Sections

Bladder Cancer

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).^[147]
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^{[148, 69, 149]}
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^[150]
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)

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.^[151]

No major organization recommends screening for bladder cancer in asymptomatic adults. The American Academy of Family Physicians supports the USPSTF recommendation.^[152] 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.^[153]

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.^[148]

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.^[148] 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

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^[148]:

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.^[147]

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.^{[147, 112]}

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.^[149]

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.^{[148, 147, 69, 150, 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.^{[148, 147, 69, 150, 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

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).^{[147, 69, 150, 1]}

Urothelial carcinoma is histologically graded as low grade (LG) or high grade (HG). 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; 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^[148]:

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.

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 detrusor muscle is present in the specimen, strongly consider repeating resection (except in cases of Ta LG/G1 tumors and primary carcinoma in situ [CIS]^[69]). 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 with bacillus Calmette-Guérin (BCG) after TURBT is recommended and is superior to intravesical chemotherapy for preventing tumor recurrence^{[147, 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, and small papillary recurrences detected more than 1 yr after a previous TURBT: One immediate instillation of chemotherapy (eg, mitomycin, epirubicin, pirarubicin, gemcitabine) 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 (induction plus 3-weekly instillations at 3, 6, 12, 18, 24, 30, and 36 mo); the additional beneficial effect of the second and third years of maintenance BCG should be weighed against added costs, adverse effects, and problems connected with BCG shortages; immediate radical cystectomy may also be discussed with the patient
Very-high-risk tumors: Discuss immediate 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^[147]:

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 European Society for Medical Oncology (ESMO) recommendations for treatment of NMIBC are as follows^[150]:

Follow a risk-stratified approach with TURBT and intravesical chemotherapy or BCG in intermediate- and high-risk patients.
Offer radical cystectomy in subsets of patients with very-high-risk disease. Radical cystectomy should be carried out in patients with CIS or high-grade T1 disease unresponsive to BCG, due to the high risk of progression.
Pembrolizumab or nadofaragene firadenovec can be considered in patients with BCG-unresponsive disease who are ineligible for or refuse cystectomy.
In patients with high-risk NMIBC, administer full-dose intravesical BCG for one to three years; treat for at least one year; three-year maintenance is more effective for preventing recurrences.

The AUA/SUO recommendations for intravesical therapy are as follows^[147]:

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.

The ESMO recommendations for intravesical therapy after TURBT are as follows^[150]:

In patients with low-risk NMIBC and those with small papillary recurrences detected > 1 year after the previous tumor, immediately administer a single dose of intravesical chemotherapy (eg, mitomycin C).
In patients with intermediate-risk NMIBC, administer additional courses of intravesical therapy, consisting of either chemotherapy instillations for a maximum of one year or induction therapy with six BCG instillations at weekly intervals, followed by maintenance therapy with three BCG instillations each at 3, 6, and 12 months after the start of the induction cycle.
In patients with high-risk NMIBC, treat with full-dose intravesical BCG for 1-3 years.

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^[147]:

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 bladder cancer (MIBC) 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 provides a survival benefit in MIBC; the preferred regimen is DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) with growth factor support for three to six cycles.
For adjuvant therapy in patients who did not receive platinum-based neoadjuvant therapy, DDMAVC with growth factor support is preferred; for patients who did receive platinum-based neoadjuvant therapy, nivolumab is recommended.
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 locally advanced or metastatic disease, first-line chemotherapy regimens are as follows:

Gemcitabine and cisplatin, followed by avelumab maintenance therapy (ca (category 1 recommendation)
DDMVAC with growth factor support, followed by avelumab maintenance therapy (ca (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, followed by avelumab maintenance therapy (category 1)
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 or other chemotherapy: Pembrolizumab (category 1 for post platinum)
Post–checkpoint inhibitor, cisplatin ineligible, chemotherapy naïve: Enfortumab vedotin-ejfv or gemcitabine and 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 MIBC, T2-T4a, N0-Nx, M0.^[148]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^[148]:

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.

Muscle-invasive disease – ESMO recommendations

ESMO guidelines recommend multidisciplinary care via tumor board discussions and/or directed consultations with a medical oncologist, radiation oncologist, and urologist.^[150]Other recommendations are as follows:

Radical cystectomy with pelvic lymph node dissection (PLND) is the standard treatment for MIBC cT2-T4a, N0 M0.
Cystectomy can be considered in patients with radiologic suspicion of node-positive disease (cN1).
Three to four cycles of cisplatin-based neoadjuvant chemotherapy should be given for MIBC. Cisplatin-gemcitabine or accelerated methotrexate, vinblastine, Adriamycin (doxorubicin) and cisplatin (MVAC) are the regimens most widely used and can be recommended. Cross-sectional imaging should be performed after chemotherapy and before cystectomy.
Organ-preservation therapy with RT is a reasonable option for patients seeking an alternative to radical cystectomy and an option for those who are medically unfit for surgery.
The trimodality combination of TURBT, RT, and chemotherapy is the preferred organ-preservation protocol.
Palliative RT can be offered for relief of bleeding or pain.
Adjuvant RT (with or without radiosensitizing chemotherapy is not standard treatment for MIBC.
There is weak evidence to support the use of adjuvant cisplatin-based adjuvant chemotherapy in patients who did not receive neoadjuvant therapy; neoadjuvant chemotherapy is preferred.

Metastatic disease

According to the EAU, first-line treatment for cisplatin-eligible patients is with one of the following cisplatin-containing combination chemotherapy regimens^[148]:

GC (gemcitabine plus cisplatin)
MVAC, 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.

ESMO recommendations for treatment of metastatic bladder cancer are as follows^[150]:

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, 154]}

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:^[149]

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^[149]:

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.

Medication

[Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer. NCCN.org. Available at http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Version 3.2022 — December 21, 2022; Accessed: January 18, 2023.
Escudero DO, Shirodkar SP, Lokeshwar VB. Bladder Carcinogenesis and Molecular Pathways. Lokeshwar VB. Bladder Tumors: Molecular Aspects and Clinical Management. New York: Springer Science; 2010. 23-41.
Spruck CH 3rd, Ohneseit PF, Gonzalez-Zulueta M, Esrig D, Miyao N, Tsai YC, et al. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res. 1994 Feb 1. 54(3):784-8. [QxMD MEDLINE Link].
Trias I, Algaba F, Condom E, Español I, Seguí J, Orsola I, et al. Small cell carcinoma of the urinary bladder. Presentation of 23 cases and review of 134 published cases. Eur Urol. 2001 Jan. 39(1):85-90. [QxMD MEDLINE Link].
Compérat EM, Burger M, Gontero P, Mostafid AH, Palou J, Rouprêt M, et al. Grading of Urothelial Carcinoma and The New "World Health Organisation Classification of Tumours of the Urinary System and Male Genital Organs 2016". Eur Urol Focus. 2019 May. 5 (3):457-466. [QxMD MEDLINE Link]. [Full Text].
Bessette PL, Abell MR, Herwig KR. A clinicopathologic study of squamous cell carcinoma of the bladder. J Urol. 1974 Jul. 112(1):66-7. [QxMD MEDLINE Link].
Faysal MH. Squamous cell carcinoma of the bladder. J Urol. 1981 Nov. 126(5):598-9. [QxMD MEDLINE Link].
Lagwinski N, Thomas A, Stephenson AJ, Campbell S, Hoschar AP, El-Gabry E, et al. Squamous cell carcinoma of the bladder: a clinicopathologic analysis of 45 cases. Am J Surg Pathol. 2007 Dec. 31(12):1777-87. [QxMD MEDLINE Link].
El-Sebaie M, Zaghloul MS, Howard G, Mokhtar A. Squamous cell carcinoma of the bilharzial and non-bilharzial urinary bladder: a review of etiological features, natural history, and management. Int J Clin Oncol. 2005 Feb. 10(1):20-5. [QxMD MEDLINE Link].
Heyns CF, van der Merwe A. Bladder cancer in Africa. Can J Urol. 2008 Feb. 15(1):3899-908. [QxMD MEDLINE Link].
Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007 Sep. 213(1):91-8. [QxMD MEDLINE Link]. [Full Text].
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005 Apr. 16(2):139-49. [QxMD MEDLINE Link].
Fadl-Elmula I. Chromosomal changes in uroepithelial carcinomas. Cell Chromosome. 2005 Aug 7. 4:1. [QxMD MEDLINE Link]. [Full Text].
Knowles MA. Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese?. Carcinogenesis. 2006 Mar. 27(3):361-73. [QxMD MEDLINE Link].
Salinas-Sánchez AS, Lorenzo-Romero JG, Giménez-Bachs JM, Sánchez-Sánchez F, Donate-Moreno MJ, Rubio-Del-Campo A, et al. Implications of p53 gene mutations on patient survival in transitional cell carcinoma of the bladder: a long-term study. Urol Oncol. 2008 Nov-Dec. 26(6):620-6. [QxMD MEDLINE Link].
Miyamoto H, Shuin T, Ikeda I, Hosaka M, Kubota Y. Loss of heterozygosity at the p53, RB, DCC and APC tumor suppressor gene loci in human bladder cancer. J Urol. 1996 Apr. 155(4):1444-7. [QxMD MEDLINE Link].
Karam JA, Lotan Y, Karakiewicz PI, Ashfaq R, Sagalowsky AI, Roehrborn CG, et al. Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy. Lancet Oncol. 2007 Feb. 8(2):128-36. [QxMD MEDLINE Link].
Campbell SC, Volpert OV, Ivanovich M, Bouck NP. Molecular mediators of angiogenesis in bladder cancer. Cancer Res. 1998 Mar 15. 58(6):1298-304. [QxMD MEDLINE Link].
Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci U S A. 2009 Aug 18. 106(33):14016-21. [QxMD MEDLINE Link]. [Full Text].
Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 2006 Feb 10. 24(5):778-89. [QxMD MEDLINE Link].
Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P, et al. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies. Int J Cancer. 2000 Apr 15. 86(2):289-94. [QxMD MEDLINE Link].
Fortuny J, Kogevinas M, Chang-Claude J, González CA, Hours M, Jöckel KH, et al. Tobacco, occupation and non-transitional-cell carcinoma of the bladder: an international case-control study. Int J Cancer. 1999 Jan 5. 80(1):44-6. [QxMD MEDLINE Link].
Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011 Aug 17. 306(7):737-45. [QxMD MEDLINE Link]. [Full Text].
Cumberbatch MG, Cox A, Teare D, Catto JW. Contemporary Occupational Carcinogen Exposure and Bladder Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2015 Dec. 1 (9):1282-90. [QxMD MEDLINE Link].
Baris D, Waddell R, Beane Freeman LE, Schwenn M, Colt JS, et al. Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic. J Natl Cancer Inst. 2016 Sep. 108 (9):[QxMD MEDLINE Link].
Nelson R. Arsenic-Contaminated Well Water Boosts Bladder Cancer Risk. Medscape Medical News. Available at http://www.medscape.com/viewarticle/862914. May 5, 2016; Accessed: May 7, 2016.
Stein JP, Skinner EC, Boyd SD, Skinner DG. Squamous cell carcinoma of the bladder associated with cyclophosphamide therapy for Wegener's granulomatosis: a report of 2 cases. J Urol. 1993 Mar. 149(3):588-9. [QxMD MEDLINE Link].
Figueroa JD, Koutros S, Colt JS, Kogevinas M, Garcia-Closas M, et al. Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms. J Natl Cancer Inst. 2015 Nov. 107 (11):[QxMD MEDLINE Link].
El-Bolkainy MN, Mokhtar NM, Ghoneim MA, Hussein MH. The impact of schistosomiasis on the pathology of bladder carcinoma. Cancer. 1981 Dec 15. 48(12):2643-8. [QxMD MEDLINE Link].
Botelho M, Ferreira AC, Oliveira MJ, Domingues A, Machado JC, da Costa JM. Schistosoma haematobium total antigen induces increased proliferation, migration and invasion, and decreases apoptosis of normal epithelial cells. Int J Parasitol. 2009 Aug. 39(10):1083-91. [QxMD MEDLINE Link].
Ahmad I, Barnetson RJ, Krishna NS. Keratinizing squamous metaplasia of the bladder: a review. Urol Int. 2008. 81(3):247-51. [QxMD MEDLINE Link].
Khan MS, Thornhill JA, Gaffney E, Loftus B, Butler MR. Keratinising squamous metaplasia of the bladder: natural history and rationalization of management based on review of 54 years experience. Eur Urol. 2002 Nov. 42(5):469-74. [QxMD MEDLINE Link].
Newman DM, Brown JR, Jay AC, Pontius EE. Squamous cell carcinoma of the bladder. J Urol. 1968 Oct. 100(4):470-3. [QxMD MEDLINE Link].
Faysal MH, Freiha FS. Primary neoplasm in vesical diverticula. A report of 12 cases. Br J Urol. 1981 Apr. 53(2):141-3. [QxMD MEDLINE Link].
Yurdakul T, Avunduk MC, Piskin MM. Pure squamous cell carcinoma after intravesical BCG treatment. A case report. Urol Int. 2005. 74(3):283-5. [QxMD MEDLINE Link].
STUART WT. Carcinoma of the bladder associated with exstrophy. Report of a case and review of the literature. Va Med Mon (1918). 1962 Jan. 89:39-42. [QxMD MEDLINE Link].
Ribeiro JC, Silva C, Sousa L, García P, Santos A. [Squamous cell carcinoma in bladder extrophy]. Actas Urol Esp. 2005 Jan. 29(1):110-2. [QxMD MEDLINE Link].
Gupta S, Gupta IM. Ectopia vesicae complicated by squamous cell carcinoma. Br J Urol. 1976 Aug. 48(4):244. [QxMD MEDLINE Link].
Rieder JM, Parsons JK, Gearhart JP, Schoenberg M. Primary squamous cell carcinoma in unreconstructed exstrophic bladder. Urology. 2006 Jan. 67(1):199. [QxMD MEDLINE Link].
Sheldon CA, Clayman RV, Gonzalez R, Williams RD, Fraley EE. Malignant urachal lesions. J Urol. 1984 Jan. 131(1):1-8. [QxMD MEDLINE Link].
Lin RY, Rappoport AE, Deppisch LM, Natividad NS, Katz W. Squamous cell carcinoma of the urachus. J Urol. 1977 Dec. 118(6):1066-7. [QxMD MEDLINE Link].
SHAW RE. Squamous-cell carcinoma in a cyst of the urachus. Br J Urol. 1958 Mar. 30(1):87-9. [QxMD MEDLINE Link].
Chow YC, Lin WC, Tzen CY, Chow YK, Lo KY. Squamous cell carcinoma of the urachus. J Urol. 2000 Mar. 163(3):903-4. [QxMD MEDLINE Link].
Fujiyama C, Nakashima N, Tokuda Y, Uozumi J. Squamous cell carcinoma of the urachus. Int J Urol. 2007 Oct. 14(10):966-8. [QxMD MEDLINE Link].
Cancer Facts & Figures 2023. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf. Accessed: January 23, 2023.
Cancer Stat Facts: Bladder Cancer. National Cancer Institute. Available at https://seer.cancer.gov/statfacts/html/urinb.html. Accessed: January 23, 2023.
Dawson C, Whitfield H. ABC of Urology. Urological malignancy--II: Urothelial tumours. BMJ. 1996 Apr 27. 312(7038):1090-4. [QxMD MEDLINE Link]. [Full Text].
Schafer EJ, Jemal A, Wiese D, Sung H, Kratzer TB, Islami F, et al. Disparities and Trends in Genitourinary Cancer Incidence and Mortality in the USA. Eur Urol. 2022 Dec 21. [QxMD MEDLINE Link]. [Full Text].
Abrahams NA, Moran C, Reyes AO, Siefker-Radtke A, Ayala AG. Small cell carcinoma of the bladder: a contemporary clinicopathological study of 51 cases. Histopathology. 2005 Jan. 46(1):57-63. [QxMD MEDLINE Link].
Lohrisch C, Murray N, Pickles T, Sullivan L. Small cell carcinoma of the bladder: long term outcome with integrated chemoradiation. Cancer. 1999 Dec 1. 86(11):2346-52. [QxMD MEDLINE Link].
Gouda I, Mokhtar N, Bilal D, El-Bolkainy T, El-Bolkainy NM. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. J Egypt Natl Canc Inst. 2007 Jun. 19(2):158-62. [QxMD MEDLINE Link].
Felix AS, Soliman AS, Khaled H, Zaghloul MS, Banerjee M, El-Baradie M, et al. The changing patterns of bladder cancer in Egypt over the past 26 years. Cancer Causes Control. 2008 May. 19(4):421-9. [QxMD MEDLINE Link].
Elsobky E, El-Baz M, Gomha M, Abol-Enein H, Shaaban AA. Prognostic value of angiogenesis in schistosoma-associated squamous cell carcinoma of the urinary bladder. Urology. 2002 Jul. 60(1):69-73. [QxMD MEDLINE Link].
Griffiths TR, Charlton M, Neal DE, Powell PH. Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance. J Urol. 2002 Jun. 167(6):2408-12. [QxMD MEDLINE Link].
Pycha A, Mian C, Posch B, Haitel A, Mokhtar AA, El-Baz M, et al. Numerical chromosomal aberrations in muscle invasive squamous cell and transitional cell cancer of the urinary bladder: an alternative to classic prognostic indicators?. Urology. 1999 May. 53(5):1005-10. [QxMD MEDLINE Link].
Shaaban AA, Javadpour N, Tribukait B, Ghoneim MA. Prognostic significance of flow-DNA analysis and cell surface isoantigens in carcinoma of bilharzial bladder. Urology. 1992 Mar. 39(3):207-10. [QxMD MEDLINE Link].
Ghoneim MA, Ashamallah AK, Awaad HK, Whitmore WF Jr. Randomized trial of cystectomy with or without preoperative radiotherapy for carcinoma of the bilharzial bladder. J Urol. 1985 Aug. 134(2):266-8. [QxMD MEDLINE Link].
Cheng L, Pan CX, Yang XJ, Lopez-Beltran A, MacLennan GT, Lin H, et al. Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer. 2004 Sep 1. 101(5):957-62. [QxMD MEDLINE Link].
Shahab N. Extrapulmonary small cell carcinoma of the bladder. Semin Oncol. 2007 Feb. 34(1):15-21. [QxMD MEDLINE Link].
Mackey JR, Au HJ, Hugh J, Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival. J Urol. 1998 May. 159(5):1624-9. [QxMD MEDLINE Link].
Choong NW, Quevedo JF, Kaur JS. Small cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer. 2005 Mar 15. 103(6):1172-8. [QxMD MEDLINE Link].
van Rhijn BW, Burger M, Lotan Y, Solsona E, Stief CG, Sylvester RJ, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol. 2009 Sep. 56(3):430-42. [QxMD MEDLINE Link].
Fernandez-Gomez J, Solsona E, Unda M, Martinez-Piñeiro L, Gonzalez M, Hernandez R, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials. Eur Urol. 2008 May. 53(5):992-1001. [QxMD MEDLINE Link].
Lotan Y, Inman B, Porten S. Bladder Neoplasms: Non-Muscle Invasive Bladder Cancer. AUA. Available at https://university.auanet.org/modules/webapps/core/index.cfm#/corecontent/76. March 21, 2021; Accessed: February 1, 2023.
[Guideline] Barocas DA, Boorjian SA, Alvarez RD, Downs TM, Gross CP, Hamilton BD, et al. Microhematuria: AUA/SUFU Guideline. J Urol. 2020 Oct. 204 (4):778-786. [QxMD MEDLINE Link]. [Full Text].
Cha EK, Tirsar LA, Schwentner C, Christos PJ, Mian C, Hennenlotter J, et al. Immunocytology is a strong predictor of bladder cancer presence in patients with painless hematuria: a multicentre study. Eur Urol. 2012 Jan. 61(1):185-92. [QxMD MEDLINE Link].
Strittmatter F, Buchner A, Karl A, Sommer ML, Straub J, Tilki D, et al. Individual learning curve reduces the clinical value of urinary cytology. Clin Genitourin Cancer. 2011 Sep. 9(1):22-6. [QxMD MEDLINE Link].
Lotan Y, Roehrborn CG. Cost-effectiveness of a modified care protocol substituting bladder tumor markers for cystoscopy for the followup of patients with transitional cell carcinoma of the bladder: a decision analytical approach. J Urol. 2002 Jan. 167(1):75-9. [QxMD MEDLINE Link].
[Guideline] Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ). Eur Urol. 2022 Jan. 81 (1):75-94. [QxMD MEDLINE Link]. [Full Text].
Apolo AB, Vogelzang NJ, Theodorescu D. New and promising strategies in the management of bladder cancer. Am Soc Clin Oncol Educ Book. 2015. 35:105-12. [QxMD MEDLINE Link]. [Full Text].
Murphy WM, Crabtree WN, Jukkola AF, Soloway MS. The diagnostic value of urine versus bladder washing in patients with bladder cancer. J Urol. 1981 Sep. 126(3):320-2. [QxMD MEDLINE Link].
Lokeshwar VB, Soloway MS. Current bladder tumor tests: does their projected utility fulfill clinical necessity?. J Urol. 2001 Apr. 165(4):1067-77. [QxMD MEDLINE Link].
Grossman HB, Soloway M, Messing E, Katz G, Stein B, Kassabian V, et al. Surveillance for recurrent bladder cancer using a point-of-care proteomic assay. JAMA. 2006 Jan 18. 295(3):299-305. [QxMD MEDLINE Link].
Al-Sukhun S, Hussain M. Molecular biology of transitional cell carcinoma. Crit Rev Oncol Hematol. 2003 Aug. 47(2):181-93. [QxMD MEDLINE Link].
Halling KC, Kipp BR. Bladder cancer detection using FISH (UroVysion assay). Adv Anat Pathol. 2008 Sep. 15(5):279-86. [QxMD MEDLINE Link].
Soloway MS, Briggman V, Carpinito GA, Chodak GW, Church PA, Lamm DL, et al. Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J Urol. 1996 Aug. 156(2 Pt 1):363-7. [QxMD MEDLINE Link].
van Rhijn BW, van der Poel HG, van der Kwast TH. Urine markers for bladder cancer surveillance: a systematic review. Eur Urol. 2005 Jun. 47 (6):736-48. [QxMD MEDLINE Link].
Hall MC, Chang SS, Dalbagni G, Pruthi RS, Seigne JD, Skinner EC, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol. 2007 Dec. 178(6):2314-30. [QxMD MEDLINE Link].
American Joint Committee on Cancer. Urinary bladder. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.
Svatek RS, Daneshmand S, Singh P. Bladder Neoplasms: Muscle Invasive Bladder Cancer. AUA. Available at https://university.auanet.org/modules/webapps/core/index.cfm#/corecontent/177. March 1, 2021; Accessed: January 23, 2023.
PDQ Adult Treatment Editorial Board. Bladder Cancer Treatment (PDQ®): Health Professional Version. January 18, 2023. [QxMD MEDLINE Link]. [Full Text].
Chedgy EC, Black PC. Radical Cystectomy and the Multidisciplinary Management of Muscle-Invasive Bladder Cancer. JAMA Oncol. 2016 May 5. [QxMD MEDLINE Link]. [Full Text].
Mitin T. Rethinking Radical Cystectomy as the Best Choice for Most Patients With Muscle-Invasive Bladder Cancer. JAMA Oncol. 2016 May 5. [QxMD MEDLINE Link]. [Full Text].
Teo MT, Dyrskjøt L, Nsengimana J, Buchwald C, Snowden H, Morgan J, et al. Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer. Ann Oncol. 2014 Apr. 25 (4):877-83. [QxMD MEDLINE Link]. [Full Text].
Serretta V, Galuffo A, Pavone C, Allegro R, Pavone-MacAluso M. Gemcitabine in intravesical treatment of Ta-T1 transitional cell carcinoma of bladder: Phase I-II study on marker lesions. Urology. 2005 Jan. 65(1):65-9. [QxMD MEDLINE Link].
Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol. 2005 Jul. 174(1):86-91; discussion 91-2. [QxMD MEDLINE Link].
Witjes JA, Hendricksen K. Intravesical pharmacotherapy for non-muscle-invasive bladder cancer: a critical analysis of currently available drugs, treatment schedules, and long-term results. Eur Urol. 2008 Jan. 53(1):45-52. [QxMD MEDLINE Link].
Zaharoff DA, Hoffman BS, Hooper HB, Benjamin CJ Jr, Khurana KK, Hance KW, et al. Intravesical immunotherapy of superficial bladder cancer with chitosan/interleukin-12. Cancer Res. 2009 Aug 1. 69(15):6192-9. [QxMD MEDLINE Link]. [Full Text].
Islam MA, Bhuiyan ZH, Shameem IA. Intravesical adjuvant therapy using mitomycin C. Mymensingh Med J. 2006 Jan. 15(1):40-4. [QxMD MEDLINE Link].
Herr HW, Dalbagni G, Donat SM. Bacillus Calmette-Guérin without maintenance therapy for high-risk non-muscle-invasive bladder cancer. Eur Urol. 2011 Jul. 60(1):32-6. [QxMD MEDLINE Link].
Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol. 2004 Jan. 171(1):135-8. [QxMD MEDLINE Link].
Jichlinski P, Guillou L, Karlsen SJ, Malmström PU, Jocham D, Brennhovd B, et al. Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer--a multicenter study. J Urol. 2003 Jul. 170(1):226-9. [QxMD MEDLINE Link].
Hungerhuber E, Stepp H, Kriegmair M, Stief C, Hofstetter A, Hartmann A, et al. Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology. 2007 Feb. 69(2):260-4. [QxMD MEDLINE Link].
Kausch I, Sommerauer M, Montorsi F, Stenzl A, Jacqmin D, Jichlinski P, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur Urol. 2010 Apr. 57(4):595-606. [QxMD MEDLINE Link].
Waknine Y. FDA Approves Cysview for Cystoscopic Detection of Papillary Bladder Cancer. Medscape Medical News, June 4, 2010. Available at http://www.medscape.com/viewarticle/722923. Accessed: January 10, 2013.
Booth CM, Tannock IF. Benefits of Adjuvant Chemotherapy for Bladder Cancer. JAMA Oncol. 2015 Sep. 1 (6):727-8. [QxMD MEDLINE Link].
Standard or Extended Pelvic Lymphadenectomy in Treating Patients Undergoing Surgery for Invasive Bladder Cancer. ClinicalTrials.gov. ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct2/show/NCT01224665. Accessed: August 17, 2018.
Mukesh M, Cook N, Hollingdale AE, Ainsworth NL, Russell SG. Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the Anglian Cancer Network. BJU Int. 2009 Mar. 103(6):747-52. [QxMD MEDLINE Link].
Brinkman MT, Karagas MR, Zens MS, Schned A, Reulen RC, Zeegers MP. Minerals and vitamins and the risk of bladder cancer: results from the New Hampshire Study. Cancer Causes Control. 2010 Apr. 21(4):609-19. [QxMD MEDLINE Link]. [Full Text].
Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021 Jan. 22 (1):107-117. [QxMD MEDLINE Link]. [Full Text].
O'Donnell MA, Lilli K, Leopold C. Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer. J Urol. 2004 Sep. 172(3):888-93. [QxMD MEDLINE Link].
Nepple KG, Lightfoot AJ, Rosevear HM, O'Donnell MA, Lamm DL. Bacillus Calmette-Guérin with or without interferon a-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol. 2010 Nov. 184(5):1915-9. [QxMD MEDLINE Link].
Kamat AM, Dickstein RJ, Messetti F, Anderson R, Pretzsch SM, Gonzalez GN, et al. Use of fluorescence in situ hybridization to predict response to bacillus Calmette-Guérin therapy for bladder cancer: results of a prospective trial. J Urol. 2012 Mar. 187(3):862-7. [QxMD MEDLINE Link]. [Full Text].
Mulcahy N. FDA Approves Pembrolizumab for High-Risk Bladder Cancer. Medscape Medical News. Available at https://www.medscape.com/viewarticle/923568. January 8, 2020; Accessed: January 9, 2020.
Balar AV, Kulkarni GS, Uchio EM, Boormans J, Mourey L, Krieger LEM, et al. Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG). Journal of Clinical Oncology 37, no. 7_suppl (March 01, 2019) 350-350. [Full Text].
Barlow L, McKiernan JM, Benson MC. Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy. J Urol. 2013 Mar. 189(3):834-9. [QxMD MEDLINE Link].
Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol. 2004 Jan. 171(1):135-8. [QxMD MEDLINE Link].
Jichlinski P, Guillou L, Karlsen SJ, Malmström PU, Jocham D, Brennhovd B, et al. Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer--a multicenter study. J Urol. 2003 Jul. 170(1):226-9. [QxMD MEDLINE Link].
Hungerhuber E, Stepp H, Kriegmair M, Stief C, Hofstetter A, Hartmann A, et al. Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology. 2007 Feb. 69(2):260-4. [QxMD MEDLINE Link].
Fradet Y, Grossman HB, Gomella L, Lerner S, Cookson M, Albala D, et al. A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. J Urol. 2007 Jul. 178(1):68-73; discussion 73. [QxMD MEDLINE Link].
Jocham D, Witjes F, Wagner S, Zeylemaker B, van Moorselaar J, Grimm MO, et al. Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol. 2005 Sep. 174(3):862-6; discussion 866. [QxMD MEDLINE Link].
Stenzl A, Burger M, Fradet Y, Mynderse LA, Soloway MS, Witjes JA, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol. 2010 Nov. 184(5):1907-13. [QxMD MEDLINE Link].
Hermann GG, Mogensen K, Carlsson S, Marcussen N, Duun S. Fluorescence-guided transurethral resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour tissue in Ta/T1 patients: a randomized two-centre study. BJU Int. 2011 Oct. 108(8 Pt 2):E297-303. [QxMD MEDLINE Link].
Tilki D, Reich O, Svatek RS, Karakiewicz PI, Kassouf W, Novara G, et al. Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients. J Urol. 2010 May. 183(5):1757-63. [QxMD MEDLINE Link].
Djaladat H, Bruins HM, Miranda G, Cai J, Skinner EC, Daneshmand S. Reproductive organ involvement in female patients undergoing radical cystectomy for urothelial bladder cancer. J Urol. Dec 2012. 188:2134-2138.
Liedberg, F., Jancke, G., Sörenby, A., et al. Should we refrain from performing oophorectomy in conjunction with radical cystectomy for bladder cancer?. Eur Urol. 2017. 71:851-853.
Nik, N.N., Vang, R., Shih, I.M., et al. Origin and pathogenesis of pelvic (ovarian, tubal, and primary peritoneal) serous carcinoma. Annu Rev Pathol. 2014. 9:27-45.
Davis JW, Castle EP, Pruthi RS, Ornstein DK, Guru KA. Robot-assisted radical cystectomy: an expert panel review of the current status and future direction. Urol Oncol. 2010 Sep-Oct. 28(5):480-6. [QxMD MEDLINE Link].
Chang SS, Cookson MS. Radical cystectomy for bladder cancer: the case for early intervention. Urol Clin North Am. 2005 May. 32(2):147-55. [QxMD MEDLINE Link].
Sánchez-Ortiz RF, Huang WC, Mick R, Van Arsdalen KN, Wein AJ, Malkowicz SB. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol. 2003 Jan. 169(1):110-5; discussion 115. [QxMD MEDLINE Link].
Jürgen E Gschwend 1, Matthias M Heck 2, Jan Lehmann 3, Herbert Rübben 4, Peter Albers 5, Johannes M Wolff 6, et al. Extended Versus Limited Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Survival Results from a Prospective, Randomized Trial. European Urology. Apr 2019. 75:604-611. [QxMD MEDLINE Link].
Raghavan D, Burgess E, Gaston KE, Haake MR, Riggs SB. Neoadjuvant and adjuvant chemotherapy approaches for invasive bladder cancer. Semin Oncol. 2012 Oct. 39(5):588-97. [QxMD MEDLINE Link].
Winquist E, Kirchner TS, Segal R, Chin J, Lukka H. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol. 2004 Feb. 171(2 Pt 1):561-9. [QxMD MEDLINE Link].
Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28. 349(9):859-66. [QxMD MEDLINE Link].
Herr HW, Faulkner JR, Grossman HB, Natale RB, deVere White R, Sarosdy MF, et al. Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol. 2004 Jul 15. 22(14):2781-9. [QxMD MEDLINE Link].
von der Maase H1, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18. 17:3068-77.
Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1. 29(16):2171-7. [QxMD MEDLINE Link]. [Full Text].
Mooso BA, Vinall RL, Mudryj M, Yap SA, deVere White RW, Ghosh PM. The role of EGFR family inhibitors in muscle invasive bladder cancer: a review of clinical data and molecular evidence. J Urol. 2015 Jan. 193 (1):19-29. [QxMD MEDLINE Link].
Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015 Jan. 16 (1):76-86. [QxMD MEDLINE Link].
Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul. 15(7):2564-9. [QxMD MEDLINE Link].
Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan. 42(1):50-4. [QxMD MEDLINE Link].
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20. 23(21):4602-8. [QxMD MEDLINE Link].
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20. 23(21):4602-8. [QxMD MEDLINE Link].
Iwasaki K, Obara W, Kato Y, Takata R, Tanji S, Fujioka T. Neoadjuvant gemcitabine plus carboplatin for locally advanced bladder cancer. Jpn J Clin Oncol. 2013 Feb. 43(2):193-9. [QxMD MEDLINE Link].
Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009 Sep 20. 27(27):4454-61. [QxMD MEDLINE Link].
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 Mar 4. [QxMD MEDLINE Link].
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7. 389 (10064):67-76. [QxMD MEDLINE Link].
Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24. 391 (10122):748-757. [QxMD MEDLINE Link].
Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Jan 25. [QxMD MEDLINE Link].
Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3. 384 (22):2102-2114. [QxMD MEDLINE Link]. [Full Text].
Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol. 2017 Apr 4. JCO2016716795. [QxMD MEDLINE Link].
Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov. 18 (11):1483-1492. [QxMD MEDLINE Link].
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017 Mar 16. 376 (11):1015-1026. [QxMD MEDLINE Link].
Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1. 41 (1):22-31. [QxMD MEDLINE Link]. [Full Text].
Loriot Y, et al; BLC2001 Study Group. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 Jul 25. 381 (4):338-348. [QxMD MEDLINE Link].
Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10. 37 (29):2592-2600. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Joint Guideline. AUA. Available at https://www.auanet.org/guidelines/bladder-cancer-non-muscle-invasive-guideline. 2020; Accessed: February 1, 2023.
[Guideline] Witjes JA, Bruins HM, Cathomas R, Compérat EM, Cowan NC, Gakis G, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol. 2020 Apr 29. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Rouprêt M, Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update. Eur Urol. 2021 Jan. 79 (1):62-79. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, et al. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Mar. 33 (3):244-258. [QxMD MEDLINE Link]. [Full Text].
[Guideline] U.S. Preventive Services Task Force. Final Recommendation Statement: Bladder Cancer in Adults: Screening. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/bladder-cancer-in-adults-screening. May 2019; Accessed: May 6, 2020.
Clinical Preventive Service Recommendation: Bladder Cancer. American Academy of Family Physicians. Available at https://www.aafp.org/family-physician/patient-care/clinical-recommendations/all-clinical-recommendations/bladder-cancer.html. Accessed: February 2, 2023.
Bladder Cancer. American Cancer Society. Available at https://www.cancer.org/cancer/bladder-cancer.html. Accessed: February 2, 2023.
Flaig TW. NCCN Guidelines Updates: Management of Muscle-Invasive Bladder Cancer. J Natl Compr Canc Netw. 2019 May 1. 17 (5.5):591-593. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

In an ileal conduit, a small segment of ileum is taken out of continuity with the gastrointestinal tract but is maintained on its mesentery. Ureters are anastomosed to one end of this ileal segment, and the other end is brought out as a stoma to the abdominal wall.
In an Indiana pouch, a urinary reservoir is created from detubularized right colon and an efferent limb of terminal ileum. Terminal ileum is plicated and brought to the abdominal wall. The continence mechanism is the ileocecal valve.
In an orthotopic neobladder, a segment of ileum is used to construct a neobladder, which is connected to the urethra. Orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder.
Bladder cancer. The classic appearance of carcinoma in situ is as a flat, velvety patch. However, using special staining techniques such as 5-aminolevulinic acid, it has been shown that significant areas of carcinoma in situ are easily overlooked by conventional cystoscopy. Courtesy of Abbott and Vysis Inc.
Bladder cancer. Papillary bladder tumors such as this one are typically of low stage and grade (Ta-G1). Courtesy of Abbott and Vysis Inc.
Bladder cancer. Sessile lesions as shown usually invade muscle, although occasionally a tumor is detected at the T1-G3 stage prior to muscle invasion. Courtesy of Abbott and Vysis Inc.
Bladder cancer. Photograph in which fluorescence in situ hybridization centromere staining identifies aneuploidy of chromosome 3. Multiple instances of overexpression of the chromosome (note the multiple red dots, which identify centromeres of this chromosome) prove aneuploidy.
Bladder cancer. Cross-section through the bladder, uterus, and vagina with squamous cell carcinoma of the bladder infiltrating through the bladder wall into the vaginal wall.
Bladder cancer. High power, Pap stain showing high grade urothelial carcinoma on a bladder wash cytology.
Bladder cancer, Intermediate power, H&E stain of urothelial carcinoma in situ. The superficial cells shed into the urine and correlate with those seen in cytologic bladder washing or urine cytology.
Bladder cancer. High power, H&E stain of high grade urothelial carcinoma. This tumor is now invasive into the muscularis propria (smooth muscle seen in center of image).
Bladder cancer. Histopathology of bladder shows eggs of Schistosoma haematobium surrounded by intense infiltrates of eosinophils and other inflammatory cells.
Bladder cancer. (A) When infused into the bladder, the optical imaging agent hexaminolevulinate (Cysview) accumulates preferentially in malignant cells. (B) On blue-light cystoscopy, the collection of hexaminolevulinate within tumors is visible as bright red spots. Courtesy of Gary David Steinberg, MD, FACS.

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Table 1. Clinical Findings and Recommended Action in Patients with Negative Cystoscopy

Cystoscopy Findings	Urine Cytology Findings	*FISH Findings**	Action
Negative	Negative	Negative†	Routine follow-up
Negative	Negative	Positive‡	Increased frequency of surveillance, whether FISH findings are false positive or anticipatory positive
Negative	Positive	Negative or positive	Cancer until proven otherwise Upper tract imaging with contrast Cystoscopy with random bladder and urethral biopsies, retrograde pyelography, selective ureteral washings, and/or ureteroscopy Evaluate urethra Increased frequency of surveillance upon negative findings
*FISH - Fluorescent in situ hybridization. †Negative predictive value 95%. ‡Positive predictive value 30%.

Table 2. Recurrence and Progression Rates at 5 Years for Ta, T1, and CIS TCC of the Bladder Treated With BCG

Stage	Recurrence, %	Progression, %
Ta	55	11
T1	61	31
CIS	45	23
G1	61	2-4
G2	56	5-7
G3	50-70	30-40

Table 3. Most Common Complications of Radical Cystectomy

Early Complications	Rate, %	Late Complications	Rate, %
Ileus	10	Small-bowel obstruction	7.4
Wound infection	5.5	Ureteroenteric stricture	7.0
Sepsis	4.9	Renal calculi	3.9
Pelvic abscess	4.7	Acute pyelonephritis	3.1
Hemorrhage	3.4	Parastomal hernia	2.8
Wound dehiscence	3.3	Stomal stenosis	2.8
Bowel obstruction	3.0	Incisional hernia	2.2
Enterocutaneous fistula	2.2	Fistula	1.3
Rectal injury	2.2	Rectal complications	< 1

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Author

Kara N Babaian, MD, FACS Assistant Professor, Director of Urologic Oncology, Division of Urology, Southern Illinois University School of Medicine

Kara N Babaian, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society of Clinical Oncology, American Urological Association, European Association of Urology, North Central Section of the American Urological Association (AUA), Society of Urologic Oncology, Society of Women in Urology

Disclosure: Participation in a clinical trial for: Janssen.

Coauthor(s)

Parker G Adams, BS DO Candidate, Kansas City University of Medicine and Biosciences College of Osteopathic Medicine

Parker G Adams, BS is a member of the following medical societies: American Urological Association

Disclosure: Nothing to disclose.

Courtney McClure, DO Resident Physician, Department of Urology, Ascension Healthcare

Disclosure: Nothing to disclose.

Brandon Tompkins, BS DO Candidate, Kansas City University of Medicine and Biosciences College of Osteopathic Medicine

Disclosure: Nothing to disclose.

Megan McMurray, DO Resident Physician, Department of Urology, Southern Illinois University School of Medicine

Megan McMurray, DO is a member of the following medical societies: American Association of Clinical Urologists, American Urological Association, Association of Women Surgeons, Society of Women in Urology

Disclosure: Nothing to disclose.

Chief Editor

Bradley Fields Schwartz, DO, FACS Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine

Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoscopic and Robotic Surgeons, Society of University Urologists

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Endourological Society Board of Directors; President Elect North Central Section of the American Urological Association<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical.

Additional Contributors

Gary D Steinberg, MD, FACS Professor and Director, Perlmutter Cancer Center, Goldstein Bladder Cancer Program, NYU Langone Health, NYU Urology Associates

Gary D Steinberg, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Society of Clinical Oncology, American Urological Association, International Society of Urology, Society of Laparoscopic and Robotic Surgeons, Society of Urologic Oncology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Heat Biologics; CG Oncology; PhotoCure; Merck; Roche/Genentech; Ciclomed; Taris Biomedical (now Janssen); MDxHealth; Fidia Farmaceuticals; Urogen, Ferring; Aduro; Boston Scientific; Bristol Myers Squibb; Astra Zeneca; Pfizer, Janssen; others<br/>Member of Clinical Trial Protocol Committees for: for: Merck; BMS; Janssen; CG Oncology; Pfizer; PhotoCure; Fidia; Seagen; Protara.

Kush Sachdeva, MD Southern Oncology and Hematology Associates, Inspira Health Network

Disclosure: Nothing to disclose.

Bagi RP Jana, MD, MBA, MHA, FACP Professor of Cancer Medicine, MD Anderson Cancer Center; Professor of Medicine, University of Texas Medical Branch at Galveston

Bagi RP Jana, MD, MBA, MHA, FACP is a member of the following medical societies: American Cancer Society, American Medical Association, American Society of Clinical Oncology, SWOG

Disclosure: Nothing to disclose.

Acknowledgements

Sujeet S Acharya, MD Resident Physician, Department of Surgery, Section of Urology, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine