Elsevier

European Urology

Volume 64, Issue 4, October 2013, Pages 639-653
European Urology

Guidelines
EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2013

https://doi.org/10.1016/j.eururo.2013.06.003Get rights and content

Abstract

Context

The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated.

Objective

To present the 2013 EAU guidelines on non–muscle-invasive bladder cancer (NMIBC).

Evidence acquisition

Literature published between 2010 and 2012 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence and grades of recommendation were assigned.

Evidence synthesis

Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for individual patients using the EORTC scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or by further instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the guidelines is available from the EAU Web site: http://www.uroweb.org/guidelines/.

Conclusions

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

Patient summary

The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated version of their guidelines. Current clinical studies support patient selection into different risk groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystectomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are in the highest risk group for progression.

Introduction

The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated, and the most recent version is available from the EAU Web site (http://www.uroweb.org/guidelines/). An overview of the updated 2013 EAU guidelines on non–muscle-invasive bladder cancer (NMIBC) (Ta, T1, and carcinoma in situ [CIS]) is provided in this paper. The information presented is limited to urothelial carcinoma, if not specified otherwise. The aim is to provide practical guidance on the clinical management of NMIBC with a focus on clinical presentation and recommendations.

Section snippets

Evidence acquisition

A systematic literature search was performed by the panel members. For identification of original and review articles published between 2010 and 2012, Medline, Web of Science, and Embase databases were used. Focus of the searches was identification of all level 1 scientific data (ie, randomised controlled trials [RCTs], systematic reviews, and meta-analyses of RCTs).

Panel members selected records with the highest level of evidence (LE) according to a modified classification system from the

Epidemiology

Bladder cancer (BCa) is the most common malignancy of the urinary tract and the 7th most common cancer in men and the 17th in women. In the European Union, the age-standardised incidence rate is 27 per 100 000 in men and six per 100 000 in women [3].

Incidence varies between regions and countries; in Europe, the highest age-standardised incidence rate has been reported in Spain (41.5 in men and 4.8 in women [per 100 000 inhabitants]) and the lowest in Finland (18.1 in men and 4.3 in women) [3].

Risk factors

Genetic predisposition has a significant influence on BCa, especially via its impact on susceptibility to other risk factors [6]. Tobacco smoking is the most important risk factor for BCa, accounting for approximately 50% of cases [6], [7] (LE: 3).

Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons is the second most important risk factor for BCa, accounting for about 10% of all cases. Such occupational exposure occurs mainly in the paint

TNM classification and definition of non–muscle-invasive bladder cancer

The Tumour, Node, Metastasis (TNM) classification system approved by the Union International Contre le Cancer (UICC), which was updated in 2009, is used in these guidelines (Table 1) [9]. Papillary tumours confined to the mucosa and those which have invaded the lamina propria are classified as stage Ta and stage T1, respectively. Ta and T1 tumours can be removed by transurethral resection (TUR), and therefore they are grouped under the heading of NMIBC for therapeutic purposes. Also included

Symptoms

Patient history should be taken and recorded for all important information with any possible connection to BCa. Haematuria is the most common finding in NMIBC. Lower urinary tract symptoms may reveal a CIS.

Imaging

Intravenous urography (IVU) is used to detect filling defects in the calyces, renal pelvis and ureters, and hydronephrosis, which can indicate the presence of a ureteral tumour. Large exophytic tumours may be seen as filling defects in the bladder. The necessity to perform routine IVU once a

Prognosis of Ta, T1 tumours

Patients with Ta, T1 tumours can be divided into risk groups based on prognostic factors. To predict separately the short- and long-term risks of both recurrence and progression in individual patients, a scoring system and risk tables were developed by the EORTC [54]. The EORTC database provided individual data for 2596 patients who did not have a second TUR or receive maintenance BCG therapy. The EORTC scoring system is based on the six most significant clinical and pathologic factors:

  • Number

Adjuvant intravesical chemotherapy

Ta, T1 tumours recur frequently and progress to muscle-invasive disease in a limited number of cases. It is therefore necessary to consider adjuvant therapy in all patients.

Bacillus Calmette-Guérin efficacy

Five meta-analyses have confirmed that BCG after TUR is superior to TUR alone or TUR and chemotherapy for the prevention of tumour recurrence [76], [77], [78], [79], [80] (LE: 1a). Three recent RCTs on patients with intermediate- and high-risk tumours compared BCG with a combination of epirubicin and interferon [81], MMC [82], or epirubicin alone [83]. All of these studies have confirmed the superiority of BCG for the prevention of tumour recurrence (LE: 1a). It has been shown that the effect

Specific aspects of treatment of carcinoma in situ

CIS cannot be resolved by TUR alone. Histologic diagnosis of CIS must be followed by further treatment, either intravesical instillations or radical cystectomy (LE: 2). No consensus exists about whether conservative therapy (intravesical BCG instillations) or aggressive therapy (cystectomy) should be performed. Tumour-specific survival rates after early cystectomy for CIS are excellent, but up to 40–50% of patients may be overtreated [57] (LE: 3).

Failure of intravesical chemotherapy

Patients with recurrence of NMIBC after a chemotherapy regimen can profit from BCG instillations. Prior intravesical chemotherapy has no impact on the effect of BCG instillation [76] (LE: 1a).

Recurrence and failure after intravesical bacillus Calmette-Guérin immunotherapy

Categories of unsuccessful treatment with intravesical BCG are summarised in Table 7.

Patients with BCG failure are unlikely to respond to further BCG therapy; therefore, radical cystectomy is the preferred option.

Several bladder preservation strategies are available [98]. Changing from BCG to these options

Radical cystectomy for non–muscle-invasive bladder cancer

If radical cystectomy is indicated before pathologically confirmed progression into muscle-invasive tumour, immediate (directly following NMIBC diagnosis) and early (after BCG failure) radical cystectomy can be distinguished.

The potential benefit of radical cystectomy must be weighed against the risk and impact on quality of life. It is reasonable to propose immediate radical cystectomy to those patients with NMIBC who are at highest risk of progression. These are patients with the following

Follow-up of patients with non–muscle-invasive bladder cancer

As a result of the risk of recurrence and progression, patients with NMIBC need to be followed up; however, the frequency and duration of cystoscopy and imaging should reflect the individual patient's degree of risk. Using risk tables, we are able to predict the short- and long-term risks of recurrence and progression in individual patients, and can adapt the follow-up schedule accordingly [54], [55]. When planning the follow-up schedule and methods, the following aspects should be considered:

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