Guidelines

Muscle-invasive and Metastatic Bladder Cancer

1. INTRODUCTION

1.1. Aims and scope

The European Association of Urology (EAU) Guidelines Panel for Muscle-invasive and Metastatic Bladder Cancer (MIBC) have prepared these guidelines to help urologists assess the evidence-based management of MIBC and to incorporate guideline recommendations into their clinical practice.

Separate EAU guidelines documents are available addressing upper urinary tract (UUT) tumours [1],
non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) (NMIBC) [2], and primary urethral carcinomas [3].

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 - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2. Panel composition

The EAU Guidelines Panel consists of an international multidisciplinary group of clinicians, including urologists, oncologists, a pathologist, a radiologist and radiotherapists. In the course of 2021 two patient representatives formally joined the MIBC Guidelines Panel.

Section 5.3 -MIBC and health status, was developed with the assistance of Prof.Dr. S. O’Hanlon, consultant geriatrician, International Society of Geriatric Oncology (SIOG) representative and member of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG Prostate Cancer Guidelines Panel. The MIBC Panel is most grateful for his support.

All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/?type=panel

1.3. Available publications

A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version.

Several scientific publications are available (the most recent paper dating back to 2021 [4], as are a number of translations of all versions of the EAU MIBC Guidelines. All documents are accessible through the EAU website: http://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.

1.4. Publication history and summary of changes

1.4.1. Publication history

The EAU published its first guidelines on bladder cancer (BC) in 2000. This document covered both NMIBC and MIBC. Since these conditions require different treatment strategies, it was decided to give each condition its own guidelines, resulting in the first publication of the MIBC Guidelines in 2004. This 2022 document presents a limited update of the 2021 version.

1.4.2. Summary of changes

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

incorporated in the various chapters of the 2022 EAU MIBC Guidelines resulting in new sections and added and revised recommendations in:

  • Section 5.2 Imaging for staging of MIBC, and in particular Section 5.2.1 Local staging of MIBC, with the provision of a revised recommendation.
5.2.6 Summary of evidence and guidelines for staging in muscle-invasive bladder cancer

Summary of evidence

LE

In local staging, MRI is superior to CT in terms of differentiating T1 from T2 disease.

2b

Recommendation

Strength rating

Use CT urography unless it is contraindicated for reasons related to contrast administration or radiation dose, in that case use MRI.

Strong

Considerable new data was added to:

  • Section 7.1 Neoadjuvant therapy
  • Section 7.1.2 Role of cisplatin-based chemotherapy; this section was revised with considerable new data added.
  • Section 7.3.5 Laparoscopic/robotic-assisted laparoscopic cystectomy; a new section on stricture formation has been included.
  • Section 7.3.6.2 Different types of urinary diversion, in particular Section 7.3.6.2.1 Uretero-cutaneostomy
  • Section 7.6.2 Role of adjuvant immunotherapy has been completely revised including a new recommendation.
7.6.3 Summary of evidence and guidelines for adjuvant therapy

Summary of evidence

LE

Adjuvant cisplatin-based chemotherapy for high-risk patients (pT3, 4 and/or or N+ M0) without neoadjuvant treatment can be associated with improvement in DFS and OS but trials are underpowered to adequately answer this question.

2a

To date, studies of immune checkpoint inhibitors in the adjuvant setting for patients with high-risk MIBC who have and have not received neoadjuvant chemotherapy have demonstrated conflicting results with the CheckMate 274 study demonstrating an improvement in DFS with adjuvant nivolumab and the IMvigor 010 study failing to show an improvement in DFS with adjuvant atezolizumab.

1b

Results for adjuvant treatment with immune-checkpoint inhibitors in high-risk MIBC are conflicting: nivolumab improved DFS (Checkmate 274) whereas atezolizumab did not
(IMvigor 010).

1b

Circulating tumour DNA holds promise as both a prognostic and predictive biomarker to guide the use of adjuvant IO for UC in patients who are at a high risk of recurrence and positive for ctDNA treated with adjuvant atezolizumab demonstrating improved outcomes compared with observation.

2b

Recommendation

Strength rating

Discuss immunotherapy with nivolumab with selected patients with pT3/4 and/or pN+ disease not eligible for, or who declined, adjuvant cisplatin-based chemotherapy.

Weak

  • Section 7.7 Metastatic disease was completely revised, resulting in the inclusion of new recommendation.
7.7.9 Summary of evidence and guidelines for metastatic disease

Summary of evidence

LE

Enfortumab vedotin after prior platinum chemotherapy and checkpoint inhibitor immunotherapy has demonstrated a significant survival benefit as compared to chemotherapy.

1b

PD-L1 inhibitor atezolizumab is approved for patients with advanced or metastatic UC unfit for cisplatin-based chemotherapy in case of high PD-1 expression defined as tumour-infiltrating immune cells covering > 5% of the tumour area using the SP142 assay.

1b

PD-1 inhibitor pembrolizumab is approved for patients with advanced or metastatic UC unfit for any platinum-based chemotherapy in case of high PD-1 expression defined as CPS of > 10 using the Dako 22C33 platform (EMA; FDA approval independent of PD-1 status).

1b

Recommendation

Strength rating

Evaluate for FGFR2/3 genetic alterations for the potential use of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma who have progressed following platinum-containing chemotherapy (including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy).

Weak

Figure 7.2: Flow chart for the management of metastatic urothelial cancer*

*Treatment within clinical trials is highly encouraged.
BSC = best supportive care; CR = complete response; DD-MVAC = dose dense methotrexate vinblastine doxorubicin cisplatin; EMA = European Medicines Agency; EV = enfortumab vedotin; FDA = US Food and
Drug Administration; FGFR = fibroblast growth factor receptor; GFR = glomerular filtration rate;
IO = immunotherapy; PR = partial response; PS = performance status; SD = stable disease.

  • Section 7.8 Quality of life, one recommendation was revised based on the new data added.

Summary of evidence

LE

HRQoL data are comparable for robotic radical cystectomy (with either intracorporeal or extracorporeal urinary diversion) and open radical cystectomy.

1b

  • Chapter 8 Follow-up; a new section on variant histologies was added.