
Advances in diagnosis and management
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Pathways to clear diagnosis
Risk stratification for NMIBC
Non-muscle-invasive bladder cancer (NMIBC) is a clinically heterogeneous disease that has a high recurrence rate. Patients with high-risk NMIBC have elevated disease progression rates and represent approximately 25% of NMIBC cases.1,2
Patients with high-grade T1 bladder cancer have a 42% rate of 5-year recurrence, and a 21% progression rate3
Risk stratification of patients with NMIBC is crucial to ensure they receive appropriate treatments and surveillance schedules. Patients with high-risk NMIBC require a more intensive management and follow-up plan compared with those with low or intermediate risk.3,4
Figure 1 shows the risk stratification criteria according to the European Association of Urology (EAU) and the American Urological Association (AUA) and Society of Urologic Oncology (SUO). The National Comprehensive Cancer Network (NCCN) guidelines use the AUA/SUO criteria.5 Patients are stratified according to the number of tumors, tumor size, recurrence rate, tumor stage, presence of carcinoma in situ, and tumor grade, and are designated as low risk, intermediate risk, high risk, and very high risk.3
Figure 1. Risk stratification of NMIBC according to EAU and AUA/SUO.4,6 BCG, Bacillus Calmette–Guérin; CIS, carcinoma in situ; G1/2/3, grade 1/2/3; HG, high grade; LG, low grade; LVI, lymphovascular invasion.
High recurrence and progression rates demonstrate the need to accurately diagnose NMIBC and manage high-risk disease effectively to prevent progression.
Clinical presentation and differential diagnosis of NMIBC
Bladder cancer can coexist with, and mimic the symptoms of, urinary tract infections (UTIs), with 39% of women with bladder cancer initially misdiagnosed with UTIs, causing delays in treatment initiation3,7
Most cases of bladder cancer are diagnosed because of painless gross or microscopic hematuria.3,6 Gross hematuria (as opposed to microscopic hematuria) is associated with high-grade cancer, as statistically supported by a 2023 cross-sectional retrospective study (N=515).8
Around 20% of patients with NMIBC may present with increased urinary urgency, frequency, and dysuria.8 These features are more frequently observed in patients with carcinoma in situ than with papillary Ta/T1 tumors.3,9
Assessment of suspected bladder cancer
The precise diagnostic pathway for patients with NMIBC varies and should be individualized based on the patient’s risk of progression, and is dependent on resource availability.5,10
The initial evaluation of patients with suspected bladder cancers includes:3,5
- Focused patient history and physical examination
- Imaging of the abdomen/pelvis
- Cystoscopy
- Urinary cytology and biomarkers
- Histopathologic assessment
Of these, cystoscopy is still the universally recommended primary diagnostic tool and gold standard for the initial evaluation of patients with suspected bladder cancer.3
If a lesion is documented, transurethral resection of the bladder tumor (TURBT) should be carried out to confirm the diagnosis (and as part of initial surgical treatment).5 Figure 2 shows the diagnostic pathway, with the diagnostic tools discussed in detail below.
Figure 2. Diagnostic pathway for adults with suspected bladder cancer.3,5 CIS, carcinoma in situ; EUA, examination under anesthesia; MIBC, muscle-invasive bladder cancer; NCCN, National Comprehensive Cancer Network; NMIBC, non-muscle-invasive bladder cancer; TURBT, transurethral resection of bladder tumor.
Patient history and physical examination
EAU guidelines mandate a focused patient history and physical examination (although this will not reveal NMIBC).9 Considering 50% of bladder cancer cases are attributed to smoking, NCCN guidelines detail screening for smoking.5,11
Imaging of the abdomen/pelvis
According to the AUA/SUO guidelines, upper urinary tract imaging should be performed as part of the initial evaluation of patients with suspected bladder cancer, with computed tomography (CT) or magnetic resonance imaging (MRI) recommended.6 This is echoed by the NCCN guidelines, and imaging is recommended in parallel with cystoscopy (or in parallel with TURBT if not done prior to TURBT).5
By contrast, EAU guidelines recommend ultrasound and/or CT intravenous urography (IVU) during the initial evaluation and a CT urography only after a high-risk bladder tumor has been detected.9 CT urography can detect papillary tumors in the urinary tract, with IVU as an alternative if CT is not available.9
Ultrasound may be performed as an adjunct to physical examination since it can visualize intraluminal masses in the bladder, renal masses, and hydronephrosis, but it cannot exclude all causes of hematuria.9
Cystoscopy
Cystoscopic examination and histologic evaluation of sampled tissue are necessary for the diagnosis of bladder cancer, with cystoscopy typically performed using white light (WL).9 All the most recent recommendations advise use of “enhanced cystoscopy,” namely photodynamic diagnosis (PDD; fluorescence cystoscopy or blue light cystoscopy) or narrow-band imaging (NBI), if the equipment is available.5,9,10
These new cystoscopic technologies have a demonstrably higher sensitivity than WL cystoscopy for detecting tumors, particularly high-risk tumors such as carcinoma in situ, but have lower specificity and cannot help to rule out prostatic involvement.3,12,13 PDD and NBI can be performed with flexible endoscopic equipment in the office.3,14
Urinary cytology and biomarkers
Urinary cytology can be performed as an adjunct to cystoscopy and has high sensitivity in detecting high-risk tumors, including carcinoma in situ.3,9 European guidelines advise analysis of voided urine (fresh urine or urine with adequate fixation), using the Paris System (2nd edition).9
Currently, EAU and AUA/SUO guidelines do not recommend any urinary biomarkers as part of routine clinical practice for diagnosis or follow-up.9,10 Other guidelines, such as the UK’s National Institute for Health and Care Excellence (NICE), recommend a urinary biomarker test (such as UroVysion using fluorescence in situ hybridization [FISH], ImmunoCyt, or a nuclear matrix protein 22 [NMP22] test) for patients with suspected bladder cancer.15
Histopathologic assessment
Histopathology of the tissue obtained through cystoscopy-guided biopsies and TURBT is one of the most reliable tools for assessing the depth of tumor infiltration, and hence essential for risk stratification of NMIBC.3
Of note, there is significant variability among pathologists regarding the diagnosis of carcinoma in situ, and there is inter-observer variability in the classification of stage T1 versus Ta tumors and tumor grading using both the 1973 and 2022 World Health Organization (WHO) classification.9
European guidelines strongly recommend using the 2017 TNM system to classify the depth of tumor invasion, and weakly recommend the use of both the 1973 and 2004/2022 WHO grading classification systems (or a hybrid system).9
TURBT
TURBT has key diagnostic and treatment roles – the goal is to confirm the clinical diagnosis and remove all visible lesions.3 A successful TURBT will identify the factors required to assign disease risk and clinical stage.9 To ensure accurate staging, guidelines recommend a second TURBT for certain patients, including those with incompletely resected tumors, T1 tumors, or with high-grade NMIBC, and a repeat TURBT is recommended 2–6 weeks after the initial TURBT.5,9,10
To ensure correct pathological assessment following TURBT, resected and analyzed tissue must be of high quality.9 EAU guidelines uniquely recommend use of a ‘TURBT checklist’ to support high-quality biopsy sample collection, shown in Figure 3.9
Figure 3. The TURBT checklist is recommended by EAU guidelines to obtain all relevant information for an accurate NMIBC diagnosis.9 CIS, carcinoma in situ; NBI, narrow-band imaging; NMIBC, non-muscle-invasive bladder cancer; PDD, photodynamic diagnosis; TURBT, transurethral resection of bladder tumor.
References
- Bedke, 2023. Optimizing outcomes for high-risk, non-muscle-invasive bladder cancer: The evolving role of PD-(L)1 inhibition. https://www.doi.org/10.1016/j.urolonc.2023.10.004
- Grabe-Heyne, 2023. Intermediate and high-risk non-muscle-invasive bladder cancer: An overview of epidemiology, burden, and unmet needs. https://www.doi.org/10.3389/fonc.2023.1170124
- Lopez-Beltran, 2024. Advances in diagnosis and treatment of bladder cancer. https://www.doi.org/10.1136/bmj-2023-076743
- Sylvester, 2021. European Association of Urology (EAU) prognostic factor risk groups for non–muscle-invasive bladder cancer (NMIBC) incorporating the WHO 2004/2016 and WHO 1973 classification systems for grade: An update from the EAU NMIBC Guidelines Panel. https://www.doi.org/10.1016/j.eururo.2020.12.033
- NCCN, 2024. Clinical practice guidelines in oncology. Bladder cancer V5.
- Chang, 2016. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. https://www.doi.org/10.1016/j.juro.2016.06.049
- 2023. World Bladder Cancer Patient Coalition. Press release: More than half of people with bladder cancer are misdiagnosed with another disease. https://worldbladdercancer.org/news_events/press-release-more-than-half-of-people-with-bladder-cancer-are-misdiagnosed-with-another-disease/
- Jakus, 2023. The impact of the initial clinical presentation of bladder cancer on histopathological and morphological tumor characteristics. https://www.doi.org/10.3390/jcm12134259
- 2024. EAU guidelines on non-muscle-invasive bladder cancer (TaT1 and CIS).
- Holzbeierlein, 2024. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline: 2024 amendment. https://www.doi.org/10.1097/ju.0000000000003846
- Jubber, 2023. Epidemiology of bladder cancer in 2023: A systematic review of risk factors. https://www.doi.org/10.1016/j.eururo.2023.03.029
- Mowatt, 2011. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: Systematic review and meta-analysis. https://www.doi.org/10.1017/s0266462310001364
- Russo, 2021. Performance of narrow-band imaging (NBI) and photodynamic diagnosis (PDD) fluorescence imaging compared to white light cystoscopy (WLC) in detecting non-muscle invasive bladder cancer: A systematic review and lesion-level diagnostic meta-analysis. https://www.doi.org/10.3390/cancers13174378
- Eva M. Wojcik, 2022. The Paris System for reporting urinary cytology. https://www.doi.org/10.1007/978-3-030-88686-8
- NICE, 2015. NICE guideline bladder cancer: diagnosis and management (NG2).
The NMIBC treatment landscape
For patients with non-muscle-invasive bladder cancer (NMIBC), transurethral resection of the bladder tumor (TURBT) represents the mainstay in confirming diagnosis and risk stratification, as well as the initial treatment step.1,2 Where possible, the goal is to achieve complete resection of the tumor with the first (or repeat) TURBT.
The gold standard for post-TURBT treatment is intravesical instillation of Bacillus Calmette–Guérin (BCG); unfortunately, it has an estimated treatment failure rate of 40–50%.1 Treatment options for BCG-unresponsive disease have traditionally been scarce but, more recently, the treatment landscape began evolving (Figure 1).1
Figure 1. Initial management options for patients with low-, intermediate-, and high-risk NMIBC following risk stratification and TURBT with or without intravesical chemotherapy.3-6 Nadofaragene firadenovec-vncg and nogapendekin alfa inbakicept (NAI) are only approved for use in the USA.5,6 AUA, American Urology Association; BCG, Bacillus Calmette–Guérin.
Unmet needs in NMIBC
NMIBC can be challenging to manage, with significant rates of treatment failure and disease progression, especially for high-risk patients.7
Despite BCG treatment, around 20% of patients with high-risk NMIBC progress to muscle-invasive disease8
For patients with BCG-unresponsive disease or with “very high-risk” features, radical cystectomy remains the preferred recommended option.1,3,9-11 While potentially curative, patients undergoing radial cystectomy experience considerable physical and psychological burdens, as well as urinary and sexual dysfunction, which may significantly impact quality of life.1,7
Far more radical cystectomies are canceled due to patient lack of consent than medical contraindications.1 Reflecting this, results from a qualitative study show that patient respondents (N=107) were willing to accept a 44% increase in the risk of progression to MIBC, in order to delay radical cystectomy for 5 years.12 The considerable hesitation toward radical cystectomy shown by patients highlights a need for expanded bladder-sparing treatment approaches.
Intravesical BCG for high-risk NMIBC
The precise mechanism of action of intravesical BCG remains to be defined; however, it is known to trigger innate and adaptive immune responses leading to the destruction of cancerous cells.13
While a first-line therapy, BCG has many adverse events that can impact treatment adherence; in a European study, around 70% of patients (N=1,316) experienced local or systemic adverse events and 8% discontinued due to toxicity.14
Potential adverse events and toxicities of BCG include:
- Urinary frequency14
- Cystitis14
- Fever14
- Hematuria14
- Granulomatous prostatitis15,16
- Epididymo-orchitis17
- Distant infections, such as granulomatous pneumonia, hepatitis, aortic infection, dermatologic and ophthalmic manifestations and, more rarely, sepsis13
Unfortunately, global shortage of BCG continues to be an issue despite efforts to increase its production.18,19 The European Association of Urology (EAU) and American Urology Association (AUA) prioritize full-strength BCG for patients with high-risk NMIBC.19,20 If BCG is unavailable, intravesical chemotherapy or radical cystectomy are alternative options; however, treatment with the former is associated with a higher risk of recurrence compared with BCG immunotherapy.20
The global shortage of BCG, in addition to its potential adverse events and the high proportion of patients with BCG-unresponsive disease, has driven the development of alternative immunotherapies for patients with high-risk NMIBC.18
PD1/PD-L1 inhibition
Pembrolizumab was approved for NMIBC in 2020 and was the first alternative option to radical cystectomy for patients with BCG-unresponsive disease.4,13,21,22 While BCG is a nonspecific and intravesical immunotherapy, pembrolizumab is an intravenously administered monoclonal immunoglobulin (Ig)G4 antibody, specifically inhibiting the immune checkpoint protein programmed cell death 1 (PD-1).1
Systemic pembrolizumab was approved following data from the KEYNOTE-057 study, in which 41% of participants (N=101) with BCG-unresponsive NMIBC receiving 200 mg pembrolizumab every 3 weeks had a complete response at 3 months, 46% of whom maintained a response for at least 12 months.23,24 Regarding safety, 13% of participants experienced grade 3 or 4 treatment-related adverse events, and 22% had immune-related adverse events.23
In a recent KEYNOTE-057 analysis, 43.5% of participants with BCG-unresponsive high-grade Ta or any-grade T1 tumors without carcinoma in situ (CIS; N=132) had 12-month disease-free survival (DFS).24
The 2024 AUA / Society of Urologic Oncology (SUO) Guideline amendment recommends offering pembrolizumab to patients with CIS completing adequate BCG therapy within 12 months.11 The 2024 National Comprehensive Cancer Network (NCCN) guidelines recommend pembrolizumab for the treatment of patients with BCG-unresponsive, high-risk disease with either CIS or high-grade papillary Ta/T1-only tumors who are ineligible for or have elected not to undergo cystectomy.3
By contrast, European guidelines give a weak recommendation for systemic immunotherapy in BCG-unresponsive tumors, since all alternatives are considered inferior to radical cystectomy.10
Programmed death-ligand 1 (PD-L1) expression in tumors may play a role in attenuating responses to BCG; it has been speculated that by inhibiting PD-1 interaction with its ligands PD-L1 and PD-L2, pembrolizumab may improve the antitumor activity of BCG. The efficacy and safety of pembrolizumab in combination with BCG in BCG-naive patients with high-risk NMIBC is being investigated in KEYNOTE-676, an open-label, comparator-controlled phase 3 study currently underway.25
IL-15 agonism
Interleukin 15 (IL-15) is a potent stimulator of CD8+ T cells, memory T cells, and natural killer cells, all of which can reduce the tumor burden.5 IL-15 superagonist nogapendekin alfa inbakicept-pmin (NAI) received U.S. Food and Drug Administration (FDA) approval for NMIBC in April 2024; it is currently only approved in the USA for use in combination with BCG in patients with BCG-unresponsive NMIBC CIS with or without papillary tumors.5,26
NAI is administered intravesically with BCG as induction therapy once a week for 6 weeks, with a second induction course administered if complete response is not achieved at month 3, followed by maintenance therapy. Maintenance therapy consists of NAI administration with BCG once a week for 3 weeks at months 4, 7, 10, 13, and 19 for a total of 15 doses.5
The approval for NAI came following data from the ongoing QUILT-3.032 trial: in a cohort of patients with BCG-unresponsive CIS treated with NAI combined with BCG, complete response at any time was achieved in 71% of participants (N=82).27 For participants who experienced a complete response, the estimated probability of avoiding cystectomy at month 24 was 89.2% and disease-specific survival was estimated to be 100%. In participants with BCG-unresponsive high-grade Ta/T1 papillary NMIBC (N=72), the estimated DFS was 55.4% at 12 months.27
Most treatment-emergent adverse events with NAI plus BCG were grade 1 or 2 and were experienced by 86% of participants; three grade 3 immune-related adverse events occurred.27
The most recent NCCN guidelines (October 2024) recommend NAI plus BCG as an option for BCG-unresponsive/BCG-intolerant patients with high-risk NMIBC CIS.3 The recent International Bladder Cancer Group Recommendations (August 2024) also recommend (off-label) considering NAI plus BCG for patients with BCG-unresponsive, high-grade papillary Ta/T1 tumors without CIS, and BCG-unresponsive papillary-only tumors.4
Applications for regulatory approval of NAI in the European Union and UK have been submitted and are currently pending.28,29 Furthermore, trials to investigate the efficacy and safety of NAI in BCG-naive disease are planned (QUILT-2.005), with enrollment of patients in the USA, India, and South Africa scheduled.29
Other immunotherapies
Additional immunotherapies are currently under investigation for the treatment of patients with NMIBC, including:1
- Atezolizumab (PD-L1 inhibitor)
- Durvalumab (PD-L1 inhibitor)
- Nivolumab (PD-1 inhibitor)
- Sasanlimab (PD-1 inhibitor)
References
- Jaromin, 2024. Revolutionizing treatment: Breakthrough approaches for BCG-unresponsive non-muscle-invasive bladder cancer. https://www.doi.org/10.3390/cancers16071366
- Babjuk, 2022. European Association of Urology guidelines on non–muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). https://www.doi.org/10.1016/j.eururo.2021.08.010
- NCCN, 2024. Clinical practice guidelines in oncology. Bladder cancer V5.
- Li, 2024. Bladder-sparing therapy for Bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer: International Bladder Cancer Group recommendations for optimal sequencing and patient selection. https://www.doi.org/10.1016/j.eururo.2024.08.001
- Keam, 2024. Nogapendekin alfa inbakicept: First approval. https://www.doi.org/10.1007/s40265-024-02060-1
- Lee, 2023. Nadofaragene firadenovec: First approval. https://www.doi.org/10.1007/s40265-023-01846-z
- Grabe-Heyne, 2023. Intermediate and high-risk non-muscle-invasive bladder cancer: An overview of epidemiology, burden, and unmet needs. https://www.doi.org/10.3389/fonc.2023.1170124
- Van Den Bosch, 2011. Long-term cancer-specific survival in patients with high-risk, non–muscle-invasive bladder cancer and tumour progression: A systematic review. https://www.doi.org/10.1016/j.eururo.2011.05.045
- NICE, 2015. NICE guideline bladder cancer: diagnosis and management (NG2).
- 2024. EAU guidelines on non-muscle-invasive bladder cancer (TaT1 and CIS).
- Holzbeierlein, 2024. Long-term cancer-specific survival in patients with high-risk, non–muscle-invasive bladder cancer and tumour progression: A systematic review. https://www.doi.org/10.1097/ju.0000000000003846
- Collacott, 2023. Patient preferences for treatment of Bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer: A cross-country choice experiment. https://www.doi.org/10.1016/j.euros.2022.12.016
- Lidagoster, 2024. BCG and alternative therapies to BCG therapy for non-muscle-invasive bladder cancer. https://www.doi.org/10.3390/curroncol31020079
- Brausi, 2014. Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: Results of the EORTC Genito-Urinary Cancers Group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. https://www.doi.org/10.1016/j.eururo.2013.07.021
- Oates, 1988. Granulomatous prostatitis following Bacillus Calmette-Guerin immunotherapy of bladder cancer. https://www.doi.org/10.1016/s0022-5347(17)41803-9
- Logan, 2014. Changes observed in multiparametric prostate magnetic resonance imaging characteristics correlate with histopathological development of chronic granulomatous prostatitis after intravesical Bacillus Calmette-Guerin therapy. https://www.doi.org/10.1097/rct.0b013e3182aac58a
- Harada, 2006. Epididymo‐orchitis caused by intravesically instillated bacillus Calmette‐Guérin: Genetically proven using a multiplex polymerase chain reaction method. https://www.doi.org/10.1111/j.1442-2042.2006.01257.x
- Passarelli, 2024. Contemporary treatment of NMIBC—Is it time to move on from BCG? https://www.doi.org/10.3390/jcm13144112
- AUA. 2020. BCG shortage information. https://www.auanet.org/about-us/bcg-shortage-info
- Babjuk. 2012. Statement concerning the shortage of BCG vaccine from the EAU Guidelines Panel on non-muscle invasive bladder cancer. https://d56bochluxqnz.cloudfront.net/documents/guideline-publications/non-muscle-invasive-bladder-cancer/NMIBC-Guidelines-Panel-Statement-Concerning-Shortage-of-BCG-Vaccine.pdf
- Keytruda prescribing information, 2021.
- EMA, 2024. Keytruda summary of product characteristics.
- Balar, 2021. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm, multicentre, phase 2 study. https://www.doi.org/10.1016/s1470-2045(21)00147-9
- Necchi, 2024. 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. https://www.doi.org/10.1016/s1470-2045(24)00178-5
- UroToday. 2024. ASCO GU 2024: Phase 3 KEYNOTE-676 cohort A: Bacillus Calmette-Guérin with or without pembrolizumab for high-risk non–muscle-invasive bladder cancer that persists/recurs after BCG induction. https://www.urotoday.com/conference-highlights/asco-gu-2024/asco-gu-2024-bladder-cancer/149535-asco-gu-2024-phase-3-keynote-676-cohort-a-bacillus-calmette-guerin-with-or-without-pembrolizumab-for-high-risk-non-muscle-invasive-bladder-cancer-that-persists-recurs-after-bcg-induction.html
- ANKTIVA prescribing information, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761336s000lbl.pdf
- Chamie, 2023. IL-15 superagonist NAI in BCG-unresponsive non–muscle-invasive bladder cancer. https://www.doi.org/10.1056/evidoa2200167
- OncLive. 2024. Nogapendekin alfa inbakicept plus BCG maintains CR rate in BCG-unresponsive NMIBC with CIS. 19 November. https://www.onclive.com/view/nogapendekin-alfa-inbakicept-plus-bcg-maintains-cr-rates-in-bcg-unresponsive-nmibc-with-cis
- ImmunityBio. 2024. ImmunityBio’s ANKTIVA® now covered by more than a dozen insurance plans representing over 100 million lives within months of FDA approval. 12 August. https://ir.immunitybio.com/news-releases/news-release-details/immunitybios-anktivar-now-covered-more-dozen-insurance-plans?field_nir_news_date_value[min]=
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