Non-muscle-invasive Bladder Cancer

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2021

Additional data has been included throughout this document text. In particular in chapters/sections:

  • 4.4 – Histological grading of non-muscle-invasive bladder urothelial carcinomas. New Section 4.5.1 – Prognostic value of histological grading, has been included, and Table 4.3 WHO 2004/2016 histological classification for flat lesions, was revised, resulting in changes to:

4.9          Summary of evidence and guidelines for bladder cancer classification

Summary of evidence LE
Histological grading of urothelial NMIBC is classified according to the WHO 1973 (G1-G3) and/or the WHO 2004/2016 (PUNLMP, LG, HG) systems. 2a
Both the WHO 1973 and 2004/2016 classification systems are prognostic for progression, but not for recurrence. 2a
The WHO 1973 was a stronger prognosticator of progression in Ta/T1 NMIBC than the WHO 2004/2016. However, a four-tier combination (LG/G1, LG/G2, HG/G2 and HG/G3) of both classification systems proved to be superior to either classification system alone. 2a
PUNLMP lesions have the same prognosis as Ta/LG carcinomas. 2a

 

  • Chapter 6 – Predicting disease recurrence and progression, has been completely revised based on the findings of a recent IPD analysis [5]. New risk groups have been developed (Table 6.1) as well as a new table addressing disease progression (Table 6.2), resulting in changes to Sections 6.5, 7.6 and new Section 7.7:

6.5 Summary of evidence and guidelines for stratification of non-muscle-invasive bladder cancer

 

Summary of evidence LE
The EAU NMIBC 2021 scoring model and risk tables predict the short- and long-term risks of disease progression in individual patients with primary non-muscle-invasive bladder cancer (NMIBC) using either the WHO 1973 or the WHO 2004/2016 classification system (see Section 6.1.2.1). 2a
The 2006 EORTC scoring model and risk tables predict the short- and long-term risks of disease recurrence and progression in individual patients with NMIBC using the WHO 1973 classification system (see Section 6.1.1.1). 2a
Patients with Ta G1/G2 tumours receiving chemotherapy have been further stratified into three risk groups for recurrence, taking into account the history of recurrences, history of intravesical treatment, tumour grade (WHO 1973), number of tumours and adjuvant chemotherapy (see Section 6.1.1.2). 2a-b
In patients treated with 5-6 months of BCG, the CUETO scoring model predicts the short- and long-term risks of disease recurrence and progression using the WHO 1973 grading system (see Section 6.1.1.3). 2a
In patients receiving at least one year of BCG maintenance; prior recurrence rate and number of tumours are the most important prognostic factors for disease recurrence. Stage and grade are the most important prognostic factors for disease progression and disease-specific survival; patient age and grade (WHO 1973) are the most important prognostic factors for overall survival (see Section 6.1.1.4). 2a

 

Recommendations Strength rating
Stratify patients into four risk groups according to Table 6.1. A patient’s risk group can be determined using the EAU risk group calculator available at www.nmibc.net. Strong
For information about the risk of disease progression in a patient with primary TaT1 tumours, use data from Table 6.2 Strong
Use the 2006 EORTC scoring model to predict the risk of tumour recurrence in individual patients not treated with bacillus Calmette-Guerin (BCG). Strong
Use the 2016 EORTC scoring model or the CUETO risk scoring model to predict the risk of tumour recurrence in individual patients treated with BCG intravesical immunotherapy (the 2016 EORTC model is calculated for 1─3 year of maintenance, the CUETO model for 5 to 6 months of BCG). Strong

 

  • In Chapter 7, Section 7.2.2.4 – Optimal BCG schedule, has been expanded; new section: 7.3 – Individual treatment strategy in primary or recurrent tumours after TURB without previous BCG intravesical immunotherapy, has been added. Sections 7.4.2 – Treatment failure after intravesical BCG immunotherapy and 7.4.3. – Treatment of BCG failure, have been revised. The following recommendations were changed:

7.6          Guidelines for adjuvant therapy in TaT1 tumours and for therapy of carcinoma in situ

General recommendations Strength rating
The type of further therapy after transurethral resection of the bladder (TURB) should be based on the risk groups shown in Section 6.3 and Table 6.1. For determination of a patient’s risk group use the 2021 EAU risk group calculator available at www.nmibc.net.
In patients with tumours presumed to be at low risk and in those with small papillary recurrences (presumably Ta LG/HG) detected more than one year after previous TURB, offer one immediate chemotherapy instillation. Strong
In patients with very high risk tumours discuss immediate radical cystectomy (RC) (see Section 7.5). Strong
Offer transurethral resection of the prostate, followed by intravesical instillation of BCG to patients with CIS in the epithelial lining of the prostatic urethra. Weak
The definition of BCG unresponsive should be respected as it most precisely defines patients who are unlikely to respond to further BCG instillations. Weak

 

7.7 Guidelines for the treatment of TaT1 tumours and carcinoma in situ according to risk stratification

 

Recommendations Strength rating
EAU risk group: Low
Offer one immediate instillation of intravesical chemotherapy after TURB. Strong
EAU Risk Group: Intermediate
In all patients either one-year full- dose Bacillus Calmette-Guerin (BCG) treatment (induction plus 3-weekly instillations at 3, 6 and 12 months), or instillations of chemotherapy (the optimal schedule is not known) for a maximum of one year is recommended. The final choice should reflect the individual patient’s risk of recurrence and progression as well as the efficacy and side effects of each treatment modality. Offer one immediate chemotherapy instillation to patients with small papillary recurrences detected more than one year after previous TURB. Strong
EAU risk group: High
Offer intravesical full-dose BCG instillations for one to three years or radical cystectomy (RC). Strong
EAU risk group: Very High
Consider RC and offer  intravesical full-dose BCG instillations for one to three years to those who refuse or are unfit for RC. Strong

 

  • Chapter 8 8 – Follow-up of patients with NMIBC, was expanded resulting in amended recommendations:

8.1 Summary of evidence and guidelines for follow-up of patients after transurethral resection of the bladder for non-muscle-invasive bladder cancer

Recommendations Strength rating
Patients with high-risk and those with very high-risk tumours treated conservatively should undergo cystoscopy and urinary cytology at three months. If negative, subsequent cystoscopy and cytology should be repeated every three months for a period of two years, and every six months thereafter until five years, and then yearly. Weak

 

Regular (yearly) upper tract imaging (computed tomography-intravenous urography [CT-IVU] or IVU) is recommended for high-risk and very high-risk tumours. Weak

 

 

 

2020

Non-muscle-invasive Bladder Cancer 2020

 

 Summary of changes

Additional data has been included throughout this document text. In particular in sections:

 

  • 4.7 – Variants of urothelial carcinoma and lymphovascular invasion: this section has been expanded to include further information on variant histologies.
  • 7.3 – Treatment of failure of intravesical therapy. This section has been considerably expanded, alongside a revision of Figure 7.2, Table 7.2 (Categories of unsuccessful treatment with intravesical BCG) and 7.7 Guidelines for the treatment of BCG failure.

 

Recommendations have been changed in sections:

 

7.5 Guidelines for adjuvant therapy in TaT1 tumours and for therapy of carcinoma in situ

 

General recommendations Strength rating
Offer a RC to patients with BCG unresponsive tumours (see Section 7.7). Strong
Offer patients with BCG unresponsive tumours, who are not candidates for RC due to comorbidities, preservation strategies (intravesical chemotherapy, chemotherapy and microwave-induced hyperthermia, electromotive administration of chemotherapy, intravesical- or systemic immunotherapy; preferably within clinical trials). Weak

 

 

7.7 Guidelines for the treatment of BCG failure

 

Category Treatment options Strength rating
BCG-unresponsive 1.    Radical cystectomy (RC) Strong
2.    Enrollment in clinical trials assessing new treatment strategies. Weak
3.    Bladder-preserving strategies in patients unsuitable or refusing RC. Weak
Late BCG relapsing:

T1Ta/HG recurrence > 6 months or CIS > 12 months of last BCG exposure

1.    Radical cystectomy or repeat BCG course according to individual

situation.

 

Strong
2.    Bladder-preserving strategies Weak
LG recurrence after BCG for primary 1.    Repeat BCG or intravesical chemotherapy Weak
2.    Radical cystectomy Weak

 

 

2019

Additional data has been included throughout this document text. In particular in sections:

  • 5.4.3 – Multiparametric magnetic resonance imaging (mpMRI);
  • 5.10.2 – Surgical and technical aspects of tumour resection: a new paragraph on TUR best practice has been included;

A new recommendation has been added to:

  • Section 5.14 – Summary of evidence and guidelines for transurethral resection of the bladder, biopsies and pathology report
Recommendation Strength rating
Outpatient fulguration or laser vaporisation of small papillary recurrences can be used in patients with a history of TaG1/LG tumours. Weak

 

  • 7.3.2 – Recurrence and failure after intravesical Bacillus Calmette-Guérin (BCG) immunotherapy: this section, including Table 7.2 (Categories of unsuccessful treatment with intravesical BCG) has been expanded.

2018

Additional data has been included in sections:

  • 4.4 4.4 – Histological grading of non-muscle-invasive bladder urothelial carcinomas
  • 5.11.1 – Photodynamic diagnosis (fluorescence cystoscopy);
  • 5.12 – Second resection;
  • 7.2.1.3.2 – Device-assisted intravesical chemotherapy.

 

New recommendations have been added to:

  • Section 5.9 – Summary of evidence and guidelines for the primary assessment of non-muscle-invasive bladder cancer
Recommendations Strength rating
In men, use flexible cystoscope, if available. Strong
Describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities during cystoscopy. Use a bladder diagram (Figure 5.1). Strong

 

Use the Paris system for cytology reporting. Strong

 

  • Section 5.14 – Summary of evidence and guidelines for transurethral resection of the bladder, biopsies and pathology report
Recommendations Strength rating
Performance of individual steps
Use methods to improve tumour visualization (FC, NBI) during TURB, if available. Weak

 

2017

New relevant references have been identified through a structured assessment of the literature and

incorporated in the various chapters of the 2017 Non-muscle-invasive Bladder Cancer Guidelines.

Key changes in the 2017 print:

  • Section 4.3 – T1 subclassification. This is a new section.
  • Section 5.5 – Urinary Cytology. Diagnostic categories based on the Paris Working Group Classification have been added.
  • Section 5.10.2 – Surgical and technical aspects of tumour resection. This section has been revised and enlarged, resulting in changes in the recommendations (Section 5.14).
  • Section 5.12 – Second resection. Additional literature has been included, resulting in changes in the recommendations (Section 5.14).
  • Section 6.4 – Subgroup of highest risk tumours. This is a new section.
  • Section 7.2.1.3.2 – Device-assisted intravesical chemotherapy. This is a new section.

Changes in the recommendations

 

Section 5.9: A new recommendation has been added.

Recommendations for the primary assessment of NMIBC GR
Repeat urine cytology in patients with suspicious initial cytology results. C

 

Section 5.14: Additional information has been included.

Recommendations for transurethral resection of the bladder (TURB) and/or biopsies and pathology report GR
Perform en-block resection or resection in fractions (exophytic part of the tumour, the underlying bladder wall and the edges of the resection area). The presence of detrusor muscle in the specimen is required in all cases except for TaG1/LG tumours. B
Perform a second TURB in the following situations:

  • after (suspicion of) incomplete initial TURB (in the case of any doubt about completeness of a TURB);
  • if there is no muscle in the specimen after initial resection, with exception of TaLG/G1 tumours and primary CIS;
  • in T1 tumours.
A
Register the results of a second TURB as it reflects the quality of the initial resection. A

 

Section 7.5: A new recommendation has been included.

Recommendations for adjuvant therapy in TaT1 tumours and for therapy of CIS GR
In patients with bacillus Calmette-Guérin failure, who are not candidates of radical cystectomy due to comorbidities, use preservation strategies (device-assisted instillations of chemotherapy, intravesical chemotherapy, intravesical immunotherapy). C

 

Section 8.1: A new recommendation has been added.

Recommendation GR
In patients initially diagnosed with TaLG/G1-2 bladder cancer, use ultrasound of the bladder during surveillance in case cystoscopy is not possible, or refused by the patient. C

2016

All chapters of the 2016 RCC Guidelines have been updated, based on the 2015 version of the guideline.

Conclusions and recommendations have been rephrased and added to, throughout the current document.

Key changes in the 2016 print:

Changes in recommendations

 In Section 5.16 – a recommendation has been added:

Recommendations for TURB and/or biopsies, tumour classification and pathology report GR
In patients suspected of harbouring bladder cancer TURB followed by pathology investigation of the obtained specimen(s) is recommended as a diagnostic procedure and initial treatment step. A

TURB = transurethral resection of the bladder.

Section 7.2.1.1 – A single, immediate, post-operative intravesical instillation of chemotherapy – has been expanded to include the findings of 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? [4].

  • The recommendations as presented in Section 7.5 and Table 7.6 – Treatment recommendations in Ta, T1 tumours and CIS according to risk stratification – have been adapted. The recommendation grade did not change.
Section 7.5 Recommendations for adjuvant therapy in Ta, T1 tumours and for therapy of CIS GR
In patients with tumours presumed to be at low risk and in those presumed to be at intermediate risk with previous low recurrence rate (less than or equal to one recurrence per year) and expected EORTC recurrence score < 5, one immediate chemotherapy instillation is recommended. A

 CIS = carcinoma in situ; EORTC = European Organization for Research and Treatment of Cancer.

Table 7.6 – Treatment recommendations in Ta, T1 tumours and CIS according to risk stratification

Risk category Definition Treatment recommendation
Intermediate-risk tumours All cases between categories of low and high risk In patients with previous low recurrence rate (less than or equal to one recurrence per year) and expected EORTC recurrence score < 5, one immediate instillation of intravesical chemotherapy after TURB.In all patients either 1-year full-dose BCG treatment (induction plus 3-weekly instillations at 3,6 and 12 months), or instillations of chemotherapy (the optimal schedule is not known) for a maximum of 1 year.

BCG = Bacillus Calmette-Guérin; EORTC = European Organization for Research and Treatment of Cancer;

TURB = transurethral resection of the bladder.

 1.4.2.2 Summary of evidence

  • Section 3.4 – A summary of evidence has been added to Chapter 3 – Epidemiology, aetiology and pathology.
  • Section 4.7 – A summary of evidence has been added to Chapter 4 – Staging and classification systems.
  • Section 5.15 – Summary of evidence has been added to Chapter 5 – Diagnosis.
  • Section 6.4 – A summary of evidence has been added to Chapter 6 – Predicting disease recurrence and progression.
  • Section 7.2.1.4 – A summary of evidence has been added to Section 7.2.1 Intravesical chemotherapy.
  • Section 7.2.2.7 – A summary of evidence has been added to Section 7.2.2 Intravesical bacillus Calmette Guérin immunotherapy.
  • Section 7.2.4.5 – A summary of evidence has been added to Section 7.2.4 Specific aspects of treatment of CIS.
  • Section 7.3.4 – A Summary of evidence has been added to Section 7.3 Treatment failure of intravesical therapy.

2015

The literature for the complete document has been assessed and updated, whenever relevant.

Key changes for the 2015 publication:

  • A new section on resection techniques has been added, also expanding on the significance of biopsy for bladder cancer pathology.
  • The sections on the role of imaging for initial diagnosis and follow-up have been updated (Section 5.4).
  • The sections on stratification of patients into risk groups and high-risk disease have been enlarged.
  • A new section on Bacillus Calmette-Guérin (BCG) is included and the section on intravesical BCG and immunotherapy schedule has been expanded.

Recommendations have been rephrased and added to throughout the current document, not resulting in a change in the grade of recommendation (GR). New recommendations have been included in sections:

 

5.14      Guidelines for TURB and/or biopsies, tumour classification and pathology report 

  GR
Avoid cauterization as much as possible during TURB to avoid tissue deterioration. C
In patients with positive cytology, but negative cystoscopy, exclude a UTUC, CIS in the bladder (random biopsies or PDD targeted biopsies) and tumour in prostatic urethra (prostatic urethra biopsy). C
If indicated, perform a second TURB within 2-6 weeks after initial resection. It should include the resection of the primary tumour site. C
Classification and pathological report
Do not use the term “Superficial BC”. A
In difficult cases, consider an additional review by an experienced genitourinary pathologist. B

CIS = carcinoma in situ; PDD = photodynamic diagnosis; TURB = transurethral resection of the bladder.

 

 6.3.1     Recommendations for stratification of NMIBC 

  GR
In patients treated with BCG use CUETO risk tables for individual prediction of the risk of tumour recurrence and progression. B

BCG = Bacillus Calmette-Guérin; CUETO = Club Urológico Español de Tratamiento Oncológico.

 

7.5        Recommendations for adjuvant therapy in Ta, T1 tumours and for therapy of CIS

  GR
In patients with intermediate-risk tumours, one immediate instillation of chemotherapy should be followed by 1-year full-dose BCG treatment, or by further instillations of chemotherapy for a maximum of 1 year. The final choice should reflect the individual patient’s risk of recurrence and progression as well as the efficacy and side effects of each treatment modality. A
In patients with high-risk tumours, full-dose intravesical BCG for 1-3 years is indicated. The additional beneficial effect of the second and third years of maintenance should be weighed against its added costs and inconvenience. A
Intravesical chemotherapy
Give clear instructions to the nursing staff to control the free flow of the bladder catheter at the end of the immediate instillation. C

BCG = Bacillus Calmette-Guérin.

 

8.1        Guidelines for follow-up in patients after TURB of NMIBC

  GR
Consider R-biopsies or biopsies with PDD after intravesical treatment (at 3 or 6 months) in patients with CIS. C

TURB = transurethral resection of the bladder; R-biopsies = random biopsies.

2014

For all chapters in these guidelines the literature has been assessed and has resulted in the inclusion of 23 new publications. Two new treatment algorithms have been provided: ‘Management of patients with a primary or recurrent BC without previous BCG’ and ‘Management of patients with recurrence after intravesical BCG for NMIBC’.

A short new section on smoking cessation was added (see Section 7).

2013

For all chapters the literature has been assessed.

Chapter 4
Classification: A clear definition of non-muscle-invasive bladder cancer is presented. Since appropriate classification and grading directly influences treatment decisions, additional information on pathological parameters has been added.

Chapter 5
Diagnosis: An illustration on bladder diagram to facilitate the description of cystoscopy finding has been added. The new data on endoscopic diagnosis and pathological evaluation of the tissue included in this section resulted in a number of changes in the recommendations.

Chapter 6
Predicting disease recurrence and progression: The new stratification of patients into 3 risk groups facilitating treatment recommendation is presented.

Chapter 7
Adjuvant treatment: Updated information on intravesical chemo- and immunotherapy is provided. The definition and stratification of BCG toxicity and side-effects is provided in an overview table. The definition of BCG failures has been specified.

Chapter 8
Radical cystectomy for NMIBC: The indication criteria were updated.

2011

In 2011 there was a complete update of Non-Muscle Invasive (TaT1 and CIS) Bladder Cancer.