Bladder Cancer Guidelines

Updated: Feb 23, 2021
  • Author: Kara N Babaian, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
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Guidelines

Guidelines Summary

Organizations and Recommendation Approaches

Guidelines for the diagnosis and management of bladder cancer have been issued by the following organizations:

  • American Urological Association/Society of Urological Oncology (AUA/SUO)
  • European Association of Urology (EAU)
  • European Society for Medical Oncology (ESMO)
  • National Comprehensive Cancer Network (NCCN)

Each organization uses a different methodology to determine levels of evidence and grades for recommendations, as follows:

  • AUA/SUO – Guideline recommendations are based on literature review or expert consensus. The evidence strength is rated based on level of certainty from A (high certainty) to C (low certainty) and the magnitude and balance between benefits and risks/burdens. Recommendations range from Strong (substantial benefit of harm), Moderate (moderate benefit or harm), Conditional ((No apparent net benefit or harm), Clinical Statement (clinical care that is widely agreed upon by urologists or other clinicians with or without medical evidence) or Expert Opinion (consensus of the panel based on members' clinical training, experience, knowledge, and judgment). [143]

  • EAU - Guideline recommendations have been graded on the basis of the Oxford Centre for Evidence-based Medicine levels of Evidence; however, the link between the level of evidence and grade of recommendation is not directly linear (eg, overwhelming clinical experience and consensus may compensate for absence of high-level evidence [144, 69, 145]

  • ESMO - Guideline recommendations are graded A (strongly recommended) through E (never recommended) based on the Infectious Diseases Society of America–United States Public Health Service Grading System [146]

  • NCCN - Recommendations are derived from critical evaluation of evidence, integrated with the clinical expertise and consensus of a multidisciplinary panel of cancer specialists, clinical experts and researchers in those situations where high-level evidence does not exist [1] ; all guideline recommendations are category 1 (supported by uniform consensus based on high-level evidence) or category 2A (uniform consensus based on lower-level evidence)

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Screening

In 2019, the US Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to determine the balance of benefits and harms of screening for bladder cancer in asymptomatic adults. Although adults with mild lower urinary tract symptoms (eg, urinary frequency, hesitancy, urgency, dysuria, nocturia) are not strictly asymptomatic, these symptoms are common and are not believed to be associated with an increased risk of bladder cancer. The USPSTF considered it reasonable to include these persons in the population under consideration for screening. Adults with gross hematuria or acute changes in lower urinary tract symptoms were not included in this population. [147]

No major organization recommends screening for bladder cancer in asymptomatic adults. The American Academy of Family Physicians supports the USPSTF recommendation. [148]  The American Cancer Society states that prompt attention to bladder symptoms is the best approach for finding bladder cancer in its earliest, most treatable stages in persons with no known risk factors. [149]

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Risk Reduction

Cigarette smoking is the most established risk factor for bladder cancer, increasing relative risk four- to five-fold relative to never smoking for current smokers and two- to three-fold for former smokers. It is the cause of 50% of cases in both men and women  [23]

The European Association of Urology (EAU) guidelines estimate a 40% reduction in the risk of developing bladder cancer within 1-4 years of quitting smoking, increasing to a 60% reduction after 25 years of smoking cessation. [144]

In addition to smoking cessation, the EAU guidelines address the second most important risk factor, occupational exposure to carcinogens, with a recommendation that workers be informed of the risk and protective measures taken. [144]  Occupational exposures include the following [64] :

  • Aromatic hydrocarbons - common in metal processing
  • Aromatic amines - used in dyes
  • N-nitrosamines - found in rubber and tobacco
  • Formaldehyde
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Diagnosis

The following studies are used in the diagnosis of bladder cancer:

  • Urinary cytology
  • Urinary tract imaging
  • Cystoscopy
  • Histologic examination of specimens obtained by transurethral resection of the bladder tumor (TURBT)

For diagnostic evaluation of muscle-invasive bladder cancer (MIBC), EUA guidelines recommend the following [144] :

  • In patients with confirmed MIBC, use computed tomography (CT) of the chest, abdomen, and pelvis as the optimal form of staging.
  • For upper tract evaluation and for staging, perform CT urography; use diagnostic ureteroscopy and biopsy only in cases where additional information will impact treatment decisions.
  • Use magnetic resonance urography when CT urography is contraindicated for reasons related to contrast administration or radiation dose.
  • Use CT or magnetic resonance imaging (MRI) for staging locally advanced or metastatic disease in patients in whom radical treatment is considered.
  • Use CT to diagnose pulmonary metastases. CT and MRI are generally equivalent for diagnosing local disease and distant metastases in the abdomen.

Novel molecular and genetic markers have been studied for the diagnosis of urothelial carcinoma (see Urine Tumor Markers in Bladder Cancer Diagnosis) but have not been shown to effectively replace urine cytology and cystoscopy. The AUA and EAU do not currently recommend the use of urinary tumor markers during initial hematuria workup due to high cost and poor specificity. However, urinary tumor markers can be used in addition to cystoscopy and cytology in patients undergoing surveillance for bladder cancer. [64]  The NCCN guidelines advise that urinary biomarker testing with US Food and Drug Administration (FDA)–approved fluorescence in situ hybridization (FISH) or nuclear matrix protein 22 (NMP-22) assays may be used in the monitoring or surveillance for bladder cancer recurrence. [1]

Urinary cytology

According to EAU guidelines, urinary cytology is most helpful in diagnosing high-grade tumors and carcinoma in situ (CIS). Low-grade, noninvasive tumors may be missed by routine cytologic analysis. The guidelines caution that cystoscopy is still required and cannot be replaced by cytology or any other noninvasive test. [69] NCCN guidelines state that urine cytology may be obtained around the time of cystoscopy. [1]

Cystoscopy

Joint AUA/SUO guidelines, issued in 2016, recommend that at the time of resection of suspected bladder cancer, a clinician should perform a thorough cystoscopic examination of the patient’s entire urethra and bladder to evaluates and document tumor size, location, configuration, number, and mucosal abnormalities. In a patient with non–muscle-invasive bladder cancer (NMIBC), blue light cystoscopy, if available, should be offered at the time of TURBT to increase detection and decrease recurrence. In a patient with normal cystoscopy and positive cytology and a history of NMIBC, blue light cystoscopy (when available); prostatic urethral biopsies and upper tract imaging, as well as ureteroscopy; or random bladder biopsies should be considerd. [143]

The EAU allows for the omission of cystoscopy if the tumor was visualized with an imaging study. [69]

The NCCN also recommends cystoscopy for all patients with clinical suspicion of bladder cancer. When cystoscopy findings are negative in the setting of positive cytology findings, the NCCN guidelines recommend further evaluation of the upper urinary tract with radiographic imaging and/or ureteroscopy, as well as evaluation of the prostatic urethra in men and the urethra in women. [1]

In general, it may be preferable to obtain upper tract imaging with intravenous contrast for patients with hematuria prior to performing cystoscopy. If the imaging findings are positive, one may forgo office-based cystoscopy and perform the cystoscopy in the operating room. In addition, photodynamic diagnosis with hexaminolevulinate blue-light cystoscopy may be associated with fewer false negatives than white-light cystoscopies. [143, 110]

If cystoscopy indicates noninvasive disease, the NCCN guidelines recommend the following further studies [1] :

  • Imaging of the upper tract collecting system
  • If the cystoscopic appearance of the tumor is solid (sessile) or high-grade, consideration of a CT scan or MRI of the abdomen and pelvis before the TURBT

For imaging of the upper tract, CT urography is generally the preferred approach. Other options are an intravenous pyelogram (IVP), renal ultrasound with retrograde pyelogram, ureteroscopy, or MRI urogram. If the tumor has a purely papillary appearance or only the mucosa appears to be abnormal, suggesting carcinoma in situ (CIS), upper tract imaging can be deferred until after surgery.

If cystoscopy indicates muscle-invasive disease, the NCCN guidelines recommend the following [1] :

  • Complete blood count and chemistry profile including alkaline phosphatase
  • Chest imaging
  • Imaging of the upper tract collecting system
  • Abdominal/pelvic CT or MRI before TURBT
  • Bone scan if alkaline phosphatase level is elevated or patient is symptomatic with bone pain 

In patients with confirmed muscle-invasive bladder cancer, the EAU recommends CT of the chest, abdomen, and pelvis as optimal for staging. The imaging studies should include excretory-phase CT urography for complete examination of the upper urinary tract. [145]

Transurethral resection of the bladder tumor

The guidelines (AUA, EAU, ESMO, NCCN) are in agreement that the final diagnosis of bladder cancer is based on cystoscopic examination and TURBT histology. [144, 143, 69, 146, 1] The guidelines further agree that all visible lesions be resected during TURBT with bimanual examination under anesthesia (EUA) and that adequate sampling is required for proper tumor identification and staging. [144, 143, 69, 146, 1]

EAU guidelines recommend performing a second TURBT 2-6 weeks after the initial resection in any of the following situations [69] :

  • After incomplete initial TURBT
  • If there is no muscle in the specimen after initial resection, with exception of Ta low-grade tumors and, possibly, completely resected primary CIS
  • In all T1 tumors
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Staging

Bladder cancer is staged using the International Union Against Cancer and the American Joint Committee on Cancer Staging’s tumor, node, and metastasis (TNM) system. [79] See Bladder Cancer Staging.

Ta and T1 tumors and carcinoma in situ (CIS) were historically considered superficial bladder tumors. T2, T3, and T4 tumors were traditionally described as invasive bladder cancer. However, use of the term superficial bladder cancer is recommended against by the AUA/SUO, NCCN and EAU guidelines because it groups together patients who may require different treatments and who may have different prognoses. Instead, all guidelines now categorize these tumors as non–muscle invasive bladder cancer (NMIBC). [143, 69, 146, 1]

Urothelial carcinoma is histologically graded as low grade or high grade. CIS is characterized by full mucosal thickness and high-grade dysplasia or marked atypia of the bladder epithelium and is associated with a poorer prognosis. By definition, CIS is confined to the epithelial surface of the urinary tract and has no other official stage definition.

The EAU uses three levels of risk stratification for non–muscle-invasive tumors, as follows [69] :

  • Low risk: Primary, solitary, TaG1 (PUNLMP, LG*), < 3 cm, no CIS
  • Intermediate risk: All tumors not meeting the definition of either low- or high-risk tumors
  • High risk: T1 tumor; G3 high grade tumor; carcinoma in situ (CIS); multiple, recurrent and large (> 3 cm) TaG1G2 /LG tumors (all features must be present)

For muscle-invasive bladder cancer (MIBC), EAU guidelines recommend the following [144] :

  • In patients with confirmed MIBC, use computed tomography (CT) of the chest, abdomen, and pelvis as the optimal form of staging.
  • For upper tract evaluation and for staging, perform CT urography; use diagnostic ureteroscopy and biopsy only in cases where additional information will impact treatment decisions.
  • Use magnetic resonance urography when CT urography is contraindicated for reasons related to contrast administration or radiation dose.
  • Use CT or magnetic resonance imaging (MRI) for staging locally advanced or metastatic disease in patients in whom radical treatment is considered.
  • Use CT to diagnose pulmonary metastases. CT and MRI are generally equivalent for diagnosing local disease and distant metastases in the abdomen.

 

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Treatment

Non─muscle-invasive disease

National Comprehensive Cancer Network (NCCN) recommendations for treatment of low-grade Ta tumors are as follows [1] :

  • Standard treatment for non–muscle invasive bladder cancer (NMIBC) is a complete transurethral resection of the bladder tumor (TURBT)

  • Intravesical chemotherapy is generally used as prophylactic or adjuvant therapy after complete endoscopic resection; it is rarely used as therapy to eradicate residual disease that could not be completely resected. The panel recommends a single dose of immediate intravesical chemotherapy of gemcitabine or mitomycin.
  • One postoperative intravesical dose (within 24 h, but usually immediately after resection) has been shown to reduce recurrence, but not progression, of disease for patients with low-risk NMIBC

  • Immediate intravesical chemotherapy is avoided when TURBT was extensive or perforation is suspected or the tumor appears invasive or high grade

  • Immediate intravesical chemotherapy can be followed by a 6-week induction of intravesical chemotherapy

  • Immunotherapy may be used but is not recommended

NCCN and European Association of Urology (EAU) recommendations for treatment of high-grade Ta tumors are as follows [69, 1] :

  • TURBT should be repeated if there is incomplete resection; if no muscle is present in the specimen, strongly consider repeating resection. In addition, repeat TURBT has prognostic, therapeutic, and surveillance indications: Up to 40-70% of patients will have residual bladder cancer at repeat TURBT performed within 2-6 weeks after initial TURBT

  • Intravesical immunotherapy bacillus Calmette-Guérin (BCG) after TURBT is recommended and is superior to intravesical chemotherapy for preventing tumor recurrence [143, 69]

NCCN recommendations for treatment of T1 tumors (low- and high-grade) are as follows [1] :

  • Repeat TURBT

  • If no residual disease after second resection, immunotherapy with BCG (category 1 recommendation)

  • If residual disease after second resection, immunotherapy with BCG (category 1 recommendation), especially if the disease is Ta high grade or carcinoma in situ

  • Consider cystectomy for T1 high grade and cystectomy for any patients upstaged to T2

The EAU recommendations for adjuvant treatment of Ta and T1 tumors are as follows [69] :

  • Low-risk Ta tumors: One immediate instillation of chemotherapy as the complete adjuvant treatment

  • Intermediate-risk Ta or T1 tumors: One immediate instillation of chemotherapy, followed by 1 year of full-dose BCG treatment, or by further instillation of chemotherapy for a maximum of 1 year

  • High-risk tumors: Full-dose intravesical BCG for 1-3 years or radical cystectomy

  • T1 high grade and concurrent CIS: Consider cystectomy

  • BCG-refractory tumors: Cystectomy; bladder-preserving strategies in patients not suitable for or refusing radical cystectomy

The American Urological Association/Society of Urological Oncology (AUA/SUO) recommendations for repeat TURBT are as follows [143] :

  • In patients with incomplete initial resection, repeat TURBT if technically feasible.
  • For high-risk, high grade Ta tumors, consider performing repeat TURBT of the primary tumor site within 6 weeks of initial TURBT.
  • In T1 disease, repeat TURBT of the primary tumor site, including muscularis propria, within 6 weeks of initial TURBT.

The AUA/SUO recommendations for intravesical therapy are as follows [143] :

  • For low- or intermediate-risk bladder cancer, consider a single postoperative instillation of intravesical chemotherapy (eg, mitomycin C or epirubicin) within 24 hours of TURBT.
  • After an extensive resection or if a perforation is suspected, postoperative chemotherapy should not be administered. 
  • Induction intravesical therapy should not be given to low-risk patients. 
  • Consider a 6-week course of induction intravesical chemotherapy or immunotherapy for intermediate-risk bladder cancer. 
  • In a high-risk patient with newly diagnosed CIS, high-grade T1, or high-risk Ta urothelial carcinoma, give a 6-week induction course of BCG. 
  • In an intermediate-risk patient who completely responds to an induction course of intravesical chemotherapy, maintenance therapy may be given.
  • In an intermediate-risk patient who completely responds to induction BCG, consider maintenance BCG for one year, as tolerated. 
  • In a high-risk patient who completely responds to induction BCG, continue maintenance BCG for three years, as tolerated. 

Carcinoma in situ

The NCCN recommendations for CIS are as follows [1] :

  • Resection followed by intravesical therapy with BCG once a week for 6 weeks, followed by a rest period of 6 weeks

  • Full re-evaluation at week 12 (ie, 3 months) after the start of therapy

  • If the patient is unable to tolerate BCG, intravesical mitomycin C may be administered (however, most patients can tolerate BCG with dose reductions and anticholinergic medication)

  • Follow-up is similar to that for T1 and Ta high-grade tumors

Follow-up and surveillance

The EAU guidelines recommend regular cystoscopy for follow-up of patients with Ta, T1 tumors and CIS who have undergone transurethral resection of the bladder tumor. Schedules are as follows [69] :

  • Patients with low-risk Ta tumors should undergo cystoscopy at 3 months, then (if no evidence of disease is found) 9 months later, then yearly for 5 years.

  • Patients with high-risk tumors should undergo cystoscopy and urinary cytology at 3 months, then every 3 months for 2 years, every 6 months thereafter until 5 years, then yearly.

  • Patients with intermediate-risk Ta tumors should have follow-up cystoscopy and cytology on a schedule that is in between those for low- and high-risk tumors and that is adapted according to personal and subjective factors.

  • Annual upper tract imaging (CT urography or intravenous urography) is recommended for high-risk tumors (note, however, that there are no data to support annual imaging for asymptomatic, recurrence-free patients).

  • Patients with suspicious findings on cystoscopy or positive urine cytology should undergo endoscopy under anesthesia and bladder biopsies (these patients may benefit from photodynamic detection with hexaminolevulinate blue-light cystoscopy).

  • In patients with CIS, consider random biopsies (these are rarely informative) or biopsies with photodynamic diagnosis at 3 or 6 months after intravesical treatment.

  • During follow-up in patients with positive cytology and no visible tumor in the bladder, random biopsies or biopsies with photodynamic diagnosis and investigation of extravesical locations (CT urography, prostatic urethra biopsy) are recommended.

The NCCN guidelines specify that cystoscopy and urinary cytology should be performed every 3-6 months for 2 years and then at increasing intervals as appropriate. [1]

The AUA/SUO–recommended surveillance schedules are as follows [143] :

  • First surveillance cystoscopy within 3-4 months of the initial evaluation and treatment 
  • For a low-risk patient whose first surveillance cystoscopy is negative, subsequent cystoscopy 6-9 months later, and then annually thereafter; after 5 years, continued surveillance should be based on shared-decision making between the patient and clinician.
  • In an asymptomatic patient with a history of low-risk NMIBC, routine surveillance upper tract imaging should not be performed.
  • For an intermediate-risk patient whose first surveillance cystoscopy is negative,  subsequent cystoscopy with cytology every 3-6 months for 2 years, then 6-12 months for years 3 and 4, and annually thereafter.
  • For a high-risk patient whose first surveillance cystoscopy is negative, subsequent cystoscopy with cytology every 3-4 months for 2 years, then 6 months for years 3 and 4, and then annually thereafter.
  • For an intermediate- or high-risk patient, a clinician should consider performing surveillance upper tract imaging at 1-2 year intervals. 

Muscle-invasive disease – NCCN recommendations

NCCN recommendations for treatment of muscle-invasive disease are as follows  [1] :

  • TURBT is the initial diagnostic procedure after CT/MRI imaging of the abdomen, pelvis, and in some cases the chest, to help identify the clinical stage of the bladder cancer.

  • Radical cystectomy is the primary treatment for all muscle-invasive disease, with strong consideration for cisplatin-based neoadjuvant chemotherapy (category 1 recommendation), especially for patients with hydronephrosis, vascular/lymphatic invasion, extravesical disease, or aberrant histologic variants.

  • Neoadjuvant chemotherapy may be preferred over adjuvant chemotherapy; however, there are no data to support this preference.

  • Regimens include DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) with growth factor support for three or four cycles; gemcitabine and cisplatin for three or four cycles (both 21- and 28-day regimens are acceptable); or accelerated-dose MVAC for three cycles.

  • The NCCN panel prefers DDMVAC over standard MVAC, based on category 1 evidence that DDMVAC is better tolerated and more effective than conventional MVAC in advanced disease.

  • Partial cystectomy may be performed in highly selected patients with a solitary lesion in a suitable location and no CIS or previous tumors; cisplatin-based neoadjuvant chemotherapy should be considered.

  • Bladder preservation following TURBT with concurrent chemotherapy and radiation is an alternative therapy for patients with multiple medical co-morbidities or who refuse radical cystectomy; the decision should be based, in part, on the location, size and depth of invasion, and absence of hydronephrosis, as well as the bladder capacity, function, and comorbidities.

For patients with advanced or metastatic disease, first-line chemotherapy regimens are as follows:

  • Gemcitabine and cisplatin (category 1 recommendation)
  • DDMVAC with growth factor support (category 1 recommendation)

For patients who cannot receive cisplatin-based chemotherapy due to renal impairment or other comorbidities, the NCCN lists the following regimens as preferred:

  • Gemcitabine and carboplatin
  • Atezolizumab (only for patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression)
  • Pembrolizumab (only for patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression)

For subsequent systemic therapy for locally advanced or metastatic disease stage IV, the NCCN recommends participation in clinical trials of new agents. Preferred agents are as follows:

  • Post-platinum: Pembrolizumab (category 1)
  • Post–checkpoint inhibitor, cisplatin ineligible, chemotherapy naïve: Gemcitabine/carboplatin
  • Post–checkpoint inhibitor, cisplatin eligible, chemotherapy naïve: Gemcitabine and cisplatin or DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) with growth factor support

Muscle-invasive disease – EAU recommendations

The EAU notes that radical cystectomy has traditionally been recommended for patients with muscle-invasive bladder cancer (MIBC), T2-T4a, N0-Nx, M0. [144] Other indications include the following:

  • High-risk and recurrent non–muscle-invasive tumors
  • T1G3 tumors that are unresponsive or refractory to BCG, or that relapse after BCG therapy
  • Extensive papillary disease that cannot be controlled with TURBT and intravesical therapy alone

Other EAU recommendations for muscle-invasive disease are as follows [144] :

  • Base the decision on bladder-sparing treatment or radical cystectomy in elderly/frail patients with invasive bladder cancer on tumor 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

Bladder-sparing treatments for localized disease:

  • Offer surgical intervention or multimodality treatments (MMT) as primary curative therapeutic approaches for localized bladder cancer.
  • Offer MMT as an alternative to selected well-informed and compliant patients, especially those for whom radical cystectomy is not an option.
  • Do not offer TURBT alone as a curative treatment option, as most patients will not benefit.
  • Do not offer radiotherapy or chemotherapy alone as primary therapy for localized bladder cancer.

Treatment failure:

  • Discuss immediate radical treatment (radical cystectomy) with patients at the highest risk of tumor progression (ie, high grade, multifocality, CIS, tumor size).
  • Offer radical cystectomy to patients with tumors that are unresponsive t o BCG therapy .
  • In patients with BCG-unresponsive tumors who are not candidates for radical cystectomy due to comorbidities, offer preservation strategies (intravesical chemotherapy, chemotherapy and microwave-induced hyperthermia, electromotive administration of chemotherapy, intravesical- or systemic immunotherapy; preferably within clinical trials).

Neoadjuvant therapy:

  • Offer neoadjuvant chemotherapy for T2-T4a, cN0M0 bladder cancer.
  • Always use a cisplatin-based combination regimen for neoadjuvant chemotherapy. Do not offer neoadjuvant chemotherapy to patients who are ineligible for cisplatin-based combination chemotherapy.
  • Only offer neoadjuvant immunotherapy to patients within a clinical trial setting.
  • Do not offer preoperative radiotherapy (RT) for operable MIBC since it will only result in down-staging, but will not improve survival.
  • Do not offer preoperative RT when subsequent radical cystectomy with urinary diversion is planned.

Radical cystectomy:

  • Do not delay radical cystectomy for > 3 months, as that increases the risk of progression and cancer-specific mortality.
  • In hospitals where radical cystectomy is offered, at least 10, and preferably > 20, of the procedures should be performed annually.
  • Do not offer sexual-function–preserving radical cystectomy to men as standard therapy for MIBC; offer these techniques to men motivated to preserve their sexual function, since the majority will benefit. Select male patients based on organ-confined disease, with absence of any kind of tumor at the level of the prostate, prostatic urethra, or bladder neck.

  • Do not offer pelvic organ–preserving radical cystectomy to women as standard therapy for muscle-invasive bladder cancer. Select female patients based on organ-confined disease, with absence of tumor in bladder neck or urethra.

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

  • Preoperative bowel preparation is not mandatory. "Fast track" measurements may reduce the time to bowel recovery.
  • Perform a lymph node dissection as an integral part of radical cystectomy.    
  • Do not preserve the urethra if margins are positive.
  • Offer pharmacological prophylaxis, such as low molecular weight heparin, to patients who have undergone radical cystectomy, starting the first day post-surgery, for a period of 4 weeks.

Adjuvant therapy:

  • Offer adjuvant cisplatin-based combination chemotherapy to patients with pT3/4 and/or pN+ disease if no neoadjuvant chemotherapy has been given.
  • Only offer immunotherapy with a checkpoint inhibitor in a clinical trial setting.

Recurrent disease

Recommendations vary by recurrence site, as follows:

  • Local - Offer radiotherapy, chemotherapy, and possibly surgery as options for treatment, either alone or in combination.
  • Distant - Offer chemotherapy as the first option, and consider metastasectomy in case of unique metastasis site.
  • Upper urinary tract – Treat as per guidelines on upper urinary tract urothelial carcinomas.

Secondary urethral tumor should be staged and treated as for primary urethral tumors.

Palliative cystectomy:

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

Metastatic disease

According to the EAU, first-line treatment for cisplatin-eligible patients is with one of the following cisplatin-containing combination chemotherapy regimens [144] :

  • GC (gemcitabine plus cisplatin)
  • MVAC (methotrexate, vinblastine, Adriamycin [doxorubicin], cisplatin), preferably with granulocyte colony-stimulating factor (G-CSF)
  • HD-MVAC (high-dose methotrexate, vinblastine, doxorubicin, cisplatin) with G-CSF
  • PCG (paclitaxel, cisplatin, gemcitabine)

Do not offer carboplatin and non-platinum combination chemotherapy.

First-line treatment in patients ineligible (unfit) for cisplatin whose tumors are programmed death ligand 1 (PD-L1)–positive is with the checkpoint inhibitors pembrolizumab or atezolizumab. Offer carboplatin combination chemotherapy if PD-L1 is negative.

Other recommendations are as follows:

  • Offer pembrolizumab to patients who experience progression during or after platinum-based combination chemotherapy for metastatic disease. Alternatively, offer treatment within a clinical trial setting.
  • Offer zoledronic acid or denosumab for supportive treatment in case of bone metastases.
  • Offer vinflunine as subsequent-line treatment only if immunotherapy, combination chemotherapy, fibroblast growth factor receptor 3 (FGFR3) inhibitor therapy, or inclusion in a clinical trial is not feasible.

European Society for Medical Oncology (ESMO) recommendations for treatment of metastatic bladder cancer are as follows [146] :

  • Radical cystectomy with pelvic lymphadenectomy

  • Age is not a limiting factor for surgery (however, 6-month overall survival is lower in octagenarians than in patients younger than age 80)

  • Organ preservation therapy is reasonable for patients seeking an alternative to cystectomy or as a palliative treatment for those who are medically unfit for surgery

  • External beam radiotherapy may be considered as part of a multimodality bladder-preserving approach

  • Cisplatin-based neoadjuvant chemotherapy is appropriate before radical cystectomy or radiotherapy; standard regimens include GC and MVAC

For patients who cannot receive cisplatin-based chemotherapy, palliation with carboplatin-based regimen or single-agent taxane or gemcitabine is an option.

There is insufficient evidence for the routine use of adjuvant chemotherapy; high-risk patients who did not receive neoadjuvant chemotherapy may benefit from adjuvant treatment.

When the patient is unfit for cystectomy, radiotherapy can also be offered for palliation (bleeding, pain)

According to NCCN guidelines, in patients with locally advanced/metastatic bladder cancer who are platinum-ineligible and whose tumors have no PD-L1 expression, preferred first-line regimens are atezolizumab and pembrolizumab. Other options include gemcitabine and gemcitabine/paclitaxel. Patients who are cisplatin-ineligible but carboplatin-eligible should receive carboplatin over immune checkpoint inhibitors in first-line treatment. [1, 150]

 

 

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Upper Urinary Tract Urothelial Cell Carcinoma

Diagnosis

The NCCN states that patients with suspected upper tract urothelial carcinoma (UTUC), including both renal pelvis and ureteral tumors, should undergo cystoscopy, upper tract imaging with retrograde ureteropyelography, ureteroscopy with biopsy and/or selective washings, and optional urine cytology. A chest x-ray can help to evaluate for metastatic disease. Additionally, evaluation for Lynch syndrome should be considered. given the syndrome's high prevalence in patients with UTUC. [1]

Treatment

The NCCN provides treatment recommendations based on the location and disease extent, as follows [1] :

  • Tumors that originate in the upper ureter typically are treated with nephroureterectomy with a cuff of bladder plus regional lymphadenectomy for high-grade tumors; a portion of the bladder is removed to ensure complete removal of the entire intramural ureter
  • Endoscopic resection of upper ureter tumors is acceptable, but those are more commonly treated with nephroureterectomy with a bladder cuff, plus regional lymphadenectomy for high-grade tumors.
  • Neoadjuvant chemotherapy should be considered in select patients, including patients with retroperitoneal lymphadenopathy, bulky (> 3cm) high-grade tumor, sessile histology, or suspected parenchymal invasion.
  • Tumors that originate in the mid-portion are divided into small, low-grade tumors and large, high-grade tumors. 
  • Treatment of small, low-grade tumors is excision and ureteroureterostomy or complete ureterectomy and ileal ureter in highly selected patients; endoscopic resection; or, if the tumor cannot be managed endoscopically and the ureteral extent is too great, nephroureterectomy with a cuff of bladder may be considered.
  • Nephroureterectomy with a cuff of bladder and regional lymphadenectomy is used for larger, high-grade lesions; neoadjuvant chemotherapy should be considered for selected patients.
  • Distal ureteral tumors may be managed with a distal ureterectomy and reimplantation of the ureter (preferred if clinically feasible); endoscopic resection; or, in some cases, a nephroureterectomy with a cuff of bladder, with the addition of regional lymphadenectomy recommended for high-grade tumors.
  • Nephroureterectomy is contraindicated in patients with bilateral disease, solitary kidney, renal insufficiency, or a hereditary predisposition to genitourinary cancer; such patients should receive nephron-sparing treatment.

The EUA provides recommendations for conservative management, as well as recommendations for radical nephroureterectomy (RNU). The indications for RNU are as follows: [145]

  • Suspicion of infiltrating UTUC on imaging
  • High-grade tumor
  • Multifocality (in patients with two functional kidneys)
  • Noninvasive but large (>2 cm) UTUC
  • Neoadjuvant chemotherapy should be considered in all of these categories (however, this has not been adequately studied in randomized clinical trials)

Recommendations regarding RNU include the following:

  • Open and laparoscopic access are equivalent in terms of efficacy
  • Bladder cuff removal is imperative
  • Several techniques for bladder cuff excision are acceptable, except stripping
  • Lymphadenectomy is recommended
  • Postoperative instillation chemotherapy in the bladder may prevent recurrence

The indications for conservative management are as follows:

  • Unifocal tumor
  • Tumor < 1 cm
  • Low-grade tumor
  • No evidence of an infiltrative lesion on CT urography
  • Understanding of close follow-up

Recommendations regarding conservative treatment include the following:

  • Flexible ureteroscopy is preferable to rigid ureteroscopy
  • A percutaneous approach remains an option in small, low-grade calyceal tumors unsuitable for ureteroscopic treatment
  • Ureteroureterostomy for noninvasive low-grade tumors of the proximal ureter or mid-ureter that cannot be removed completely by endoscopic means, and for high-grade or invasive tumors when renal-sparing surgery (RSS) for preservation of renal function is a goal
  • Complete distal ureterectomy and neocystostomy for noninvasive, low-grade tumors in the distal ureter that cannot be removed completely by endoscopic means and for high-grade, locally invasive tumors

Follow-up and surveillance

The EAU recommends follow-up for at least 5 years after treatment of UTUC; however, the surveillance schedules specified are all grade C recommendations. Surveillance schedules are as follows [145] :

  • Noninvasive tumors treated with RNU - Cystoscopy and urinary cytology at 3 months and then annually; CT annually
  • Invasive tumors treated with RNU - Cystoscopy and urinary cytology at 3 months and then annually; CT urography every 6 months over 2 years and then annually. After 5 years of recurrence free years, recurrence risk is low and cystoscopy can be replaced with a less invasive surveillance regimen.
  • If there are concerning lesions on cystoscopy, conducting endoscopy under anesthesia to obtain bladder biopsies is strongly recommended.
  • Conservatively managed tumors - Urinary cytology and CT urography at 3, 6, and 12 months and annually thereafter; cystoscopy, ureteroscopy, and cytology in situ at 3 and 6 months, then every 6 months over 2 years, then annually
  • There is a weak recommendation to conduct ultrasound if cystoscopy is not possible or refused by a patient.
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