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EAU GUIDELINES ON
MUSCLE-INVASIVE AND METASTATIC BLADDER CANCER
(Limited text update March 2017)
J.A. Witjes (Chair), E. Compérat, N.C. Cowan, G. Gakis, A.G. van der Heijden, V. Hernández, T. Lebret, A. Lorch, M.J. Ribal
Guidelines Associates: M. Bruins, E. Linares Espinós, M. Rouanne, Y. Neuzillet, E. Veskimae
Optimal treatment strategies for Muscle-invasive Bladder Cancer (MIBC) require the involvement of a specialist multidisciplinary team and a model of integrated treatment strategies to avoid fragmentation of patient care.
Staging and grading systems
The 2017 TNM (Tumour, Node, Metastasis Classification) is used for staging (Table 1). For grading, the 1973 and 2016 WHO grading classifications are used (Table 2).
Table 1: TNM Classification 2017
T - Primary Tumour
Primary tumour cannot be assessed
No evidence of primary tumour
Non-invasive papillary carcinoma
Carcinoma in situ: ’flat tumour’
Tumour invades subepithelial connective tissue
Tumour invades muscle
Tumour invades superficial muscle (inner half)
Tumour invades deep muscle (outer half)
Tumour invades perivesical tissue
Microscopically (extravesical mass)
Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
Tumour invades prostate stroma, seminal vesicles, uterus or vagina
Tumour invades pelvic wall or abdominal wall
N – Regional Lymph Nodes
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral)
Metastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral)
Metastasis in a common iliac lymph node(s)
M - Distant Metastasis
No distant metastasis
Non-regional lymph nodes
Orther distant metastasis
Table 2: WHO grading in 1973 and 2016
1973 WHO grading
Grade 1: well differentiated
Grade 2: moderately differentiated
Grade 3: poorly differentiated
2016 WHO grading system (Papillary lesions)
Papillary urothelial neoplasm of low malignant potential (PUNLMP)
Low-grade (LG) papillary urothelial carcinoma
High-grade (HG) papillary urothelial carcinoma
Pathology of MIBC
Determination of morphological subtypes can be helpful in assessing the prognosis and treatment options of high-grade urothelial carcinomas (grade II or grade III) as discussed in these guidelines. The following differentiation is used:
Recommendations for the assessment of tumour specimens
Record the depth of invasion (categories pT2a and pT2b and pT3a and pT3b or pT4).
Record margins with special attention paid to the radial margin, prostate, ureter, urethra and peritoneal fat and uterus and vaginal top.
Record the number of lymph nodes and number of positive lymph nodes.
Record lymphatic or blood vessel invasion.
Record the presence of carcinoma in situ.
*Upgraded following panel consensus.
Recommendations for the primary assessment of presumably invasive bladder tumours*
During cystoscopy, describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended.
Take a biopsy of the prostatic urethra for cases of bladder neck tumour, when bladder carcinoma in situ is present or suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible.
Take a biopsy at the time of the second resection, if no biopsy was taken during the initial procedure.
In women undergoing subsequent orthotopic neobladder construction, obtain procedural information (including histological evaluation) of the bladder neck and urethral margin, either prior to or at the time of cystoscopy.
Specify the grade, depth of tumour invasion, and whether the lamina propria and muscle tissue are present in the specimen in the pathological report.
* For general information on the assessment of bladder tumours, see the EAU Guidelines on Non-muscle-invasive bladder cancer.
Recommendations for staging of muscle-invasive bladder cancer (MIBC)
In patients with confirmed MIBC, use computed tomography (CT) of the chest, abdomen and pelvis as the optimal form of staging. Include excretory-phase CT urography for complete examination of the upper urinary tract.
Diagnose upper urinary tract urothelial carcinoma (UTUC) using excretory-phase CT urography rather than magnetic resonance (MR) urography as excretory-phase CT urography has greater diagnostic accuracy and is associated with less cost, and greater patient acceptability.
Use MR urography when CT urography is contraindicated for reasons related to contrast administration or radiation dose.
Perform endoscopically-guided biopsy for histopathological confirmation of pre-operative diagnosis of UTUC.
Use CT or magnetic resonance imaging (MRI) for staging locally advanced or metastatic disease in patients in whom radical treatment is being considered.
Use CT to diagnose pulmonary metastases. CT and MRI are generally equivalent for diagnosing local disease and distant metastases in the abdomen.
Recommendations for the assessment of elderly patients
Base the decision on bladder-sparing treatment or radical cystectomy in elderly/geriatric patients with invasive bladder cancer on tumour stage and comorbidity.
Assess comorbidity by a validated score, such as the Charlson Comorbidity Index, the American Society of Anesthesiologists score should not be used in this setting.
Recommendations for treatment failure of non-muscle-invasive bladder cancer
Consider immediate radical treatment in all T1 tumours at high risk of progression (i.e., high grade, multifocality, carcinoma in situ, and tumour size, as outlined in the EAU Guidelines for Non-muscle-invasive Bladder Cancer).
Offer radical treatment to all T1 patients failing intravesical therapy.
Neoadjuvant chemotherapy (NAC)
Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival (5-8% at five years), irrespective of the type of definitive treatment used. Currently, no tools are available to select patients who have a higher probability of benefitting from NAC. However, NAC has its limitations regarding patient selection, current development of surgical techniques, and current chemotherapy combinations.
Recommendations for neoadjuvant chemotherapy
Offer neoadjuvant chemotherapy for T2-T4a, cN0M0 bladder cancer. In this case, always use cisplatin-based combination therapy.
Do not offer neoadjuvant chemotherapy to patients who are ineligible for cisplatin-based combination chemotherapy.
Recommendations for pre- and post-operative radiotherapy in muscle-invasive bladder cancer
Do not offer pre-operative radiotherapy to improve survival.
Offer pre-operative radiotherapy for operable MIBC since it can result in tumour downstaging after four-six weeks.
Radical cystectomy and urinary diversion
Contraindications for orthotopic bladder substitution are positive margins at the level of urethral dissection, positive margins anywhere on the bladder specimen (in both sexes), if the primary tumour is located at the bladder neck or in the urethra (in women), or if tumour extensively infiltrates the prostate (in men).
Recommendations for radical cystectomy and urinary diversion
Do not delay cystectomy for > 3 months as it increases the risk of progression and cancer-specific mortality.
Before cystectomy, fully inform the patient about the benefits and potential risks of all possible alternatives. The final decision should be based on a balanced discussion between the patient and the surgeon.
Offer an orthotopic bladder substitute or ileal conduit diversion to male and female patients lacking any contraindications and who have no tumour in the urethra or at the level of urethral dissection.
Do not offer pre-operative radiotherapy when subsequent cystectomy with urinary diversion is planned.
Do not offer sexual-preserving cystectomy as standard therapy for MIBC.
Offer sexual-preserving techniques to men motivated to preserve their sexual function since the majority will benefit.
Select patients based on:
absence of any kind of tumour at the level of the prostate, prostatic urethra or bladder neck.
Do not offer pelvic organ-preserving radical cystectomy to female patients as standard therapy for MIBC.
Offer sexual-preserving techniques to female patients motivated to preserve their sexual function since the majority will benefit.
Select patients based on:
absence of tumour in bladder neck or urethra.
Pre-operative bowel preparation is not mandatory.
“Fast track” measurements may reduce the time of bowel recovery.
Offer radical cystectomy in T2-T4a, N0M0, and high-risk non-MIBC.
Perform a lymph node dissection as an integral part of cystectomy.
Preserve the urethra if margins are negative.
Check the urethra regularly if no bladder substitution is attached.
*Upgraded following EAU Panel consensus.
Recommendations for laparoscopic/robotic-assisted laparoscopic cystectomy (RARC)
Inform the patient of the advantages and disadvantages of open radical cystectomy (ORC) and RARC to allow selection of the proper procedure.
Select experienced centres, not specific techniques, both for RARC and ORC.
Beware of neobladder under-utilisation and outcome after RARC.
Fig. 1: Flow chart for the management of T2-T4a N0M0 urothelial bladder cancer
CT=computed tomography; MRI=magnetic resonance imaging; UUT=upper urinary tract.
Bladder-sparing treatments for localised disease
Transurethral resection of bladder tumour
Transurethral resection of bladder tumour alone is only possible as a therapeutic option if tumour growth is limited to the superficial muscle layer and if restaging biopsies are negative for residual tumour.
External beam radiotherapy
External beam radiotherapy alone should only be considered as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach. Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation due to extensive local tumour growth.
Chemotherapy and best supportive care
With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and partial local responses have been reported.
In a highly selected patient population, long-term survival rates of multimodality treatment are comparable to those of early cystectomy. Delay in surgical therapy can compromise survival rates.
Recommendations for bladder-sparing treatments for localised disease
Do not offer transurethral resection of bladder tumour alone as a curative treatment option as most patients will not benefit.
Do not offer pre-operative radiotherapy to improve survival.
Do not offer radiotherapy alone as primary therapy for localised bladder cancer.
Offer pre-operative radiotherapy for operable MIBC since it can result in tumour down-staging after four-six weeks.
Do not offer chemotherapy alone as primary therapy for localised bladder cancer.
Offer surgical intervention or multimodality treatments as primary curative therapeutic approaches since they are more effective than radiotherapy alone.
Offer multimodality treatment as an alternative in selected, well-informed and compliant patients, especially for whom cystectomy is not an option.
Surgically non-curable tumours
Palliative cystectomy for metastatic disease
Primary radical cystectomy in T4b bladder cancer is not a curative option. If there are symptoms, radical cystectomy may be a therapeutic/palliative option. Intestinal or non-intestinal forms of urinary diversion can be used, with or without palliative cystectomy.
Offer radical cystectomy as a palliative treatment to patients with inoperable locally advanced tumours (T4b).
In patients with symptoms, palliative cystectomy may be offered.
Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or pN+ disease if no neoadjuvant chemotherapy has been given.
First-line treatment for fit patients:
Use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with G-CSF, or HD-MVAC with G-CSF or PCG.
Do not use carboplatin and non-platinum combination chemotherapy.
First-line treatment in patients ineligible (unfit) for cisplatin:
Use carboplatin combination chemotherapy or single agents.
For cisplatin-ineligible (unfit) patients, with performance status 2 or impaired renal function, as well as those with 0 or 1 poor Bajorin prognostic factors and impaired renal function, offer carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin.
Offer vinflunine to patients progressing after platinum-based combination chemotherapy for metastatic disease. Alternatively, offer treatment within a clinical trial setting.
Offer zoledronic acid or denosumab to treat bone metastases.
* Grade A recommendation is weakened since the key studies did not reach statistical significance.
GC=gemcitabine plus cisplatin; G-CSF=granulocyte colony-stimulating factor; MVAC=methotrexate, vinblastine, adriamycin plus cisplatin; HD MVAC=high-dose methotrexate, vinblastine, adriamycin plus cisplatin; PCG=paclitaxel, cisplatin, gemcitabine.
Health-related quality-of-life (HRQoL)
Important determinants of (subjective) quality of life are a patient’s personality, coping style and social support.
Use validated questionnaires to assess HRQoL in patients with MIBC.
Offer a continent urinary diversion unless a patient’s comorbidities, tumour variables and coping abilities present clear contraindications.
Pre-operative patient information, patient selection, surgical techniques, and careful post-operative follow-up are the cornerstones for achieving good long-term results.
Encourage patients to actively participate in the decision-making process.
Provide clear and exhaustive information on all potential benefits and side-effects, allowing patients to make informed decisions.
Figure 2: Flow chart for the management of metastatic urothelial bladder cancer
GC=gemcitabine plus cisplatin; GFR=glomerular filtration rate; HD MVAC=high-dose methotrexate, vinblastine, adriamycin plus cisplatin; MVAC=methotrexate, vinblastine, adriamycin plus cisplatin; PCG=paclitaxel, cisplatin, gemcitabine; PS=performance status.
This short booklet text is based on the more comprehensive EAU Guidelines (978-90-79754-91-5), available to all members of the European Association of Urology at their website, http://www.uroweb.org/guidelines/.