumab could be a promising strategy to achieve bladder preservation. After a maximal TURBT, patients underwent a combined neoadjuvant systemic therapy with four cycles of gemcitabine and cisplatin plus nivolumab, followed by re-staging to provide a basis for the selective, risk-adapted organ-preserving strategy (Figure 2). Patients who achieved a clinical complete response (cCR), assessed by computed tomography (CT) or magnetic resonance imaging (MRI), received a bladder-preserving monotherapy with nivolumab for four months and were closely monitored. Study participants in whom a tumor was detected were treated with radical surgery. Of 76 patients with muscle-invasive bladder cancer included in the study and 72 treated, 33 (43%) achieved a cCR; of these, 32 opted for frequent follow-ups. Two patients (6%) in this group with bladder preservation developed metastases over the further clinical course. In contrast, metastases occurred in 28% of patients in the cystectomy group.

Figure 2

Trial course of the prospective clinical phase II study

Partial resection of the bladder

Currently, there are no randomized, controlled trials, comparing partial cystectomy (PZx) with radical cystectomy, available. Retrospective case series indicate that in carefully selected patients partial cystectomy could achieve oncological results similar to those seen with radical cystectomy (32, 33, 34, 35, Table 3). Consistent selection criteria for partial cystectomy include the presence of unifocal tumors without accompanying CIS which are located favorably for resection on the bladder roof or side wall; for this reason, only about 5–10% of candidates for cystectomy are eligible for PZx.

Table 3

Findings of retrospective cohort studies on partial cystectomy

Radiochemotherapy

Combined radiochemotherapy is today an established alternative to radical cystectomy in Scandinavian and Anglo-Saxon countries.

It is delivered as a so-called trimodal therapy (TMRT):

• Maximal transurethral resection of bladder tumor
• Neoadjuvant chemotherapy and
• Radiotherapy (4, 5).

Radiotherapy should be delivered using modern techniques (IMRT and IGRT) and a total dose of 60–66 Gy in conventional fractionation (dose per fraction: 1.8 to 2.0 Gy) or 55.0 Gy in hypofractionation (dose per fraction: 2.75 Gy). The efficacy of simultaneous chemotherapy with cisplatin or mitomycin C and fluorouracil (5-FU) has been proven in randomized trials (Table 4). Trimodal therapy achieves the best outcomes in patients with cT2 tumors with no evidence of CIS, complete (on-level) transurethral resection, no hydronephrosis, and good bladder capacity.

Table 4

Radiochemotherapy or radio-immunotherapy regime as a radiosensitizer in the treatment of muscle-invasive bladder cancer (cT2-cT4b cN0)

Recent data from a large propensity score matching analysis of 722 patients (n = 440 with radical cystectomy;

n = 282 with TMRT) have demonstrated the comparability of the outcomes between the two treatment methods regardless of the local tumor stage (Table 5, 36). However, 13% of patients who received TMRT needed to undergo radical salvage cystectomy. A meta-analysis confirmed that the two treatment approaches achieved comparable rates for overall survival (HR = 1.07 [0.81; 1.4], p = 0.6) and cancer-specific survival (HR = 1.12 [0.79; 1.57], p = 0.5) (37).).

Table 5

Findings of the retrospective case control study comparing radical cystectomy and trimodal radiochemotherapy for muscle-invasive or locally advanced urothelial carcinoma of the bladder

A problematic aspect of the series mentioned above is that the lack of prospective randomized trials, comparing radical cystectomy and trimodal therapy, makes it impossible to rule out selection bias.

For new treatment modalities, such as tetramodal therapy (Table 4) , a complete response in 81% of patients (125 of 154) as well as a 5-year overall survival of 91% and a rate of muscle-invasive recurrences of 4% have been reported (38).

The discussion about the potential benefits of neoadjuvant chemotherapy is not limited to radical cystectomy, but is also being conducted in a similar way for radiotherapy. In the BA06 30984 trial, neoadjuvant administration of cisplatin, methotrexate and vinblastine resulted in a significant reduction in risk of death and a significant improvement in 10-year survival (39, 40, Table 4).

After TMRT, patients are followed up by cystoscopy und urine cytology typically every 3 months for the first 2 years, every 6 months for the subsequent 3 years and then annually. Once a year, a CT urography or MR urography of the upper urinary tract would be (is?) indicated. (e17).

Immunotherapy as a radiosensitizer

In the phase 1b/2 DUART trial, 26 patients with unresectable locally advanced bladder cancer, who were not eligible for cisplatin, received definitive radiotherapy with 64 Gy and 4 cycles of durvalumab 1 500 mg every 4weeks, followed by durvalumab maintenance therapy for 12 months. A complete response was achieved in 71.4% and disease control in 95% of study participants (e18). This strategy is currently being tested in further ongoing phase II trials (NCT03702179, NCT04073160).

Conclusion

Bladder-sparing treatments for BCG-refractory NMI urothelial carcinoma as well as primary muscle-invasive bladder cancer need to be discussed on an interdisciplinary level and explained in detail to those affected. Once treated, these patients should receive structured, reliable and thorough follow-up care for the bladder and other organ systems.

Conflict of interest statement

CB received consulting fees from AstraZeneca GmbH, Bayer AG, Bristol-Myers Squibb, and Johnson & Johnson. Grants for presentations were awarded to his institution by AstraZeneca GmbH, Bristol-Myers Squibb, Cepheid Inc., and ERBE Elektromedizin GmbH. He is an Advisory Board member of Bristol-Myers Squibb and AstraZeneca GmbH. He is member of the board of the German Society of Urology (DGU). His research group received writing assistance from Bristol-Myers Squibb and AstraZeneca GmbH.

MdS received financial support, grants for presentations, fees for expert opinions, and travel expenses from AAA, Abbvie, Amgen, Astellas, AstraZeneca, Basilea, Bayer, BMS, EISAI, Ferring, Gilead, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, SeaGen, and Thermosome.

AH received consulting fees as well as lecture fees from Medac GmbH, Astellas, Janssen Cilag MSD, and BMS. He is a member of the Advisory Board of Janssen-Cilag.

CR received lecture fees from Medac and Astellas.

DB and AB declare no conflict of interest.

Manuscript received on 27 July 2024; revised version accepted on 21 January 2025.

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
Prof. Dr. med. Axel Heidenreich

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