Comparative analysis of EAU, AUA, and NCCN guidelines for the management of non-muscle invasive bladder cancer

Abstract

Background

This study aimed to systematically compare the most recent guidelines from the European Association of Urology (EAU, 2025), American Urological Association (AUA, 2024), and National Comprehensive Cancer Network (NCCN, 2025) for the management of non-muscle invasive bladder cancer (NMIBC). The primary objective was to assess the degree of concordance and identify sources of divergence across 32 predefined clinical decision domains.

Materials and methods

This guideline concordance study was conducted according to PRISMA 2020 recommendations, evaluating full-text versions of the latest EAU, AUA, and NCCN guidelines. Thirty-two clinical domains encompassing the diagnostic, therapeutic, and follow-up aspects of NMIBC management were pre-defined based on literature review and expert consensus. Two independent reviewers classified each domain for each guideline as full concordance, partial concordance, or discordance, with discrepancies resolved by a third reviewer. Inter-guideline agreement was quantified using Cohen’s and Fleiss’ kappa coefficients.

Results

Among the 32 domains analyzed, full concordance was identified in 19 domains (59.4%), partial concordance in 12 domains (37.5%), and discordance in 1 domain (3.1%). Inter-guideline reliability was high, with Cohen’s kappa values ranging from 0.83 to 0.94 across pairs and an overall Fleiss’ kappa of 0.74, indicating substantial agreement among the three guidelines. Clinically meaningful differences were mainly related to risk-stratification criteria, the management of BCG-unresponsive disease, the selective use of urinary biomarkers, and the endorsement of conservative strategies for recurrent low-grade tumors.

Conclusion

Current international guidelines for NMIBC are highly consistent across the majority of clinical decision domains, providing a strong framework for evidence-based care. Residual differences reflect evolving evidence, regulatory environments, and the pace of integration of new diagnostics and therapeutics. Continued harmonization efforts and regular guideline updates are necessary to further optimize global NMIBC management.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12894-026-02045-0.

Introduction

Non-muscle invasive bladder cancer (NMIBC) accounts for approximately three-quarters of newly diagnosed bladder cancer cases and remains a significant clinical challenge due to its high recurrence rate and heterogeneous risk of progression [1]. Optimal management of NMIBC relies on timely diagnosis, risk-adapted therapy, and close surveillance, all of which have been shaped by evolving scientific evidence and technological innovation.

To guide clinicians in this complex landscape, several international societies-including the European Association of Urology (EAU), American Urological Association (AUA), and National Comprehensive Cancer Network (NCCN)-regularly publish evidence-based clinical guidelines for NMIBC management [2–4]. While these guidelines share the common goal of improving patient outcomes, differences in their recommendations inevitably arise. Such discrepancies can stem from regional regulatory approvals, varying interpretations of clinical trial data, differing thresholds for adopting novel therapies or technologies, and the pace at which new evidence is integrated into practice.

For practicing urologists, these guideline differences present practical challenges. Clinicians must reconcile sometimes discordant recommendations while aiming to provide care that is both current and tailored to individual patient needs. Moreover, the rapid pace of innovation in bladder cancer research-spanning new intravesical agents, immunotherapies, biomarkers, and digital technologies-means that clinical guidance is in near-constant evolution.

Against this backdrop, there is a growing need for objective, up-to-date comparisons of major international NMIBC guidelines. Such analyses can illuminate the degree of global consensus, clarify ongoing controversies, and ultimately support more harmonized, evidence-based decision-making. The present study addresses this need by systematically comparing the latest EAU, AUA, and NCCN guidelines for NMIBC [2–4] across 32 key clinical domains, quantifying the extent of agreement and highlighting areas of alignment and divergence.

Materials and methods

This guideline concordance study was designed and reported in accordance with the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement, as adapted for guideline and consensus document comparisons. Our objective was to systematically compare recommendations for non-muscle invasive bladder cancer (NMIBC) across three major international guidelines: EAU (2025) [2], AUA (2024) [3], and NCCN (2025) [4], with a particular focus on 32 clinically relevant decision domains.

Domain selection and protocol registration

Domain selection was guided by a comprehensive literature review, input from urological oncology experts, and precedent from prior guideline comparison studies. The initial list of domains was compiled to ensure comprehensive coverage of all major facets of NMIBC management, including diagnosis, risk stratification, surgical interventions, adjuvant therapies, management of variant histologies, surveillance, patient-centered care, and the integration of novel technologies (see Table 1 for a full list). The protocol for this analysis, including inclusion and exclusion criteria for domains, was discussed and agreed upon by all authors prior to data extraction.

Table 1.

A comparative analysis of the EAU (2025), AUA (2024), and NCCN (2025) guidelines for non-muscle invasive bladder cancer (NMIBC) with across 32 predefined clinical decision domains

#	Domain	EAU 2025 Recommendation	AUA 2024 Recommendation	NCCN 2025 Recommendation	Concordance Type
1	Diagnosis: Cystoscopy & Cytology	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 1)	Full
2	Risk Stratification	Recommended (Strong, Moderate)	Recommended (Strong, Moderate)	Recommended (Category 2 A)	Full
3	First TURBT	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 1)	Full
4	Re-TURBT Indication	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 2 A)	Full
5	Single-dose Intravesical Chemo	Recommended (Strong, High)	Recommended (Strong, High)	Preferred (Category 1)	Full
6	BCG Induction	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 1)	Full
7	BCG Maintenance	Recommended (Strong, Moderate)	Recommended (Strong, Moderate)	Preferred (Category 1)	Full
8	Definition of BCG Failure	Defined (Consensus, Moderate)	Defined (Expert Opinion)	Defined (Category 2 A)	Full
9	Management of BCG-Unresponsive NMIBC	Cystectomy standard; alternatives limited (Moderate)	Cystectomy or FDA-approved agents (Strong)	Cystectomy, FDA-approved agents (Category 2 A)	Partial
10	Novel Agents (Nadofaragene, Pembrolizumab)	In trials only (Not routine, Moderate)	FDA-approved agents recommended (Strong)	FDA-approved agents (Category 2 A)	Partial
11	Variant Histology	Early RC recommended (Strong, High)	Early RC recommended (Strong, High)	Early RC recommended (Category 2 A)	Full
12	Urinary Biomarkers	Not for routine use; selective (Moderate)	Adjunct/optional (Expert Opinion)	Adjunctive use (Category 2B)	Partial
13	Enhanced Cystoscopy (Blue light/NBI)	Recommended (Strong, Moderate)	Recommended (Strong, Moderate)	Preferred (Category 2 A)	Full
14	Surveillance Protocol	Algorithmic, risk-based (Moderate)	Individualized, risk-based (Expert)	Individualized, risk-based (Category 2 A)	Partial
15	Patient Preference/Shared Decision	Limited emphasis (—)	Strongly emphasized (Expert)	Strongly emphasized (Category 2 A)	Partial
16	Active Surveillance in Low Risk	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 2 A)	Full
17	Upper Tract Imaging	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 2 A)	Full
18	Prostatic Urethra Evaluation	Recommended (Consensus, Moderate)	Recommended (Expert)	Recommended (Category 2B)	Full
19	Variant Histology (Subtypes)	Early RC for select subtypes (Moderate)	Early RC for select subtypes (Moderate)	Early RC for select subtypes (Category 2 A)	Full
20	Management of Carcinoma in Situ	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 2 A)	Full
21	Management in Elderly/Unfit	Expert Opinion	Expert Opinion	Category 2B	Partial
22	Perioperative Antibiotics	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 2 A)	Full
23	Smoking Cessation	Recommended (Strong, Moderate)	Recommended (Strong, Moderate)	Recommended (Category 2 A)	Full
24	TURBT Quality Control/Audit	Consensus/recommended	Mentioned	Mentioned	Partial
25	Molecular/Genetic Profiling	Not recommended for routine use; insufficient evidence	Not recommended for routine use; research only	Not recommended for routine use; research only	Partial
26	Artificial Intelligence	Not mentioned	Research/future perspective	Research/future perspective	Partial/Discordant*
27	Intravesical Chemotherapy (Gemcitabine, others)	Recommended (Strong, High)	Preferred (Strong)	Preferred (Category 1)	Full
28	Salvage Intravesical Therapy	Selective (Expert)	Recommended (Strong, Moderate)	Preferred (Category 2 A)	Partial
29	Recurrent Low-Grade NMIBC	Algorithmic	Recommended (Strong, Moderate)	Recommended (Category 2 A)	Full
30	Intravesical Therapy for CIS	Recommended (Strong, High)	Recommended (Strong, High)	Recommended (Category 2 A)	Full
31	BCG Shortage Management	Expert Opinion	Guideline-based	Guideline-based (Category 2 A)	Partial
32	Referral to Clinical Trials	Encouraged (Expert Opinion)	Encouraged (Expert Opinion)	Encouraged (Category 2 A)	Partial

Guideline inclusion and data sources

The most recent publicly available versions of the following guidelines were included: EAU Guidelines on Non-Muscle-Invasive Bladder Cancer, 2025 [2]; AUA/SUO Guideline on Diagnosis and Treatment of Non-Muscle-Invasive Bladder Cancer, 2024 Amendment [3]; NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer, Version 1.2025 (March 2025) [4].

All guideline documents were accessed in full text via the official websites of the corresponding societies and organizations. When guideline recommendations referenced primary studies or other documents, only the consensus statement as presented in the guideline was extracted.

Data extraction and reviewer calibration

For each of the 32 decision domains, two independent reviewers (with expertise in urologic oncology and evidence synthesis) extracted the corresponding recommendations from all three guidelines. Each recommendation was classified according to the degree of concordance:

• Full concordance: All three guidelines provided essentially identical or highly similar recommendations in both approach and level/strength of evidence.

• Partial concordance: Minor variations were present (e.g., differences in recommendation strength, implementation details, or evidence levels), but the overall clinical approach was comparable.

• Discordance: At least one guideline offered a recommendation that was absent, substantively different, or in direct opposition to the others.

The strength of recommendation and level of evidence for each domain, when provided by the guidelines, were also recorded. Discrepancies between reviewers regarding domain classification were resolved through discussion, and when necessary, by a third independent adjudicator.

PRISMA Compliance and transparency

The review process, domain selection, and consensus procedures were conducted in accordance with PRISMA 2020 guidelines for reporting systematic reviews and guideline comparisons.

Statistical analysis

Each domain was numerically coded as follows: full concordance = 2, partial concordance = 1, discordance = 0. Frequencies and percentages were calculated for each concordance category. Pairwise agreement (EAU-AUA, EAU-NCCN, AUA-NCCN) was evaluated both by simple concordance proportions and Cohen's kappa coefficients, which account for chance agreement. Fleiss' kappa statistic was used to quantify overall agreement across all three guidelines simultaneously.

All analyses were conducted using standard, open-source statistical packages (Python v3.11 and R v4.3.0), and results were summarized both in tabular and narrative formats.

Ethical considerations

No new patient-level data were collected or analyzed in this study. All data were derived from publicly available guideline documents, and ethics approval was not required.

Results

Out of the 32 domains evaluated, full concordance was observed in 19 domains (59.4%), partial concordance in 12 domains (37.5%), and discordance in 1 domain (3.1%). Thus, 31 out of 32 domains (97%) demonstrated at least partial or full concordance among the three guidelines (Table 1).

Clinically relevant areas of partial concordance were identified in several key domains. Risk stratification was categorized as partially concordant due to differences in the specific criteria, thresholds, and definitions used by the EAU, AUA, and NCCN for assigning risk groups. In the management of BCG-unresponsive NMIBC, all guidelines endorse radical cystectomy as the standard of care; however, the AUA and NCCN provide explicit recommendations for FDA-approved bladder-sparing agents, whereas the EAU restricts these alternatives primarily to clinical trial settings. Regarding urinary biomarkers, the AUA and NCCN allow selective adjunctive use in scenarios such as equivocal cytology, while the EAU advises against routine use, citing limited evidence and concerns related to cost-effectiveness. For recurrent low-grade tumors, conservative strategies—including active surveillance and office fulguration—receive broader endorsement in the AUA and NCCN guidelines compared with the more structured, algorithm-driven recommendations of the EAU. Taken together, these findings demonstrate that despite the overall high level of alignment, several domains retain clinically meaningful differences across international guidelines.

Inter-guideline reliability metrics supported these observations. Cohen’s kappa coefficients were 0.83 for EAU–AUA, 0.86 for EAU–NCCN, and 0.94 for AUA–NCCN, indicating substantial to almost perfect pairwise agreement. The overall Fleiss’ kappa was 0.74, confirming substantial three-way concordance. Taken together, these results show that the most recent EAU, AUA, and NCCN guidelines remain highly consistent across the majority of clinical decision areas, with the few observed variations largely driven by evolving evidence, differing regulatory environments, and differences in the emphasis placed on emerging therapeutic or surveillance strategies.

Discussion

This comprehensive guideline comparison provides an in-depth evaluation of the EAU (2025), AUA (2024), and NCCN (2025) recommendations for the management of non-muscle invasive bladder cancer (NMIBC) [2–4] across 32 distinct clinical decision domains. Our findings demonstrate a high degree of international concordance, with 59.4% of domains classified as full concordance and 37.5% as partial concordance, and only one domain (3.1%) categorized as discordant. These results highlight the global consistency in the foundational aspects of NMIBC management, while also identifying specific areas where nuanced differences or ongoing controversies persist.

Although our concordance analysis demonstrated substantial agreement across the three contemporary NMIBC guidelines, important content-level differences persist, particularly within the domain of risk stratification. The EAU’s introduction of the ‘very-high-risk’ (VHR) category incorporates additional adverse prognostic features such as lymphovascular invasion, concurrent extensive CIS, large tumor size, and multifocality, resulting in a more granular risk segmentation. The AUA guideline does not include a distinct VHR category and allocates these same patients within the high-risk group, while the NCCN guideline adopts a four-tier model but uses different thresholds and therapeutic triggers. These structural differences have practical implications, including variations in recommendations for early cystectomy, intensity of BCG maintenance, and surveillance intervals. Our findings mirror the variability highlighted in Contieri et al., underscoring the importance of considering both numerical concordance and underlying content when interpreting guideline alignment [5].

Management of recurrent low-grade Ta NMIBC has undergone a notable shift toward deintensification, as highlighted in the recent IBCG collaborative review [6]. Emerging strategies such as active surveillance, office fulguration, and chemoablation have gained increasing support based on their safety profile and patient-centered advantages. The AUA 2024 and NCCN 2025 guidelines explicitly incorporate these less-invasive management pathways, allowing active surveillance and office-based fulguration for selected recurrent low-grade tumors with low tumor burden. In contrast, the EAU 2025 guideline adopts a more conservative stance, restricting these approaches to very carefully selected patients and continuing to prioritize TURBT as the primary modality. This heterogeneity reflects differing interpretations of the evolving evidence base and underscores the need for individualized, risk-adapted decision-making in recurrent low-grade NMIBC [6].

However, several domains continue to be characterized by partial concordance, reflecting subtle but clinically relevant variations in guideline language, the strength or context of recommendations, and the local regulatory or healthcare environment. Notably, areas such as the management of BCG-unresponsive NMIBC, the use of novel agents (e.g., nadofaragene, pembrolizumab), urinary biomarker utilization, and patient-centered decision-making showed minor differences in implementation and emphasis. For example, while none of the guidelines recommend the routine use of biomarkers for diagnosis or surveillance, the AUA and NCCN [3, 4] are more open to their use alongside other methods in challenging clinical situations, such as after BCG treatment or when cytology results are inconclusive. In contrast, the EAU remains reserved, citing insufficient evidence and concerns about cost-effectiveness [2]. These differences highlight the influence of regional health policy, technology availability, and the threshold for clinical adoption on guideline recommendations. Surveillance protocols and the degree of individualized, patient-centered care also illustrate these contrasts. The AUA and NCCN increasingly emphasize shared decision-making and personalized follow-up schedules, consistent with a broader trend in US healthcare towards patient empowerment and flexibility. Meanwhile, the EAU maintains a more algorithmic, standardized approach, reflecting cultural differences and the organizational structure of European healthcare systems.

Similarly, although all guidelines endorse cystectomy as the standard for BCG-unresponsive disease, the threshold for recommending novel agents and the strength of endorsement differ, largely reflecting differences in regional regulatory approvals and available clinical trial evidence. With the publication of NCCN Bladder Cancer v1.2025 [4], several updates have further differentiated its recommendations, including the adoption of nogapendekin alfa inbakicept-pmln (with BCG) for selected BCG-unresponsive patients, a stronger preference for gemcitabine as perioperative chemotherapy, and additional emphasis on risk-adapted surveillance and patient-centered care. The guideline's rapid adaptation to new evidence, compared with the more cautious EAU approach, remains evident. These updates underscore the importance of integrating new clinical trial data and highlight the continued divergence in regulatory and cultural philosophies between US and European guidelines.

Two domains-molecular/genetic profiling and artificial intelligence-were identified as areas of either partial concordance or discordance, primarily due to differences in the extent of discussion or the explicitness of recommendations. While all guidelines agree that molecular/genetic profiling is not recommended for routine clinical use, the AUA and NCCN explicitly support ongoing research, whereas the EAU restricts its position to acknowledging insufficient evidence. Artificial intelligence is briefly acknowledged in the AUA and NCCN guidelines as an emerging research area, but none recommend clinical use; therefore, detailed evaluation was beyond the scope of this study. Our findings are consistent with previous comparative studies, which have also identified areas such as BCG-unresponsive NMIBC management and the integration of novel diagnostics and therapeutics as persistent sources of international variation. The increased inclusion of real-world evidence, ongoing large-scale multicenter trials, and enhanced collaboration among guideline committees may help further harmonize global recommendations.

Methodological differences across guidelines

Beyond the clinical recommendations themselves, the three international guidelines differ substantially in their underlying methodological frameworks, which may contribute to the observed variations in concordance. The AUA relies on a structured hierarchy that incorporates expert opinion statements and ‘clinical principles’ when high-level evidence is lacking, allowing greater flexibility in areas with limited data. In contrast, the EAU guideline emphasizes systematic evidence synthesis and minimizes recommendations that rely solely on expert consensus, resulting in a more uniform, evidence-driven structure. The NCCN guideline employs a multidisciplinary panel consensus model that is updated multiple times per year and integrates U.S. regulatory considerations, including FDA approvals and real-world practice patterns. These methodological differences influence not only the strength and phrasing of recommendations but also the categorization of risk groups and treatment pathways, thereby shaping the degree of concordance observed across domains.

This study has several strengths, including its systematic, PRISMA-aligned methodology, independent data extraction, and the use of robust statistical approaches to quantify concordance. However, limitations should be acknowledged. The analysis is inherently limited by the timing of guideline updates, and recommendations may lag behind the most recent clinical trial evidence. Additionally, although domain-level comparisons provide clarity, they may not fully capture nuances in implementation or the practical impact of recommendations in real-world clinical settings. Finally, some domains remain controversial or insufficiently addressed due to limited evidence or the early stage of relevant technologies.

Conclusion

The EAU, AUA, and NCCN guidelines for NMIBC are broadly aligned across most decision domains, providing clinicians with a robust and consistent framework for patient care. Ongoing dialogue, timely incorporation of new evidence, and international collaboration will be essential to minimize discrepancies and ensure optimal, evidence-based management for patients worldwide.

Abbreviations

AUA

American Urological Association

BCG

Bacillus Calmette-Guérin

EAU

European Association of Urology

NCCN

National Comprehensive Cancer Network

NMIBC

Non-muscle invasive bladder cancer

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

VHR

Very-high-risk

Authors’ contributions

Concept and design: MEA, AA. Acquisition of data: AA, CK. Analysis and interpretation of data: MEA, AA, CK. Drafting of the manuscript: AA, MS. Critical revision of the manuscript for important intellectual content: MEA, AA, CK, MS. Statistical analysis: CK, MS. Supervision: AA, MS. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Ethics committee approval was not required for this study as it did not involve human participants, or identifiable patient information. Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.