Muscle-Invasive and Metastatic Bladder Cancer

Counsel patients to stop active and avoid passive smoking.

Inform workers in potentially hazardous workplaces of the potential carcinogenic effects
of a number of recognised substances, including duration of exposure and latency periods. Protective measures are recommended.

Do not prescribe pioglitazone to patients with active bladder cancer or a history of bladder
cancer.

Record the depth of invasion for the entire specimen (categories pT2a and pT2b, pT3a and pT3b or pT4a and pT4b).

Record margins with special attention paid to the radial margin, prostate, ureter, urethra, peritoneal fat, uterus and vaginal vault.

Record the total number of lymph nodes (LNs), the number of positive LNs, and extranodal spread.

Record lymphovascular invasion.

Record the presence of carcinoma in situ.

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

Describe all macroscopic features of the tumor (site, size, number, and appearance) and mucosal abnormalities during cystoscopy. Use a bladder diagram.

Take a biopsy of the prostatic urethra in cases of bladder neck tumor, when bladder carcinoma in situ is present or suspected, when there is positive cytology without evidence of tumor in the bladder, or when abnormalities of the prostatic urethra are visible.

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

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.

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 cystectomy.

In the pathology report, specify the grade, depth of tumor invasion, and whether the lamina propria and muscle tissue are present in the specimen.

If an MRI is performed for local staging of bladder cancer it should be done before TURBT.

In patients with confirmed muscle-invasive bladder cancer, use computed tomography (CT) of the chest, abdomen and pelvis for staging, including some form of CT urography with designated phases for optimal urothelial evaluation.

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

Offer MRI to assess the response to systemic therapy, which aids in the selection of patients for radical treatment, surveillance, and bladder-sparing surgery.

Base the decision on bladder-sparing treatment or radical cystectomy in older/frail patients with invasive bladder cancer on tumor stage and frailty.

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.

Use susceptible FGFR3 alterations to select patients with unresectable or metastatic urothelial carcinoma for treatment with erdafitinib.

If eligible for cisplatin-based chemotherapy, offer neoadjuvant cisplatin-based combination chemotherapy to patients with muscle-invasive bladder cancer (T2-T4a, cN0 M0).

Do not offer neoadjuvant cisplatin-containing combination chemotherapy to patients who are ineligible for cisplatin-based combination chemotherapy.

Only offer neoadjuvant immunotherapy with checkpoint inhibitors alone to patients within a clinical trial setting.

Do not offer pre-operative radiotherapy (RT) for operable muscle-invasive bladder cancer since it will not improve survival.

Adjuvant RT can be offered following RC (pT3b-4 or positive nodes or positive margins) to improve loco-regional relapse free survival, but not overall survival.

Do not offer radiotherapy alone as primary therapy for localized bladder cancer.

Only offer sexual-preserving techniques to eligible men who are highly motivated to preserve their sexual function.

Select patients based on: organ-confined disease and absence of any kind of tumor at the level of the prostate, prostatic urethra or bladder neck.

Perform sexual organ-preserving techniques in eligible women. Select patients based on absence of tumor in the area to be preserved to avoid positive soft tissue margins.

Inform the patient of the advantages and disadvantages of open radical cystectomy (ORC) and robot-assisted radical cystectomy (RARC) to allow selection of the proper procedure.

Select experienced centers, not specific techniques, both for RARC and ORC.

Offer radical cystectomy (RC) to patients with T2-T4a, N0M0 disease or very high-risk nonmuscle-invasive bladder cancer.

Do not delay RC for >3 months as it increases the risk of progression and cancer-specific mortality, unless the patient receives neoadjuvant chemotherapy.

Perform a lymph node dissection as an integral part of RC.

Perform a standard LND, as an extended LND does not improve survival and increases the risk of morbidity.

Perform at least 20 RCs per hospital/per year.

Before RC, 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.

Do not offer an orthotopic bladder substitute diversion to patients who have an invasive tumor in the urethra or at the level of urethral dissection.

Do not offer pre-operative bowel preparation.

Employ "Fast track" measurements to reduce the time to bowel recovery.

Offer pharmacological VTE prophylaxis, such as low-molecular-weight heparin to RC patients, starting the first day post-surgery, for a period of at least four weeks.

Offer radical cystectomy as a palliative treatment to patients with locally-advanced tumors (T4b).

Offer palliative cystectomy to patients with symptoms if control is not possible by less invasive methods.

Offer salvage cystectomy to patients with muscle-invasive bladder cancer after TMT.

Do not offer transurethral resection of bladder tumor alone as a curative treatment option as most patients will not benefit.

Do not offer chemotherapy alone as primary therapy for localized bladder cancer.

Offer radical cystectomy or trimodality bladder-preserving treatments (TMT) as primary curative option for eligible patients since they are more effective than radiotherapy alone.

Manage all patients who are candidates for TMT in a multidisciplinary team setting. The choice of treatment modality should be made through a shared-decision making process.

Advise patients who are candidates for TMT that life-long bladder monitoring is essential.

Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or pN+ disease if no neoadjuvant chemotherapy has been given.

Offer adjuvant nivolumab to selected patients with pT3/4 and/or pN+ disease not eligible for, or who declined, adjuvant cisplatin-based chemotherapy (FDA approval irrespective of PD-L1 status, EMA approval only for PD-L1 tumor cell expression ≥ 1%).

Use antibody drug conjugate enfortumab vedotin (EV) in combination with checkpoint inhibitor (CPI) pembrolizumab.

If contraindications for EV or EV not available: Offer platinum-containing combination chemotherapy (cisplatin or carboplatin plus gemcitabine) followed by maintenance treatment with CPI avelumab in patients with at least stable disease on chemotherapy.

If contraindications for EV (or EV not available) and cisplatin-eligible: Consider cisplatin/gemcitabine in combination with CPI nivolumab.

If contraindications for EV and checkpoint inhibitor therapy: Use platinum-containing combination chemotherapy (cisplatin or carboplatin plus gemcitabine).

Consider single agent CPI pembrolizumab or atezolizumab in case of high PD-1 expression.

Offer platinum-containing combination chemotherapy (cisplatin or carboplatin plus gemcitabine).

If actionable fibroblast growth factor receptor (FGFR) alterations: offer erdafitinib.

Consider antibody drug conjugate Trastuzumab deruxtecan in case of HER2 over expression (IHC 3+).

Consider single agent chemotherapy (docetaxel, paclitaxel, vinflunine).

Offer antibody drug conjugate enfortumab vedotin.

If actionable FGFR alterations and prior CPI: offer erdafitinib.

If no prior CPI: offer pembrolizumab.

Consider single agent chemotherapy (docetaxel, paclitaxel, vinflunine).

General statement: Offer treatment in clinical trials. Consider best supportive care alone if patient is not a candidate for further cancer-specific systemic therapy.

If actionable FGFR alterations: offer erdafitinib.

Use validated questionnaires to assess health-related quality of life in patients with muscle invasive bladder cancer, both at baseline and post-treatment.

Discuss the type of urinary diversion taking into account patient preference, existing comorbidities, tumor variables, and coping abilities.

Offer radiotherapy, chemotherapy and possibly surgery as options for treatment, either alone or in combination.

Offer chemotherapy as the first option, and consider metastasectomy or radiotherapy in case of unique metastasis site.

See EAU Guidelines on Upper Urinary Tract Urothelial Carcinomas.

See EAU Guidelines on Primary Urethral Carcinoma.