Muscle-invasive and Metastatic Bladder Cancer

Full Text Guidelines Summary of Changes Scientific Publications & Appendices Pocket Guidelines Archive Panel


J.A. Witjes (Chair), H.M. Bruins, R. Cathomas, E. Compérat, N.C. Cowan, J.A. Efstathiou, R. Fietkau, G. Gakis, V. Hernández, A. Lorch, M.I. Milowsky, M.J. Ribal (Vice-chair), G.N Thalmann, A.G. van der Heijden, E. Veskimäe
Guidelines Associates: E. Linares Espinós, M. Rouanne, Y. Neuzillet

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. Section 5.3 -MIBC and health status, was developed with the assistance of Dr. S. O’Hanlon, consultant geriatrician, International Society of Geriatric Oncology (SIOG) representative and member of the EAU-EANM-ESTRO-ESUR-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/.

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 2020 [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 2021 document presents a limited update of the 2020 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 2021 EAU MIBC Guidelines resulting in new sections and added and revised recommendations in:

  • Section 3.3.3 Guidelines for the assessment of tumour specimens

Recommendation

Strength rating

Record the sampling sites, as well as information on tumour size when providing specimens to the pathologist.

Strong

  • Section 5.1.8 Summary of evidence and guidelines for the primary assessment of presumably invasive bladder tumours

Summary of evidence

LE

In men, prostatic urethral biopsy includes resection from the bladder neck to the verumontanum (between the 5 and 7 o’clock position) using a resection loop. In case any abnormal-looking areas in the prostatic urethra are present at this time, these need to be biopsied as well.

2b

Recommendations

Strength rating

In men with a negative prostatic urethral biopsy undergoing subsequent orthotopic neobladder construction, an intra-operative frozen section can be omitted.

Strong

In men with a prior positive transurethral prostatic biopsy, subsequent orthotopic neobladder construction should not be denied a priori, unless an intra-operative frozen section of the distal urethral stump reveals malignancy at the level of urethral dissection.

Strong

  • Section 5.2.1 - Local staging of MIBC; inclusion of data on multiparametric MRI using the Vesical Imaging Reporting and Data System (VI-RADS) scoring system. No new recommendation has been provided.

  • Section 5.3 - MIBC and health status; this section has been updated, introducing the concept of frailty.

  • Chapter 6 - Markers; this chapter has been significantly revised, presenting two new recommendations.

6.5 Summary of evidence and recommendations for urothelial markers

Summary of evidence

LE

There is insufficient evidence to use TMB, molecular subtypes, immune or other gene expression signatures for the management of patients with urothelial cancer.

-

Recommendations

Strength rating

Evaluate PD-L1 expression (by immunohistochemistry) to determine the potential for use of pembrolizumab or atezolizumab in previously untreated patients with locally advanced or metastatic urothelial cancer who are unfit for cisplatin-based chemotherapy.

Weak

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

  • 7.2 - Pre- and post-operative radiotherapy in muscle-invasive bladder cancer; this section was revised and new data added, resulting in an additional recommendation.

7.2.3 Summary of evidence and guidelines for pre- and post-operative radiotherapy

Summary of evidence

LE

Addition of adjuvant RT to chemotherapy is associated with an improvement in local relapse-free survival following cystectomy for locally advanced bladder cancer (pT3b─4, or node-positive).

2a

Recommendation

Strength rating

Consider offering adjuvant radiation in addition to chemotherapy following radical cystectomy, based on pathologic risk (pT3b4, or positive nodes, or positive margins).

Weak

7.3.10 Summary of evidence and guidelines for radical cystectomy and urinary diversion

Summary of evidence

LE

Ensuring that patients are well informed about the various urinary diversion options prior to making a decision may help prevent or reduce decision regret, independent of the method of diversion selected.

3

  • 7.5.4 Trimodality bladder-preserving treatment

  • 7.7 Metastatic disease: data from a number of key trials has been included, in particular on immunotherapy combinations in first- and later-line setting, resulting in a number of new recommendations and a change to the treatment flowchart (Figure 7.2).

7.7.8 Summary of evidence and guidelines for metastatic disease

Summary of evidence

LE

PD-1 inhibitor pembrolizumab has been approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase III trial.

PD-L1 inhibitors atezolizumab, nivolumab, durvalumab and avelumab have been FDA approved for patients that have progressed during or after previous platinum-based chemotherapy based on the results of a phase II trial.

PD-1 inhibitor pembrolizumab and PD-L1 inhibitor atezolizumab have been approved for patients with advanced or metastatic UC unfit for cisplatinum-based first-line chemotherapy and with overexpression of PD-L1 based on the results of single-arm phase II trials.

The combination of chemotherapy plus pembrolizumab or atezolizumab and the combination of durvalumab and tremelimumab have not demonstrated an OS survival benefit compared to platinum-based chemotherapy alone.

Switch maintenance with the PD-L1 inhibitor avelumab has demonstrated significant OS benefit in patients achieving at least stable disease on first-line platinum-based chemotherapy.

Recommendations

Strength rating

First-line treatment for platinum-fit patients

Use cisplatin-containing combination chemotherapy with GC or HD-MVAC.

Strong

In patients unfit for cisplatin but fit for carboplatin use the combination of carboplatin and gemcitabine.

Strong

In patients achieving stable disease, or better, after first-line platinum-based chemotherapy use maintenance treatment with PD-L1 inhibitor avelumab.

Strong

First-line treatment in patients unfit for platinum-based chemotherapy

Consider checkpoint inhibitors pembrolizumab or atezolizumab.

Weak

Second-line treatment

Offer checkpoint inhibitor pembrolizumab to patients progressing during, or after, platinum-based combination chemotherapy for metastatic disease. If this is not possible, offer atezolizumab, nivolumab (EMA, FDA approved); avelumab or durvalumab (FDA approved).

Strong

Further treatment after platinum- and immunotherapy

Offer treatment in clinical trials testing novel antibody drug conjugates (enfortumab vedotin, sacituzumab govitecan); or in case of patients with FGFR3 alterations, FGFR tyrosine kinase inhibitors.

Strong

GC = gemcitabine plus cisplatin; FGFR = fibroblast growth factor receptor; HD-MVAC = high-dose intensity methotrexate, vinblastine, adriamycin plus cisplatin.

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; EV = enfortumab vedotin; FDA = US Food and Drug Administration; FGFR = pan-fibroblast growth factor receptor tyrosine kinase inhibitor; GFR = glomerular filtration rate; IO = immunotherapy; PR = partial response; PS = performance status; SD = stable disease.

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