Elsevier

European Urology

Volume 81, Issue 1, January 2022, Pages 75-94
European Urology

Review – Bladder Cancer
European Association of Urology Guidelines on Non–muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ)

https://doi.org/10.1016/j.eururo.2021.08.010Get rights and content

Abstract

Context

The European Association of Urology (EAU) has released an updated version of the guidelines on non–muscle-invasive bladder cancer (NMIBC).

Objective

To present the 2021 EAU guidelines on NMIBC.

Evidence acquisition

A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines since the 2020 version was performed. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned.

Evidence synthesis

Tumours staged as Ta, T1 and carcinoma in situ (CIS) are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of tissue obtained via transurethral resection of the bladder (TURB) for papillary tumours or via multiple bladder biopsies for CIS. For papillary lesions, a complete TURB is essential for the patient’s prognosis and correct diagnosis. In cases for which the initial resection is incomplete, there is no muscle in the specimen, or a T1 tumour is detected, a second TURB should be performed within 2–6 wk. The risk of progression may be estimated for individual patients using the 2021 EAU scoring model. On the basis of their individual risk of progression, patients are stratified as having low, intermediate, high, or very high risk, which is pivotal to recommending adjuvant treatment. For patients with tumours presumed to be at low risk and for small papillary recurrences detected more than 1 yr after a previous TURB, one immediate chemotherapy instillation is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose intravesical bacillus Calmette-Guérin (BCG) immunotherapy or instillations of chemotherapy for a maximum of 1 yr. For patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. For patients at very high risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is also recommended for BCG-unresponsive tumours. The extended version of the guidelines is available on the EAU website at https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/.

Conclusions

These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.

Patient summary

The European Association of Urology has released updated guidelines on the classification, risk factors, diagnosis, prognostic factors, and treatment of non–muscle-invasive bladder cancer. The recommendations are based on the literature up to 2020, with emphasis on the highest level of evidence. Classification of patients as having low, intermediate, or and high risk is essential in deciding on suitable treatment. Surgical removal of the bladder should be considered for tumours that do not respond to bacillus Calmette-Guérin (BCG) treatment and tumours with the highest risk of progression.

Introduction

This overview represents the updated European Association of Urology (EAU) guidelines for non–muscle-invasive bladder cancer (NMIBC), comprising Ta, T1, and carcinoma in situ (CIS). The information presented is limited to urothelial carcinoma, unless otherwise specified. The aim is to provide practical recommendations for clinical management of NMIBC, with a focus on clinical presentation and recommendations.

It must be emphasised that clinical guidelines present the best evidence available to the experts, but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions that also take the personal values and references/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

Section snippets

Evidence acquisition

For the 2021 NMIBC guidelines, new and relevant evidence has been identified, collated, and appraised through a structured assessment of the literature.

A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines since the previous version was published in 2020 was performed. Excluded from the search were basic research studies, case series, reports, and editorial comments. Only articles published in the English language and addressing adults were included. Excluded

Epidemiology

Bladder cancer (BC) is the tenth most commonly diagnosed cancer worldwide [3]. The age-standardised incidence rate (per 100 000 person-years) is 9.5 for men and 2.4 for women worldwide, and 20 for men and 4.6 for women in the EU [3].

Worldwide, the BC age-standardised mortality rate (per 100 000 person-years) was 3.3 for men versus 0.86 for women [3]. The incidence and mortality of BC have decreased in some registries, possibly reflecting a decrease in the impact of causative agents [4].

Definition of NMIBC

Papillary tumours confined to the mucosa and invading the lamina propria are classified as stage Ta and T1, respectively, according to the TNM classification system [15]. Flat, high-grade tumours confined to the mucosa are classified as CIS (Tis). All of these tumours are grouped under the heading of NMIBC. The term non–muscle-invasive BC, however, represents a group definition; all tumours should be characterised according to their stage, grade, and further pathological characteristics. The

Patient history

A focused patient history is mandatory.

Signs and symptoms

Haematuria is the most common finding in NMIBC. Visible haematuria was found to be associated with higher-stage disease compared to nonvisible haematuria [29]. CIS might be suspected in patients with lower urinary tract symptoms, especially irritative voiding.

Physical examination

A focused urological examination is mandatory, although it does not reveal NMIBC.

Imaging

Computed tomography (CT) urography is used to detect papillary tumours in the urinary tract, indicated by filling

Ta and T1 tumours

Treatment should take into account a patient’s prognosis. In order to predict the risk of disease recurrence and/or progression, several prognostic models for specified patient populations have been introduced.

Counselling on smoking cessation

Smoking increases the risk of tumour recurrence and progression [82] (LE: 3). While it is still controversial whether smoking cessation in BC will favourably influence the outcome of BC treatment, patients should be counselled to stop smoking because of the general risks connected to tobacco smoking [83] (LE: 3).

Adjuvant treatment

Although TURB by itself can eradicate a Ta/T1 tumour completely, these tumours commonly recur and can progress to MIBC. It is therefore necessary to consider adjuvant therapy for all

Follow-up of patients with NMIBC

Owing to the risk of recurrence and progression, patients with NMIBC need surveillance following therapy. The frequency and duration of cystoscopy and imaging follow-up should reflect the individual patient’s degree of risk (see the guidelines in Table 14).

When planning the follow-up schedule and methods, the following points should be considered:

  • Prompt detection of muscle-invasive and HG/G3 non–muscle-invasive recurrence is crucial because a delay in diagnosis and therapy can be

References (167)

  • F. Millan-Rodriguez et al.

    Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups

    J Urol

    (2000)
  • S Hilton et al.

    Recent advances in imaging cancer of the kidney and urinary tract

    Surg Oncol Clin North Am

    (2014)
  • V. Panebianco et al.

    Multiparametric magnetic resonance imaging for bladder cancer: development of VI-RADS (Vesical Imaging-Reporting and Data System)

    Eur Urol

    (2018)
  • F.A. Yafi et al.

    Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer

    Urol Oncol

    (2015)
  • B. Tetu

    Diagnosis of urothelial carcinoma from urine

    Mod Pathol

    (2009)
  • M.P. Raitanen et al.

    Differences between local and review urinary cytology in diagnosis of bladder cancer. An interobserver multicenter analysis

    Eur Urol

    (2002)
  • M.N. van der Aa et al.

    Cystoscopy revisited as the gold standard for detecting bladder cancer recurrence: diagnostic review bias in the randomized, prospective CEFUB trial

    J Urol

    (2010)
  • F. Valenberg et al.

    Prospective validation of an mRNA-based urine test for surveillance of patients with bladder cancer

    Eur Urol

    (2019)
  • B. Konety

    Evaluation of Cxbladder and adjudication of atypical cytology and equivocal cystoscopy

    Eur Urol

    (2019)
  • J.Y. Teoh et al.

    An international collaborative consensus statement on en bloc resection of bladder tumour incorporating two systematic reviews, a two-round Delphi survey, and a consensus meeting

    Eur Urol

    (2020)
  • P. Mariappan et al.

    Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience

    Eur Urol

    (2010)
  • J. Palou et al.

    Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guerin

    Eur Urol

    (2012)
  • M.U. Mungan et al.

    Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder

    Eur Urol

    (2005)
  • Y. Neuzillet et al.

    Assessment of diagnostic gain with hexaminolevulinate (HAL) in the setting of newly diagnosed non-muscle-invasive bladder cancer with positive results on urine cytology

    Urol Oncol

    (2014)
  • R.O. Draga et al.

    Photodynamic diagnosis (5-aminolevulinic acid) of transitional cell carcinoma after bacillus Calmette-Guerin immunotherapy and mitomycin C intravesical therapy

    Eur Urol

    (2010)
  • R. Chou et al.

    Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis or surveillance of bladder cancer on clinical outcomes: systematic review and meta-analysis

    J Urol

    (2017)
  • S. Naito et al.

    The Clinical Research Office of the Endourological Society (CROES) multicentre randomised trial of narrow band imaging-assisted transurethral resection of bladder tumour (TURBT) versus conventional white light imaging-assisted TURBT in primary non-muscle-invasive bladder cancer patients: trial protocol and 1-year results

    Eur Urol

    (2016)
  • M.G.K. Cumberbatch et al.

    Repeat transurethral resection in non-muscle-invasive bladder cancer: a systematic review

    Eur Urol

    (2018)
  • A. Naselli et al.

    Role of restaging transurethral resection for T1 non-muscle invasive bladder cancer: a systematic review and meta-analysis

    Eur Urol Focus

    (2018)
  • P.C. Gordon et al.

    Long-term outcomes from re-resection for high-risk non-muscle-invasive bladder cancer: a potential to rationalize use

    Eur Urol Focus

    (2019)
  • J. Fernandez-Gomez et al.

    Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model

    J Urol

    (2009)
  • S. Cambier et al.

    EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1–3 years of maintenance bacillus Calmette-Guerin

    Eur Urol

    (2016)
  • P. Gontero et al.

    Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients

    Eur Urol

    (2015)
  • C.S. Voskuilen et al.

    Urothelial carcinoma in bladder diverticula: a multicenter analysis of characteristics and clinical outcomes

    Eur Urol Focus

    (2020)
  • J. Palou et al.

    Recurrence at three months and high-grade recurrence as prognostic factor of progression in multivariate analysis of T1G2 bladder tumors

    Urology

    (2009)
  • T.R. Griffiths et al.

    Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance

    J Urol

    (2002)
  • M. Rink et al.

    Smoking reduces the efficacy of intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer

    Eur Urol

    (2012)
  • J.J. Crivelli et al.

    Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the literature

    Eur Urol

    (2014)
  • C.P. Brocks et al.

    Inhibition of tumor implantation by intravesical gemcitabine in a murine model of superficial bladder cancer

    J Urol

    (2005)
  • W. Oosterlinck et al.

    A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder

    J Urol

    (1993)
  • Rj Sylvester et al.

    Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa–pT1 urothelial carcinoma of the bladder: which patients benefit from the instillation?

    Eur Urol

    (2016)
  • RJ Sylvester et al.

    A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials

    J Urol

    (2004)
  • N. Perlis et al.

    Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review

    Eur Urol

    (2013)
  • A. Bohle et al.

    Inhibition of bladder carcinoma cell adhesion by oligopeptide combinations in vitro and in vivo

    J Urol

    (2002)
  • D.A. Tolley et al.

    The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up

    J Urol

    (1996)
  • J Bosschieter et al.

    Value of an immediate intravesical instillation of mitomycin C in patients with non-muscle-invasive bladder cancer: a prospective multicentre randomised study in 2243 patients

    Eur Urol

    (2018)
  • R.J. Sylvester et al.

    The schedule and duration of intravesical chemotherapy in patients with non-muscle-invasive bladder cancer: a systematic review of the published results of randomized clinical trials

    Eur Urol

    (2008)
  • J. Bosschieter et al.

    An immediate, single intravesical instillation of mitomycin C is of benefit in patients with non-muscle-invasive bladder cancer irrespective of prognostic risk groups

    Urol Oncol

    (2018)
  • A.A. Elsawy et al.

    The value of immediate postoperative intravesical epirubicin instillation as an adjunct to standard adjuvant treatment in intermediate and high-risk non-muscle-invasive bladder cancer: a preliminary results of randomized controlled trial

    Urol Oncol

    (2019)
  • B. Phillips

    Oxford Centre for Evidence-based Medicine levels of evidence. Updated by Jeremy Howick, March 2009

    (2009)
  • Cited by (521)

    View all citing articles on Scopus
    View full text