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Advancements in the Diagnosis, Treatment, and Risk Stratification of Non-Muscle Invasive Bladder Cancer
*Corresponding author: Sameer Rajendra More, Intern, Krishna Institute of Medical Sciences, Karad, Maharashtra, India sameermore0907@gmail.com
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Received: ,
Accepted: ,
How to cite this article: More SR. Advancements in the Diagnosis, Treatment, and Risk Stratification of Non-Muscle Invasive Bladder Cancer. Karnataka J Surg. 2025;2:61–66. doi: 10.25259/KJS_5_2025
Abstract
Recent technological innovations in the management of non-muscle invasive bladder cancer (NMIBC) have had a profound impact on clinical practice in three key areas: Diagnosis, treatment, and risk stratification. Novel urine-based diagnostic technologies—messenger ribonucleic acid (mRNA) panels and new urinary biomarker tests (UBTs)—have proved to be highly sensitive and specific, enhancing early detection and decreasing dependence on invasive tests. In treatment, new therapies like immune checkpoint inhibitors and oncolytic viral vectors like CVA21, CG0070, and nadofaragene firadenovec have positive clinical outcomes, particularly in Bacillus calmetteGuérin (BCG)-refractory and high-risk NMIBC patients. Concurrently, the use of molecular profiling and genetic markers—mainly FGFR3 mutations—has enhanced risk stratification, enabling personalized treatment regimens and improved recurrence prediction. These advancements all propel the march towards precision medicine for NMIBC to deliver more targeted, more effective, more patient-specific treatments. Investigation must continue to sharpen up on and expand these strategies in the clinic.
Keywords
High-throughput nucleotide sequencing
Machine learning
Non-muscle invasive bladder neoplasms
Precision medicine
Urinary bladder neoplasms
INTRODUCTION
This report reviews recent evidence on non-muscle invasive bladder cancer (NMIBC), with particular stress on three key domains: diagnosis, treatment, and risk stratification. The information documented here is based on current studies and highlights molecular test innovation, immunotherapy and viral oncotherapy advances, and new emerging markers for risk assessment. Of particular interest, the arrival of molecular testing technologies like next-generation sequencing and liquid biopsy has greatly improved diagnostic accuracy, earlier detection, and more accurate characterisation of tumour genetics. These molecular technologies have the classical diagnostic model by offering detailed genomic profiles that help treatment and disease progression with unprecedented accuracy.
Furthermore, improving patient outcomes by lowering recurrence and progression rates are developments in new immunotherapeutic agents, including immune checkpoint inhibitors like PD-1/PD-L1 inhibitors and new BCG combinations. For patients who were once refractory to conventional treatments, these immunotherapies have been especially helpful; they also offer great hope for high-risk NMIBC. Furthermore, expanding the therapeutic toolkit accessible to doctors is the beginning of tailored treatments derived from molecular profiling. With response rates above historical norms in some patient subgroups, viral oncotherapy treatments, including CG0070 and Detalimogene Voraplasmid (EG-70), are showing encouraging first results in clinical trials. These creative ideas use altered viruses to specifically target cancer cells while sparing healthy tissue, so perhaps providing a better side effect profile than conventional treatments. Early-phase trials have demonstrated particularly encouraging results in BCG-unresponsive patients, a historically challenging population to treat.
More accurate risk assessments are also coming from fresh biomarkers, including machine learning-based predictive models, TERT promoter changes, and FGFR3 mutations. To create individualised risk profiles, these sophisticated risk stratification tools combine many data points—including histopathological results, clinical criteria, and molecular markers—including artificial intelligence methods have improved the accuracy of these predictive models, so allowing more exact patient stratification and treatment choices.
These advancements are vital for improving patient outcomes, reducing the burden of frequent surveillance, and personalising treatment strategies in NMIBC management. The shift toward precision medicine, supported by these technological and therapeutic innovations, is changing the landscape of bladder cancer care, offering more targeted, effective, and individualised treatment approaches for patients with NMIBC. This evolution in care delivery promises to optimise resource utilisation while maximising therapeutic efficacy and minimising unnecessary interventions.
DIAGNOSIS
The diagnosis of non-muscle invasive bladder cancer (NMIBC) involves a comprehensive approach utilizing multiple diagnostic modalities and clinical assessments. Initial evaluation typically begins with a thorough patient history, focusing on risk factors and presenting symptoms such as hematuria.
The diagnostic process incorporates several key components:
Clinical Evaluation
Detailed medical history and physical examination Assessment of urinary symptoms. Evaluation of risk factors including smoking history and occupational exposures.
Diagnostic Tools
Cystoscopy (gold standard for visual inspection) urine cytology and urinalysis. Advanced imaging techniques (CT urography, MRI) molecular markers and genetic testing.
Histopathological Assessment
Tissue biopsy and tumor staging grade determination using World Health Organization (WHO) classification molecular subtyping for personalized treatment planning.
Risk Stratification
Integration of clinical and pathological factors assessment of recurrence and progression risk. Determination of appropriate surveillance protocol.
Urine-Based Screening and Biomarkers
Urinary mRNA panels
A panel of five specific mRNAs—CD24, TOP2A, IQGAP3, UBE2C, and CRH—has shown greater diagnostic accuracy for NMIBC, boasting an area under the curve (AUC) of approximately 79.5% during follow-up evaluations. This panel outperforms single biomarker tests, providing enhanced sensitivity and specificity for NMIBC detection. Each mRNA contributes uniquely to the panel’s overall diagnostic accuracy by being significantly upregulated in NMIBC patients compared to healthy controls and those with haematuria.
Mechanistic insights
The selected mRNAs play crucial roles in cellular processes associated with bladder cancer development: CD24 regulates cell adhesion and migration, TOP2A is involved in DNA replication and chromosomal segregation, IQGAP3 influences cell proliferation and invasion, UBE2C controls cell cycle progression, CRH modulates stress response and inflammation.
Technical considerations
Sample collection timing, processing methods, and storage conditions significantly impact mRNA stability and test reliability. Standardized protocols have been developed to optimize specimen handling and minimize degradation.
Novel urinary biomarker tests (UBTs)
Recent studies report that UBTs can achieve a sensitivity of up to 98% and a specificity of up to 100% when distinguishing low-grade NMIBC from healthy controls. Additionally, they demonstrate a specificity of 90% for differentiating NMIBC from hematuria groups, with a positive predictive value (PPV) up to 67% and a negative predictive value (NPV) up to 99%. The sensitivity and specificity of these tests may vary across different stages and grades of NMIBC, with higher accuracy noted in high-grade tumors.
Clinical Relevance: High sensitivity ensures fewer false negatives, reducing the risk of missed diagnoses. High specificity minimizes false positives, preventing unnecessary interventions. High PPV indicates a high likelihood that a positive test result truly indicates NMIBC, while high NPV provides confidence in ruling out the disease when the test is negative.
Limitations and Mitigation: Potential sources of error in these tests include sample handling, technical variability, and biological differences among patients. Mitigation strategies such as standardization of protocols, continuous validation of biomarkers, and integration with other diagnostic methods can help improve reliability.[1]
Urine-based molecular tests overview
These noninvasive tests leverage biomarkers based on proteins, deoxyribonucleic acid (DNA) methylation, and extracellular vesicles to facilitate early detection and continuous surveillance, thereby enhancing clinical decision-making and early intervention strategies. For example, the Bladder EpiCheck test utilizes DNA methylation changes across a panel of 15 genomic biomarkers, demonstrating 69% sensitivity and 96% specificity. Comparative studies illustrate that these molecular tests can offer better accuracy than traditional cytology, especially in detecting high-grade NMIBC.
Cost-Effectiveness and Accessibility: Urine-based tests provide a non-invasive, low-cost alternative to cystoscopy, making them more accessible and practical for routine surveillance. These advantages can improve patient adherence to follow-up protocols and reduce the frequency of invasive procedures, thereby enhancing quality of life and lowering healthcare costs.
Performance in Diverse Populations: These tests must be evaluated across diverse patient populations, considering factors such as age, gender, and comorbidities, to ensure their broad applicability and effectiveness in various clinical settings.
TREATMENT
Standard Treatment Approaches
Initial management typically involves transurethral resection of bladder tumor (TURBT) intravesical therapy options include: BCG immunotherapy for high-risk cases chemotherapy agents (Mitomycin C, Gemcitabine) Maintenance protocols for recurrence prevention.
Risk-Stratified Treatment Selection
Low-risk patients: Single immediate postoperative chemotherapy instillation Intermediate-risk: Induction course of chemotherapy or BCG High-risk: BCG induction plus maintenance therapy BCG-unresponsive cases: Consider clinical trials or radical cystectomy.
Novel Therapeutic Strategies
Emerging treatment modalities
Device-assisted therapies (EMDA, Hyperthermia) Novel drug delivery systems.
Combination approaches immunotherapy innovations
PD-1/PD-L1 inhibitors Modified BCG strains Targeted antibody treatments.[2]
Treatment Monitoring and Follow-up
Regular cystoscopy surveillance Urine cytology and biomarker testing. Risk-adapted follow-up schedules quality of life assessment.
Emerging Therapeutic Modalities
Immune checkpoint inhibitors (ICIs)
Single-agent ICIs have shown mixed results in managing NMIBC. Clinical trials such as KEYNOTE-057 reported a complete response (CR) rate of 38.8% at 3 months for pembrolizumab in BCG-unresponsive NMIBC patients. Long-term outcomes from additional studies indicate that pembrolizumab has led to a median cancer-free duration of 29.6 months, with a 12-month disease-free survival rate of 43.5% and an overall survival rate of 61% at 3 years.
Combination therapies pairing ICIs (e.g., pembrolizumab, durvalumab) with intravesical agents show increased potential, particularly in BCG-unresponsive and high-risk NMIBC. Studies have indicated CR rates of up to 48% among certain patient cohorts. Sequential intravesical gemcitabine and docetaxel have also shown recurrence-free rates of 48% at 1 year and approximately 40% at 2 years.
Promising combinations include tislelizumab with nabpaclitaxel, which have demonstrated durable, clinically meaningful activity in high-risk NMIBC, with a well-tolerated safety profile and significant antitumor effectiveness.[3,4]
Oncolytic viral therapies
CVA21 oncolytic virus
Preclinical and early clinical evaluations indicate that CVA21 can both target and destroy cancer cells while stimulating an immune response. Studies suggest that CVA21 may serve as a new therapeutic agent for NMIBC, demonstrating significant immune inflammatory responses and durable antitumour effects. Combining CVA21 with low doses of chemotherapy, such as mitomycin C, has been shown to enhance viral replication and oncolysis, suggesting a synergistic effect.[5]
Clinical Trials
Various trials, including Phase Ib/II and Phase III studies, have shown promising results:
Studies on CG0070 and phase Ib/II trials of OH2 injection solution highlight feasibility, safety, and high complete response rates in high-risk patients. The Phase III BOND-003 trial of cretostimogene grenadenorepvec reported complete response rates exceeding 75%.
Additional trials using agents such as nadofaragene firadenovec and CG0070 suggest that oncolytic therapies are emerging as promising candidates for patients who do not respond to conventional intravesical therapies. Nadofaragene firadenovec has shown a 53.4% complete response rate, with a median response duration of 9.7 months and significant bladder preservation outcomes.
Overall, these emerging therapies highlight the potential for improved patient outcomes in NMIBC management through the use of innovative ICI combinations and oncolytic viral therapies. The development of predictive biomarkers and a better understanding of patient characteristics will further optimise treatment strategies.[6,7]
RISK STRATIFICATION
Molecular and Genetic Markers
FGFR3 mutations
FGFR3 is identified as the most commonly altered gene in NMIBC, especially in low-grade Ta tumours, where its presence correlates strongly with increased recurrence risk. The recurrence rate for NMIBC patients with FGFR3 mutations is significantly higher compared to those without such mutations.
Clinical Implications: FGFR3 mutations are less associated with disease progression and are considered an independent predictor for recurrence in low-grade NMIBC patients. This information allows clinicians to tailor follow-up schedules and consider targeted therapies for patients with FGFR3 mutations. The median recurrence-free survival for patients with FGFR3 alterations treated with targeted therapies like erdafitinib is notably longer compared to those receiving standard intravesical chemotherapy.
Risk group categorization
NMIBC cases are stratified into low, intermediate, and high-risk groups based on recurrence and progression likelihood. These risk groups enable tailored management strategies, ensuring that patients receive therapy corresponding to their tumour aggressiveness and recurrence potential. For instance, low-risk patients typically undergo less frequent follow-ups and less aggressive treatments, while high-risk patients require more intensive surveillance and potentially more aggressive therapeutic interventions. Recent research has also identified genetic and molecular profiles specific to intermediate and high-risk categories, which further aids in individualised treatment planning.
Emerging Genetic Markers
Beyond FGFR3 mutations, other genetic markers such as Ki-67, p53, and alterations in DDR-related genes are being studied for their potential to predict recurrence and progression more accurately. The use of next-generation sequencing and gene-expression profiling is emerging as a crucial method for risk stratification in NMIBC.
Clinical Outcomes and Future Directions
Ongoing studies are exploring the efficacy of FGFR inhibitors and other targeted therapies in patients with FGFR3 mutations, showing promising improvements in recurrence-free survival and overall survival rates. As research continues, the integration of new genetic markers and molecular profiles will likely refine risk stratification models, leading to more personalised and effective treatment strategies for NMIBC patients. The summary of the whole manuscript is shortly expressed in Table 1.
| Area | Key advancement | Clinical impact | Additional considerations |
|---|---|---|---|
| Diagnosis | 5-mRNA panel | Sensitivity of 98%, Specificity of | Reduced need for invasive procedures; cost- |
| 100% | effective screening tool | ||
| Novel UBTs | Sensitivity up to 93%, Specificity | Improved patient compliance; suitable for | |
| up to 84% | routine surveillance | ||
| DNA methylation markers | Accuracy rate of 95% in early | Potential for early intervention | |
| detection | |||
| Treatment | ICIs (e.g., pembrolizumab) | CR rate of 41% in BCG-refractory | Durable responses observed in long-term |
| NMIBC, improved survival | follow-up | ||
| Combination therapies | CR rates up to 83% in certain | Reduced resistance development; better | |
| cohorts | tolerability profile | ||
| Oncolytic viruses (e.g., CVA21) | Promising early results, enhanced | Novel mechanism of action; minimal | |
| by MMC | systemic toxicity | ||
| Enhanced BCG delivery systems | Improved retention and efficacy | Better drug delivery to tumour site | |
| Risk stratification | FGFR3 mutations | Strong predictor of recurrence in | Guides surveillance intervals |
| low-grade Ta tumours | |||
| Molecular subtypes | Enables personalized treatment | Optimises therapy selection | |
| approaches | |||
| Immune signatures | Predicts response to | Aids in patient selection | |
| immunotherapy | |||
| Follow-up care | Digital cystoscopy | Enhanced detection of subtle | Improved documentation and monitoring |
| lesions | |||
| AI-assisted imaging | Reduced interpreter variability | Supports clinical decision-making |
mRNA: Messenger ribonucleic acid; UBTs: Uterine balloon tamponade; DNA: Deoxyribonucleic acid; ICIs: Immune checkpoint inhibitors; CR: Complete response; BCG: Bacillus Calmette-Guérin; NMIBC: Non-muscle invasive bladder cancer; MMC: Mitomycin C.
CONCLUSION
These recent advancements in the diagnosis, treatment, and risk stratification of non-muscle invasive bladder cancer (NMIBC) reflect a significant shift toward more personalized and patient-friendly approaches to care. The introduction of innovative diagnostic tools, such as urine-based mRNA panels and urine biomarker tests (UBTs), has revolutionized how NMIBC is identified and monitored. These non-invasive tests offer high levels of accuracy, precision, and predictive power. Among them, the 5-mRNA panel—which examines CD24, TOP2A, IQGAP3, UBE2C, and CRH—has shown exceptional diagnostic performance. It can differentiate between low-grade NMIBC and patients with hematuria with 90% accuracy and 100% precision, and between NMIBC and healthy individuals with 98% accuracy. These biomarkers significantly reduce the reliance on invasive procedures such as cystoscopy, thereby enhancing patient comfort and compliance while ensuring consistent and reliable monitoring over time.
In terms of treatment, the landscape is also evolving rapidly. New therapeutic combinations, particularly those involving immune checkpoint inhibitors and intravesical agents, are demonstrating strong potential in treating high-risk and BCG-unresponsive NMIBC. Clinical studies of pembrolizumab have shown promising results, with a complete response rate of 41% and a median response duration of 16.2 months in patients who previously had limited options. Additionally, oncolytic viral therapies like CVA21 are being actively explored in multiple clinical trials and have shown both effectiveness and safety, offering renewed hope for patients who have exhausted standard therapies. These novel treatment modalities are not only broadening the therapeutic arsenal but are also reshaping how we approach resistant or recurrent cases of NMIBC.
Another important stride in NMIBC management is the improved stratification of risk using molecular markers. In particular, the identification of FGFR3 mutations has emerged as a valuable tool in predicting recurrence and guiding treatment decisions. Patients with FGFR3 mutations are often diagnosed at an earlier stage but are also more likely to experience disease recurrence. This insight allows clinicians to tailor interventions more effectively, optimizing surveillance schedules and therapeutic strategies to the specific needs and risk profiles of each patient. This more nuanced understanding of disease progression supports a shift from a one-size-fits-all model to a more individualized approach, ultimately improving quality of life and long-term outcomes.
Overall, the integration of advanced diagnostic biomarkers, novel therapeutic options, and personalized risk assessment represents a comprehensive and patient-centered paradigm in NMIBC management. The convergence of these elements is not only improving diagnostic accuracy and therapeutic effectiveness but is also fostering a healthcare environment that prioritizes precision, safety, and patient well-being. As ongoing research continues to refine these strategies, there is strong potential for further breakthroughs that will enhance our ability to manage NMIBC more effectively and compassionately in the years to come.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent not required as patients identity is not disclosed or compromised.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The author confirms that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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