Overview of the initial approach and management of urothelial bladder cancer

INTRODUCTION — Bladder cancer is the most common malignancy involving the urinary system. Urothelial (formerly called transitional cell) carcinoma is the predominant histologic type in the United States and Europe, where it accounts for approximately 90 percent of all bladder cancers. In other areas of the world, non-urothelial carcinomas are more frequent. Less commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

The spectrum of urothelial bladder cancer at presentation includes non-muscle invasive, muscle invasive, and metastatic disease. The extent of disease reflects its natural history and determines treatment and prognosis.

This topic provides an overview of the initial approach to and management of urothelial carcinoma of the bladder. More detailed discussions of specific issues are found in associated topics, as indicated below.

The management of urothelial tumors arising at other sites is discussed separately, as are other types of bladder cancer:

●(See "Urethral cancer".)

●(See "Non-urothelial bladder cancer".)

●(See "Small cell carcinoma of the bladder".)

DIAGNOSIS AND STAGING — The initial approach to diagnosis and evaluation is summarized in the algorithm (algorithm 1).

Diagnosis — Patients with bladder cancer typically present with gross or microscopic hematuria, although irritative and obstructive voiding symptoms (frequency, urgency, dysuria, nocturia) can be the initial presentation.

In individuals over the age of 40 years, the presence of otherwise unexplained microscopic or gross hematuria requires evaluation of the bladder and upper urinary tract in order to rule out urinary tract malignancy. A full evaluation of the entire urinary tract is indicated in such patients, unless there is clear evidence of glomerular bleeding or urinary tract infection. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Clinical presentation' and "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Initial evaluation'.)

Cystoscopy is the gold standard for the initial diagnosis of bladder cancer. Cystoscopy is combined with urine cytology, which may detect lesions that might be missed at cystoscopy or lesions of the upper urinary tract (ureter, renal pelvis). The use of approved voided urine biomarkers may also provide additional diagnostic information. (See "Urine biomarkers for the detection of urothelial (transitional cell) carcinoma of the bladder".)

The initial cystoscopy is typically done in an outpatient setting with a flexible cystoscope. Enhanced endoscopic imaging techniques, including narrow-band imaging and fluorescence cystoscopy (FC), may help identify more papillary tumors and carcinoma in situ lesions, and use of FC is associated with a modest reduction in recurrence of non-muscle invasive bladder cancer. Patients with visible tumors are either biopsied or resected transurethrally to establish the histopathologic diagnosis and provide an initial assessment of the depth of invasion (mucosa, submucosa, muscularis (figure 1)).

Site-directed biopsies are indicated in patients with high-grade cancers and any suspicious erythematous and/or flat lesions. Biopsy of normal-appearing urothelium and prostatic urethra is indicated in patients with a positive urine cytology and no visually apparent tumor within the bladder. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Transurethral resection'.)

The bladder is the source of a positive cytology in approximately 80 percent of patients. Selective catheterization of the ureters/renal pelvis with urine specimens for cytology from the upper tract is required to identify the source of a positive cytology in the absence of an identifiable bladder lesion.

Initial evaluation — Transurethral resection of bladder tumor (TURBT) combined with pelvic examination under anesthesia is the initial step in the staging evaluation and is required in order to assess the histologic grade and depth of invasion.

Imaging of the upper urinary tract by computed tomography (CT) or magnetic resonance imaging (MRI) with intravenous contrast. MRI may also be used to stage primary bladder cancer. Vesical Imaging Reporting and Data System (VI-RADS) is a validated scoring system that is useful for distinguishing between cancers confined to the detrusor muscle and those that are locally advanced (detrusor muscle penetration) [1].

Retrograde ureteropyelography performed at the time of TURBT is indicated to rule out a second primary lesion, even for patients with an established diagnosis of urothelial carcinoma of the bladder.

When the initial evaluation identifies muscle-invasive disease, cross-sectional imaging with CT or MRI and laboratory evaluation is indicated to assess the extent of pelvic disease and exclude the presence of distant metastases [2]. A positive positron emission tomography (PET) scan has a high predictive value for metastatic disease, and fused PET-CT imaging is being used for cancer staging (image 1). Of note, technique and reporting experience are still evolving, and specificity is suboptimal. A negative PET scan does not preclude the presence of occult metastatic disease [3]. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Imaging for metastatic disease'.)

Staging

Primary tumor — For patients with disease limited to the bladder, the depth of invasion of the primary tumor is the most important prognostic variable in determining the risk of recurrence or progression (figure 1). This is integrated into the standard staging system, the tumor, node, metastasis (TNM) system, in which the depth of invasion of the primary tumor conveys important prognostic information (table 1) [4]. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

●Ta lesions – Ta tumors are papillary (exophytic) lesions that tend to recur.

●Tis – Tis (also known as carcinoma in situ [CIS]) is a high-grade intraepithelial neoplasm without invasion into subepithelial connective tissue.

●T1 lesions – T1 tumors invade the submucosa or lamina propria and are usually high grade.

●T2 lesions – Invasion into muscle is present in T2 lesions. For T2 tumors, cystectomy is considered standard therapy. When muscle invasion is present, the probability of nodal and distant metastases is increased.

●T3 lesions – T3 tumors extend beyond muscle into the perivesical fat. CT or MRI scans may help to identify disease that has spread outside the bladder, and additional information may be provided by PET scans (image 2 and image 3 and image 4). (See 'Initial evaluation' above.)

●T4 lesions – The TNM system differentiates tumors extending into adjacent organs (T4) from those extending into perivesical fat (T3). Tumor invading the prostate, vagina, uterus, or bowel is classified as T4a, while tumor fixed to the abdominal wall, pelvic wall, or other organs is T4b.

Regional lymph nodes and distant metastases — The presence of involvement of regional lymph nodes or distant metastases represents advanced disease (table 1). Involvement of a single lymph node within the true pelvis constitutes N1 disease, while involvement of multiple lymph nodes within the true pelvis constitutes N2 disease. If disease has spread to the common iliac lymph nodes, this is classified as N3, and if there is lymph node involvement beyond the common iliac lymph nodes, this is considered distant metastasis (M1a). Involvement of more distant organs constitutes M1b disease.

In the eighth edition (2017) of the AJCC TNM staging system, patients with regional lymph node involvement or distant metastases are staged as follows [4]:

●Stage III disease – Disease involving lymph nodes in the true pelvis (N1-N3) in combination with a T1-T4a primary tumor.

●Stage IVA disease – Disease including metastasis to lymph nodes proximal to the aortic bifurcation or a T4b primary tumor regardless of lymph node status.

●Stage IVB disease – Disease involving non-lymph node distant (ie, visceral) metastases.

Differentiation — In addition to depth of invasion, tumors are classified based upon the degree of differentiation. The World Health Organization (WHO) and the International Society of Urologic Pathologists (ISUP) have established a consensus system for urothelial (transitional cell) neoplasms in which urothelial cancer is classified as low grade or high grade based upon the degree of nuclear anaplasia and architectural abnormalities [5]. (See "Pathology of bladder neoplasms", section on 'Classification'.)

Low-grade tumors infrequently progress to a more aggressive phenotype, whereas high-grade tumors have a more aggressive natural history. With rare exception, muscle invasive (T2) urothelial cancer is high grade. The distinction between low-grade and high-grade disease has important implications for risk stratification and management in patients with non-muscle invasive bladder cancer. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

NON-MUSCLE INVASIVE DISEASE

Risk stratification — Based upon the European Association of Urologists (EAU) guidelines, risk groups are assessed based upon both tumor and patient characteristics. Further details are discussed separately. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Risk stratification'.)

Management — For patients with non-muscle invasive bladder cancer, the risk of recurrence and/or disseminated disease after initial treatment is used to guide therapy (algorithm 2).

Conservative management may allow the preservation of a functional bladder based upon transurethral resection of bladder tumor (TURBT), potentially combined with adjuvant intravesical therapy. However, this approach must be balanced against the risk of recurrence or progression. (See 'Transurethral resection' below.)

Patients with low-risk disease are usually managed by TURBT alone plus a single dose of perioperative intravesical chemotherapy given in the operating room or within a few hours of tumor resection [6,7]. The chemotherapy is typically retained for one hour. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Risk stratification'.)

For patients with intermediate- or high-risk non-muscle invasive bladder tumors, intravesical therapy is generally recommended to decrease the risk of recurrence or progression to muscle invasive disease and the potential need for cystectomy. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

Following initial TURBT with or without intravesical therapy, careful surveillance for recurrent or second primary tumors of the urinary tract is required for both low- and high-risk patients. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Posttreatment surveillance'.)

Transurethral resection — The initial treatment of non-muscle invasive bladder tumors is a complete TURBT. Some patients with low-grade tumors may require two or more resections in order to remove all visible papillary disease. Perioperative single-dose intravesical chemotherapy (usually with gemcitabine or mitomycin) is indicated in patients with low-grade tumors.

Patients with high-risk non-muscle invasive bladder cancer should undergo a repeat cystoscopy and may require reresection of areas of high-grade urothelial cancer prior to initiation of intravesical Bacillus Calmette-Guerin (BCG) therapy. Repeat resection is important, both to eliminate any visible residual disease and to eliminate the risk of understaging. All of the guidelines are consistent with this as a standard of care for patients with high-grade T1 tumors, and this is an option for patients with high-grade Ta tumors. Biopsies of normal-appearing mucosa adjacent and remote to the tumor should be done to determine whether CIS is present. Enhanced endoscopic imaging with narrow band imaging or fluorescence cystoscopy helps detect additional papillary tumors and CIS lesions. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Transurethral resection'.)

Intravesical therapy — Induction (weekly for six weeks) intravesical therapy is indicated in patients with intermediate- and high-risk disease. This approach facilitates delivery of high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT to prevent tumor implantation, as well as treating residual flat papillary lesions or CIS. This is generally followed by maintenance therapy, and the duration of maintenance therapy is based upon risk stratification. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

Intravesical therapy utilizes large molecular weight compounds, thus limiting transmucosal absorption and systemic toxicity. However, the risk of disseminated infection with BCG or systemic toxicity from chemotherapy is increased in patients who have had extensive transurethral resection with residual denuded mucosal surfaces. Intravesical therapy may be initiated two to three weeks postoperatively and no later than four weeks after completing TURBT, allowing the bladder to heal and resolution of surgery-related lower urinary tract symptoms.

Intravesical immunotherapy with BCG, a live attenuated form of Mycobacterium bovis, is the treatment of choice for patients with high-risk disease (Ta, Tis, T1). Other intravesical agents have been compared with BCG, but none has proved consistently superior.

For patients with intermediate-risk disease, intravesical therapy with either BCG or chemotherapy is an option. Alternatives to BCG include several chemotherapy agents, such as mitomycin, epirubicin, and gemcitabine. During periods of BCG shortage, intravesical chemotherapy is a preferred option for patients with intermediate-risk disease. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

Surveillance — Careful follow-up is required for all patients with non-muscle invasive bladder cancer. Second primary tumors can develop in the urothelium anywhere along the genitourinary tract, including the renal pelvis, ureters, and urethra, as well as the bladder. Subsequent surveillance should include a careful program of cystoscopy beginning three months after the initial treatment. Cytology is obtained at the time of surveillance cystoscopy for patients with high-grade and high-risk or intermediate-risk disease. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Posttreatment surveillance'.)

Patients with low-risk disease can be surveilled annually if the initial three-month cystoscopy is negative. Patients with intermediate- or high-risk disease are usually surveilled every three months for two years, then every six months for three years, then annually.

Indications for cystectomy — If the initial TURBT identifies muscle invasive (T2) disease, definitive therapy is generally indicated. (See 'Muscle invasive disease' below.)

The indications for cystectomy in patients with non-muscle invasive bladder cancer are discussed in detail separately. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

Further discussion on the role of cystectomy is also presented separately. (See "Radical cystectomy".)

MUSCLE INVASIVE DISEASE — Radical cystectomy, with its associated urinary diversion, is the preferred treatment for muscle invasive bladder cancer (algorithm 3) [2]. Neoadjuvant chemotherapy prior to cystectomy has been shown to improve overall survival. Trimodality therapy (TMT), which incorporates maximal transurethral resection of bladder tumor (TURBT), radiation therapy, and concurrent chemotherapy, is an option for patients with muscle invasive urothelial bladder cancer who are not candidates for radical cystectomy and for those who desire to preserve their native bladder. This approach is consistent with various clinical guidelines, including the NCCN [8].

Radical cystectomy — Radical cystectomy entails removal of the bladder, adjacent organs, and regional lymph nodes. In males, radical cystectomy generally includes removal of the prostate and seminal vesicles as well as the urinary bladder. In females, organ preservation of the uterus, cervix, and ovaries is possible in many patients due to infrequent tumor involvement of these organs. (See "Radical cystectomy", section on 'Surgical steps'.)

Radical cystectomy can be performed with an open technique or a minimally invasive approach by surgeons experienced with these techniques. The feasibility of a minimally invasive laparoscopic approach is well established, and most surgeons perform this with robotic assistance. Studies comparing open versus minimally invasive approaches with radical cystectomy are discussed separately. (See "Radical cystectomy", section on 'Surgical approaches'.)

Urinary diversion is usually performed through an open approach, though some surgeons can perform this using a minimally invasive technique, including laparoscopic or robotic approaches. (See 'Urinary diversion' below and "Urinary diversion and reconstruction following cystectomy".)

Patients who have undergone radical cystectomy for urothelial bladder cancer are at risk for the development of distant metastases as well as second primary urothelial tumors in the renal pelvis, ureters, or urethra. (See 'Surveillance' above and 'Metastatic disease' below.)

Urinary diversion — Removal of the bladder requires that the urinary flow be redirected, which may take one of several forms:(See "Urinary diversion and reconstruction following cystectomy".)

●Ileal conduits – A noncontinent cutaneous diversion, in which the urine flows from the ureters through a segment of bowel (usually ileum, termed an ileal conduit) to the skin surface as a stoma, where it is collected in an external appliance (figure 2).

●Cutaneous continent reservoir – A cutaneous continent reservoir (also called an Indiana pouch) may be constructed to avoid the need for an external appliance (figure 3). The patient self-catheterizes at regular intervals to empty the reservoir.

●Orthotopic neobladder – An orthotopic neobladder may be formed from a segment of bowel and attached to the urethra, enabling the patient to void through the urethra (figure 4). Continent diversions may facilitate maintenance of patient perceptions of quality of life and self-image and increase their acceptance of radical cystectomy.

Each approach entails specific risks and benefits. In addition to patient preference, the choice of a diversion needs to be individualized based upon the patient's overall medical condition, pathologic extent of disease, and prior treatment.

Neoadjuvant and adjuvant therapy — Urothelial bladder cancer is most sensitive to cisplatin-based combination chemotherapy. This has led to its evaluation in conjunction with surgery for patients undergoing definitive treatment for urothelial cancer. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Cisplatin-eligible'.)

●Neoadjuvant chemotherapy – Randomized clinical trials have demonstrated a clinically relevant and statistically significant survival advantage for patients with muscle invasive urothelial bladder cancer who receive platinum-based neoadjuvant chemotherapy prior to undergoing cystectomy. This approach is preferred for patients who can tolerate such chemotherapy. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer", section on 'Neoadjuvant chemotherapy'.)

●Is there a role for neoadjuvant immunotherapy? – Based on the activity of checkpoint inhibitor immunotherapy in metastatic disease, there is interest in integrating immunotherapy into the neoadjuvant setting. Further details are discussed separately. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)

●Adjuvant therapy – For patients with muscle-invasive bladder cancer who elect radical cystectomy, neoadjuvant chemotherapy prior to cystectomy is the standard of care, as this approach is associated with a survival advantage in randomized trials. However, patients who receive initial treatment with definitive surgery and are at high risk for recurrence based on pathologic staging or those who have residual muscle-invasive cancer after neoadjuvant chemotherapy and cystectomy may be candidates for adjuvant therapy. Available systemic agents include cisplatin-based chemotherapy and immunotherapy (algorithm 4). Adjuvant radiation therapy may be indicated for select patients. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)

Trimodality therapy for bladder preservation — TMT incorporating maximal TURBT, radiation therapy, and concurrent chemotherapy is an option for patients with muscle invasive urothelial bladder cancer who are not candidates for radical cystectomy and for those who desire to preserve their native bladder (algorithm 5). This approach can preserve the bladder and bladder function while providing cure or long-term disease control in carefully selected patients. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

Bladder preservation approaches require careful surveillance following therapy for evidence of local recurrence and for detection of new urothelial cancers. For patients who fail to achieve a complete response and for those who subsequently relapse with muscle-invasive disease, salvage cystectomy is indicated.

Other bladder-sparing approaches — Most patients with bladder cancer would prefer to keep their native bladder, if at all possible. However, the primary goal of treatment is cure of the cancer, and bladder preservation is a secondary consideration, particularly in the younger and more robust patients.

●A "radical" TURBT has been used in selected patients with small primary tumors (≤T1b, clinical stage T2, no carcinoma in situ, and located in an area of the bladder amenable to deep resection into perivesical fat [not in the dome or high posterior wall]) [9].

●Partial cystectomy is an alternative option for patients with similar tumor characteristics, with the exception that the dome and posterior wall are ideal locations, though both procedures are indicated in a small subset of patients. Partial cystectomy is the treatment of choice for urachal adenocarcinomas.

●Patient selection is important. For the patient with a history of multiple TURBTs, chemoradiation approaches may result in a patient who is highly symptomatic with significant bladder symptoms and discomfort due to posttreatment inflammation, antecedent scarring, and local damage. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Quality of life studies'.)

Posttreatment surveillance — The optimal approach to surveillance following treatment is not well defined. The surveillance strategy following definitive therapy should take into account the treatment approach.

Patients treated with cystectomy — For patients treated with cystectomy, we perform laboratory evaluations (ie, urine cytology, liver and renal function tests, and electrolytes) every three months for the first year, every six months for the second and third years, and then annually up to year 5. After year 5, these assessments should be performed as clinically indicated. Metabolic abnormalities, including electrolyte abnormalities and acidosis, are common, and patients with chronic kidney disease and obstructive uropathy may be at increased risk. Chronic acidosis is a risk factor for osteopenia and osteoporosis, so regular electrolyte monitoring may identify at-risk patients for pharmacologic intervention.

In addition, computed tomography (CT) imaging (chest, abdomen, and pelvis) is reasonably performed every six months for the first three years, then annually to year 5, and then only as clinically indicated. The interval between imaging evaluations may vary depending on whether or not lymph nodes were involved at surgery. If node positive, then scans every three to six months are reasonable; if node negative, scans may be extended to 6- to 12-month intervals. Our approach is consistent with consensus guidelines from the American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN), which support a range in frequency of recommended imaging intervals [8,10].

The use of circulating tumor DNA (ctDNA) remains investigational for the surveillance of treated bladder cancer [11]. Further studies are necessary prior to the routine use of this test in clinical practice.

Patients treated with bladder preserving trimodality approaches — Patients who received bladder-preserving TMT require careful surveillance following therapy for evidence of local recurrence and for detection of new urothelial cancers. For patients who fail to achieve a complete response and for those who subsequently relapse with muscle invasive disease, salvage cystectomy is indicated. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Posttreatment surveillance and treatment'.)

METASTATIC DISEASE — For patients with advanced unresectable and metastatic urothelial carcinoma, treatment options include (either as single-agents or in combination) platinum-based chemotherapy, checkpoint inhibitor immunotherapy, targeted therapies, and antibody-drug conjugates (algorithm 6). Further details on the management of metastatic urothelial carcinoma are discussed separately. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

In patients who have metastatic disease at presentation, the primary tumor can sometimes contribute significant morbidity and may be associated with shortened overall survival. Palliative therapy may minimize the impact of the primary tumor on quality of life; transurethral resection of bladder tumor (TURBT), cystectomy, and palliative radiation therapy have a role [12-15].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Bladder cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Bladder cancer diagnosis and staging (Beyond the Basics)" and "Patient education: Bladder cancer treatment; non-muscle invasive (superficial) cancer (Beyond the Basics)" and "Patient education: Bladder cancer treatment; muscle invasive cancer (Beyond the Basics)")

SUMMARY

●Clinical presentation – The presence of otherwise unexplained hematuria frequently denotes urinary tract cancer in individuals over the age of 40 until proven otherwise (algorithm 1). (See "Clinical presentation, diagnosis, and staging of bladder cancer".)

●Diagnostic evaluation

•Cystoscopy and urine cytology – The initial diagnostic evaluation includes flexible cystoscopy and urine cytology. (See 'Diagnosis' above and 'Initial evaluation' above.)

•TURBT – Transurethral resection of bladder tumor (TURBT) along with examination under anesthesia is required in order to determine histology, depth of invasion, and potential involvement beyond the bladder.

•Bladder biopsy – Bladder biopsies of normal-appearing mucosa are required in patients with an otherwise unexplained positive urine cytology.

•Imaging – For patients with muscle-invasive disease, cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) and laboratory evaluation is indicated to assess the extent of pelvic disease and exclude the presence of distant metastases.

●Non-muscle invasive bladder cancer – Primary tumors without muscle invasion (Ta and T1 lesions (figure 1 and table 1)) are generally managed initially with TURBT (algorithm 2). (See 'Non-muscle invasive disease' above.)

•Patients at significant risk of recurrence and/or progression may also require intravesical therapy. (See "Treatment of primary non-muscle invasive urothelial bladder cancer".)

•All patients are at risk for recurrence both in the bladder and elsewhere in the urothelium, and long-term surveillance is required following initial therapy. (See 'Surveillance' above.)

●Muscle-invasive bladder cancer – Radical cystectomy with urinary diversion is the treatment of choice for patients with muscle invasive disease (algorithm 3). (See 'Muscle invasive disease' above and "Radical cystectomy", section on 'Surgical approaches' and "Urinary diversion and reconstruction following cystectomy".)

•Neoadjuvant chemotherapy – Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy improves overall survival and is the standard of care. (See "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)

Patients with muscle invasive (T2 to T4a) disease and regional lymph node metastasis (N1 to N3), but without more distant lymph node involvement beyond the common iliac nodes (proximal to the aortic bifurcation; M1a) or visceral metastasis (M1b) may be treated with neoadjuvant cisplatin-based chemotherapy followed by cystectomy.

•Indications for adjuvant therapy – Patients who receive initial treatment with definitive surgery and are at high risk for recurrence based on pathologic staging or those who have residual muscle-invasive cancer after neoadjuvant chemotherapy and cystectomy may be candidates for adjuvant therapy. Available systemic agents include cisplatin-based chemotherapy and immunotherapy (algorithm 4). (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder".)

•Indications for TMT – For patients unable or unwilling to undergo radical cystectomy with urinary diversion for muscle invasive urothelial bladder cancer, trimodality therapy (TMT) incorporating complete TURBT combined with radiation therapy plus chemotherapy may offer an alternative bladder-sparing approach (algorithm 5). (See 'Muscle invasive disease' above and "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer".)

●Metastatic disease – For patients with advanced unresectable and metastatic urothelial carcinoma, treatment options include (either as single-agents or in combination) platinum-based chemotherapy, checkpoint inhibitor immunotherapy, targeted therapies, and antibody-drug conjugates (algorithm 6). (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Derek Raghavan, MD, PhD, FACP, FASCO, who contributed to earlier versions of this topic review.