Bladder Cancer

Bladder cancer is a common urologic cancer. Almost all bladder cancers originate in the urothelium, which is a 3- to 7-cell mucosal layer within the muscular bladder.

Urothelial carcinoma

In North America, South America, Europe, and Asia, the most common type of urothelial tumor is urothelial carcinoma (UC); it constitutes more than 90% of bladder cancers in those regions. UC can arise anywhere in the urinary tract, including the renal pelvis, ureter, bladder, and urethra, but it is usually found in the urinary bladder. Carcinoma in situ (CIS) is frequently found in association with high-grade or extensive UC. (See the image below.)

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.

Squamous cell carcinoma

Squamous cell carcinoma (SCC) is the second most common cell type associated with bladder cancer in industrialized countries. In the United States, around 5% of bladder cancers are SCCs.[2] Worldwide, however, SCC is the most common form of bladder cancer, accounting for 75% of cases in developing nations (see Epidemiology).

In the United States, the development of SCC is associated with persistent inflammation from long-term indwelling Foley catheters and bladder stones, as well as, possibly, infections. In developing nations, SCC is often associated with bladder infection by Schistosoma haematobium (see Etiology).

Other types of bladder cancer

Approximately 2% of bladder cancers are adenocarcinomas. Nonurothelial primary bladder tumors are extremely rare and may include small cell carcinoma, carcinosarcoma, primary lymphoma, and sarcoma (see Pathophysiology). Small cell carcinoma of the urinary bladder accounts for only 0.3-0.7% of all bladder tumors. High-grade urothelial carcinomas can also show divergent histologic differentiation, such as squamous, glandular, neuroendocrine, and sarcomatous features.

Phenotypes

Clinical and pathologic data indicate that at least 3 different phenotypes, as follows, exist in urothelial carcinoma[2, 3] :

• Low-grade proliferative lesions that develop into non–muscle-invasive tumors; these account for approximately 80% of bladder cancers
• Highly proliferative invasive tumors with a propensity to metastasize
• CIS, which can penetrate the lamina propria and eventually progress

Clinical course

The clinical course of bladder cancer is marked by a broad spectrum of aggressiveness and risk. Low-grade, superficial bladder cancers have minimal risk of progression to death; however, high-grade non–muscle-invasive cancers frequently progress and muscle-invasive cancers are often lethal (see Prognosis).

The classic presentation of bladder cancer is painless gross hematuria, which is seen in approximately 80-90% of patients. Physical examination results are often unremarkable (see Presentation). Cystoscopy, cytology, and biopsy when necessary are the principal diagnostic tests (see Workup).

Upon presentation, 55-60% of patients have low-grade, noninvasive disease, which is usually treated conservatively with transurethral resection of bladder tumor (TURBT) and periodic cystoscopy. Intravesical agents may also be given selectively to decrease the frequency of recurrences. The remaining patients have high-grade disease, of which 50% is muscle invasive and is typically treated with radical cystectomy or with trimodality therapy (ie, TURBT followed by concurrent radiation therapy and systemic chemotherapy; see Treatment).

Carcinoma in situ (CIS) is managed by TURBT and instillation of chemotherapeutic or immunotherapeutic agents—most commonly, immunotherapy with bacillus Calmette-Guérin (BCG)—into the bladder via catheter. These intravesical treatments are not effective patients in whom cancer has invaded the bladder wall muscle; those cases require cystectomy or a combination of radiation therapy and chemotherapy (see Treatment).

Bladder cancer has the highest recurrence rate of any malignancy. Although most patients with bladder cancer can be treated with organ-sparing therapy, most experience either recurrence or progression, creating a great need for accurate and diligent surveillance (see Treatment).

For more information on bladder cancer, see the following:

• Urine Tumor Markers in Bladder Cancer Diagnosis
• Cystoscopy
• Pathology of Urinary Bladder Squamous Cell Carcinoma
• Pathologic Findings in Small Cell Bladder Carcinoma
• Bladder Cancer Staging
• Bladder Cancer Treatment Protocols
• Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer
• Treatment of Carcinoma In Situ
• Transurethral Resection of Bladder Tumors
• Surveillance for Recurrent Bladder Cancer

The bladder is an extraperitoneal muscular urine reservoir that lies behind the pubis symphysis in the pelvis. At the dome of the bladder lies the median umbilical ligament, a fibrous cord that is anchored to the umbilicus and that represents the obliterated urachus (allantois). The ureters, which transport urine from kidney to bladder, approach the bladder obliquely and posterosuperiorly, entering at the trigone (the area between the interureteric ridge and the bladder neck). The intravesical ureteral orifices are roughly 2-3 cm apart and form the superolateral borders of the trigone. 

In males, the seminal vesicles, vas deferens, ureters, and rectum border the inferoposterior aspect of the bladder. Anterior to the bladder is the space of Retzius, which is composed of fibroadipose tissue and the prevesical fascia. The dome and posterior surface of the bladder are covered by parietal peritoneum, which reflects superiorly to the seminal vesicles and is continuous with the anterior rectal peritoneum. In females, the posterior peritoneal reflection is continuous with the uterus and vagina.

The vascular supply to the bladder arrives primarily via the internal iliac (hypogastric) arteries, branching into the superior, middle, and inferior vesical arteries, which are often recognizable as lateral and posterior pedicles. The arterial supply also arrives via the obturator and inferior gluteal artery and, in females, via the uterine and vaginal arteries. Bladder venous drainage is a rich network that often parallels the named arterial vessels, most of which ultimately drain into the internal iliac vein.

Initial lymphatic drainage from the bladder is primarily into the external iliac, obturator, internal iliac (hypogastric), and common iliac nodes. Following the drainage to these sentinel pelvic regions, spread may continue to the presacral, paracaval, interaortocaval, and para-aortic lymph node chains.

Almost all bladder cancers originate in the urothelium, which is a 3- to 7-cell mucosal layer within the muscular bladder. Squamous cell carcinoma of the bladder can involve multiple sites; however, the lateral wall and trigone are more commonly involved by this tumor. All small cell carcinomas of the urinary system identified so far have been located in the urinary bladder, most commonly in the dome and vesical lateral wall.[4]

See Bladder Anatomy.

Bladder cancer is often described as a polyclonal field change defect with frequent recurrences due to a heightened potential for malignant transformation. However, bladder cancer has also been described as resulting from implantation of malignant cells that have migrated from a previously affected site. The latter occurs less often and may account for only a small percentage of cases.

Use of the common term superficial bladder cancer should be discouraged. The term implies a harmless nature, which is misleading in many instances. Because it was used to describe the disparate disorders of low-grade papillary bladder cancer and the markedly more aggressive form, carcinoma in situ (CIS), the World Health Organization (WHO) has recommended it be abandoned.

In its place, the term non–muscle-invasive bladder cancer should be used and qualified with the appropriate American Joint Committee on Cancer stage (ie, Ta, T1, Tis). Stage T1 cancer invades lamina propria but not the muscle of the bladder. High-grade T1 tumor associated with CIS carries a relatively high risk for disease recurrence and progression (approximately 60%).

The current WHO/International Society of Urological Pathology (ISUP) system classifies bladder cancers as low grade or high grade.[5] Tumors are also classified by growth patterns: papillary (70%), sessile or mixed (20%), and nodular (10%). (See the images below.)

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.

Urothelial carcinoma

Urothelial carcinoma (UC) arises from stem cells that are adjacent to the basement membrane of the epithelial surface. Depending on the genetic alterations that occur, these cells may follow different pathways in the expression of their phenotype.

The most common molecular biologic pathway for UCs involves the development of a papillary tumor that projects into the bladder lumen and, if untreated, eventually penetrates the basement membrane, invades the lamina propria, and then continues into the bladder muscle, where it can metastasize.

This progression occurs with high-grade cancers only. Low-grade cancers rarely, if ever, progress and are thought to have a distinct molecular pathway, different from the high-grade cancers and CIS.

CIS, which constitutes 10% of UCs, follows a different molecular pathway. This is a flat, noninvasive, high-grade UC that spreads along the surface of the bladder, staying superficial to the basement membrane. Over time, this may progress to an invasive form of cancer that behaves the same as invasive UC.

Many urothelial tumors are primarily UC but contain areas of squamous differentiation, squamous cell carcinoma (SCC), or adenocarcinoma.

Squamous cell carcinoma

SCC of the urinary bladder is a malignant neoplasm that is derived from bladder urothelium and has a pure squamous phenotype.[6, 7, 8] SCC of the bladder is essentially similar to squamous cell tumors arising in other organs. Because many urothelial carcinomas contain a minor squamous cell component, a diagnosis of SCC of the bladder should be rendered only when the tumor is solely composed of squamous cell components, with no conventional urothelial carcinoma component.

Reportedly, SCC has less of a tendency for nodal and vascular distant metastases than does urothelial carcinoma.[9, 10]

Rare forms of bladder cancer

Adenocarcinomas account for less than 2% of primary bladder tumors. These lesions are observed most commonly in exstrophic bladders and are often associated with malignant degeneration of a persistent urachal remnant.

Other rare forms of bladder cancer include leiomyosarcoma, rhabdosarcoma, carcinosarcoma, lymphoma, and small cell carcinoma. Leiomyosarcoma is the most common sarcoma of the bladder. Rhabdomyosarcomas most commonly occur in children. Carcinosarcomas are highly malignant tumors that contain a combination of mesenchymal and epithelial elements. Primary bladder lymphomas arise in the submucosa of the bladder. Except for lymphomas, all these rare bladder cancers carry a poor prognosis.

Small cell carcinoma of the urinary bladder is a poorly differentiated, malignant neoplasm that originates from urothelial stem cells and has variable expression of neuroendocrine markers. Morphologically, it shares features of small cell carcinoma of other organs, including the lung.

Genetic factors in pathogenesis

Divergent, yet interconnected and overlapping, molecular pathways are likely responsible for the development of noninvasive and invasive bladder tumors. Somatic mutations in fibroblast growth receptor3 (FGFR-3) and tumor protein p53 (TP53) in tumor cells appear to be important early molecular events in the noninvasive and invasive pathways, respectively.

FGFR-3, Ras, and PIK3CA mutations occur with high frequency in noninvasive tumors, leading to upregulation of Akt and mitogen-activated protein kinase (MAPK).[11, 12] Loss of heterozygosity (LOH) on chromosome 9 is among the most frequent genetic alterations in bladder tumors and is considered an early event.[13]

Large numbers of genomic changes have been detected using karyotyping and comparative genomic hybridization (CGH) analysis in urothelial carcinoma. Numerically common are losses of 2q, 5q, 8p, 9p, 10q, 18q, and Y. Gains of 1q, 5p, 8q, and 17q are frequently present, and high-level amplifications can be found; however, the target genes in the regions of amplifications have not been conclusively identified.[14]

Alterations in the TP53 gene are noted in approximately 60% of invasive bladder cancers. Progression-free survival is significantly shorter in patients with TP53 mutations and is an independent predictor of death among patients with muscle-invasive bladder cancer.[15]

Additionally, alterations in retinoblastoma (Rb), PTEN, and p16 are common in high-grade invasive cancers.[16] Overexpression of JUN, MAP2K6, STAT3, and ICAM1 and molecules associated with survival (Bcl-2, caspase-3, p53, survivin), as well as insensitivity to antigrowth signals (p53, p21, p16, pRB), has been demonstrated.[17]

In advanced disease, multiple mechanisms may lead to tumor progression. These include those that promote proliferation, survival, invasion, and metastasis, as well as those that involve deficiencies in DNA damage repair and the finding of stemlike cells.

In addition to tumor cell alterations, the microenvironment may promote tumor growth by paracrine influences, including vascular endothelial growth factor (VEGF) production and aberrant E-cadherin expression. Finally, a growing body of research over the last decade indicates that epigenetic alterations may silence tumor suppressor genes and that they represent important events in tumor progression.[18, 19, 20]

Up to 80% of bladder cancer cases are associated with environmental exposure. Tobacco use is by far the most common cause of bladder cancer in the United States and is increasing in importance in some developing countries. Smoking duration and intensity are directly related to increased risk.[21, 22, 2]

The risk of developing bladder carcinoma is 2-6 times greater in smokers than in nonsmokers. This risk appears to be similar between men and women.[23] Nitrosamine, 2-naphthylamine, and 4-aminobiphenyl are possible carcinogenic agents found in cigarette smoke.

A number of occupations involve exposure to substances that may increase risk for bladder cancer. Of occupationally related bladder cancer cases, the incidence rate is highest in workers exposed to aromatic amines, while mortality is greatest in those exposed to polycyclic aromatic hydrocarbons and heavy metals.[24]

Numerous occupations associated with diesel exhaust, petroleum products, and solvents (eg, auto work, truck driving, plumbing, leather and apparel work, rubber and metal work) have also been associated with an increased risk of bladder cancer. In addition, increased bladder carcinoma risk has been reported in persons, including the following, who work with organic chemicals and dyes:

• Beauticians
• Dry cleaners
• Painters
• Paper production workers
• Rope-and-twine industry workers
• Dental workers
• Physicians
• Barbers

People living in urban areas are also more likely to develop bladder cancer. The etiology in these cases is thought to be multifactorial, potentially involving exposure to numerous carcinogens.

Arsenic exposure may be a factor in the development of bladder cancer. Results of a population-based case-control study in Maine, New Hampshire, and Vermont support an association between low-to-moderate levels of arsenic in drinking water and bladder cancer risk in those states, where incidence rates of bladder cancer have long been about 20% higher than in the United States overall.[25] A likely source of the arsenic is residue of arsenic-based pesticides, which were used extensively on crops such as blueberries, apples, and potatoes in that region from the 1920s through to the 1950s.[26]

Several medical risk factors are associated with an increased risk of bladder cancer, including the following:

• Radiation treatment of the pelvis

• Chemotherapy with cyclophosphamide - Increases the risk of bladder cancer via exposure to acrolein, a urinary metabolite of cyclophosphamide[27]

• Spinal cord injuries requiring long-term indwelling catheters - A 16- to 20-fold increase in the risk of developing SCC of the bladder

Although certain common genetic polymorphisms appear to increase susceptibility in persons with occupational exposure associated with increased bladder cancer risk,[28] no convincing evidence exists for a hereditary factor in the development of bladder cancer. Nevertheless, familial clusters of bladder cancer have been reported.

Schistosomiasis

In many developing countries, particularly in the Middle East, Schistosoma haematobium infection causes most cases of bladder SCC. In a study from Egypt, 82% of patients with bladder carcinoma harbored S haematobium eggs in the bladder wall. In egg-positive patients, the tumor tended to develop at a younger age (with SCC predominant) than it did in egg-negative persons. A higher degree of adenocarcinoma has also been reported in schistosomal-associated bladder carcinomas.[29]

Along with S haematobium, the species S mansoni and S japonicum are responsible for schistosomiasis in humans. The eggs reside in the pelvic and mesenteric venous plexus. In the bladder, a severe inflammatory response and fibrosis secondary to the deposition of Schistosoma eggs is common. (See the image below.)

Bladder cancer. Histopathology of bladder shows eggs of Schistosoma haematobium surrounded by intense infiltrates of eosinophils and other inflammatory cells.

The eggs are found embedded in the lamina propria and muscularis propria of the bladder wall. Many of the eggs are destroyed by host reaction and become calcified, resulting in a lesion commonly known as a sandy patch, which appears as a granular, yellow-tan surface lesion.

In normal epithelial cells, S haematobium total antigen reportedly induces increased proliferation, migration, and invasion and decreases apoptosis.[30] Keratinous squamous metaplasia has been associated with the increased risk of developing SCC, with approximately one half of the cases arising subsequent to the metaplasia.[31, 32]

The majority of schistosomiasis-related cases of SCC will arise in the setting of chronic cystitis.[33] Chronic irritation secondary to lithiasis,[6, 7] urinary retention, and indwelling catheters has also been linked to the development of SCC.[7]

Other squamous cell carcinoma risk factors

Having bladder diverticula may increase an individual’s chance of developing SCC.[34] Rarely, bacillus Calmette-Guerin (BCG) treatment for CIS has been reported to lead to development of SCC.[35] Development of bladder cancer at a younger age has been associated with bladder exstrophy.[36, 37, 38, 39] SCC has also been described in urachal remnants.[40, 41, 42, 43, 44]

Coffee consumption does not increase the risk of developing bladder cancer. Early studies of rodents and a minority of human studies suggested a weak connection between artificial sweeteners (eg, saccharin, cyclamate) and bladder cancer; however, most recent studies show no significant correlation.

Occurrence in the United States

The American Cancer Society estimates that 82,290 new cases of bladder cancer will be diagnosed in the United States in 2023 and that 16,710 people will die of the disease.[45] The incidence of bladder cancer increases with age, with the median age at diagnosis being 73 years; bladder cancer is rarely diagnosed before age 40 years.[46]

Bladder cancer is about 4 times more common in men than in women.[45] The male predominance in bladder cancer in the United States reflects the prevalence of transitional cell carcinoma (TCC). With small cell carcinoma—in contrast to TCC—the male-to-female incidence ratio is 1:2.

Bladder cancer is the fourth most common cancer in men in the United States, after prostate, lung, and colorectal cancer, but it is not among the top 10 cancers in women. Accordingly, more men than women are expected to die of bladder cancer in 2023, with 12,160 deaths in men versus 4550 in women.[45] Nevertheless, women generally have a worse prognosis than men.

The incidence of bladder cancer is twice as high in White men as in Black men in the United States. However, Blacks have a worse prognosis than Whites.[46, 47]

From 2000 to 2019, incidence and death rates for bladder cancer decreased in most racial and ethnic groups in both men and women in the US. On average, incidence rates decreased by 1.88% annually in men and 1.34% in women; death rates decreased by 2.16% in men and 2.44% in women. However, incidence rates showed a steady increase in American Indian and Alaska Native men and women, and death rates stabilized in Asian American and Pacific Islander men and Hispanic women.[48]

Limited data indicate that small cell carcinoma of the urinary bladder probably has the same epidemiologic characteristics as urothelial carcinoma. Patients are more likely to be male and older than 50 years.[49, 50]

International occurrence

Worldwide, bladder cancer is diagnosed in approximately 275,000 people each year, and about 108,000 die of this disease. In industrialized countries, 90% of bladder cancers are TCC. In developing countries—particularly in the Middle East and Africa—the majority of bladder cancers are SCCs, and most of these cancers are secondary to Schistosoma haematobium infection. Urothelial carcinoma is reported to be the most common urologic cancer in China.

In Africa, the highest incidence of SCC has been seen in schistosomal-endemic areas, notably Sudan and Egypt, where SCC ranges from two thirds to three quarters of all malignant tumors of the bladder. In recent years, a few studies from Egypt have shown a reversal of this trend due to the better control of schistosomiasis in the region, whereas in other parts of Africa the association is unchanged.[10, 51, 52] Increased smoking incidence is believed to have contributed to the shift in Egypt toward TCC, which has a stronger smoking association.

Untreated bladder cancer produces significant morbidity, including the following:

• Hematuria
• Dysuria
• Irritative urinary symptoms
• Urinary retention
• Urinary incontinence
• Ureteral obstruction
• Pelvic pain

The recurrence rate for superficial TCC of the bladder is high. As many as 80% of patients have at least one recurrence.

The most significant prognostic factors for bladder cancer are grade, depth of invasion, and the presence of CIS. In patients undergoing radical cystectomy for muscle-invasive bladder cancer, the presence of nodal involvement is the most important prognostic factor. To date, there is no convincing evidence of genetic factors affecting outcome.[53]

Non–muscle-invasive bladder cancer has a good prognosis, with 5-year survival rates of 82-100%. The 5-year survival rate decreases with increasing stage, as follows:

• Ta, T1, CIS – 82-100%
• T2 – 63-83%
• T3a – 67-71%
• T3b – 17-57%
• T4 – 0-22%

Prognosis for patients with metastatic urothelial cancer is poor, with only 5-10% of patients living 2 years after diagnosis.

The risk of progression, defined as an increased tumor grade or stage, depends primarily on the tumor grade, as follows:

• Grade I – 2-4%
• Grade II – 5-7%
• Grade III – 33-64%

Prognosis in carcinoma in situ

CIS in association with T1 papillary tumor carries a poorer prognosis. It has a recurrence rate of 63-92% and a rate of progression to muscle invasion of 50-75% despite intravesical BCG. Diffuse CIS is an especially ominous finding; in one study, 78% of cases progressed to muscle-invasive disease.[54]

Prognosis in squamous cell carcinoma

Tumor stage, lymph node involvement, and tumor grade have been shown to be of independent prognostic value in SCC.[55, 56] However, pathologic stage is the most important prognostic factor. In one relatively large series of 154 cases, the overall 5-year survival rate was 56% for pT1 and 68% for pT2 tumors. However, the 5-year survival rate for pT3 and pT4 tumors was only 19%.[53]

Several studies have demonstrated grading to be a significant morphologic parameter in SCC.[53] In one series, 5-year survival rates for grade 1, 2, and 3 SCC was 62%, 52%, and 35%, respectively.[53] In the same study of patients undergoing cystectomy, the investigators suggested that a higher number of newly formed blood vessels predicts unfavorable disease outcome.

In SCC, the survival rate appears to be better with radical surgery than with radiation therapy and/or chemotherapy. In locally advanced tumors, however, neoadjuvant radiation improves the outcome.[57] Sex and age have not been prognostically significant in SCC.[53]

Prognosis in small cell carcinoma

Patients with small cell carcinoma of the bladder usually have disease in an advanced stage at diagnosis, and they have a poor prognosis.[58, 59, 60] Overall median survival is only 1.7 years. The 5-year survival rates for stage II, III, and IV disease are 64%, 15%, and 11%, respectively.[61]

Recurrent bladder cancer

Bladder cancer has the highest recurrence rate of any malignancy (ie, 70% within 5 y). Although most patients with bladder cancer can be treated initially with organ-sparing therapy, most experience either recurrence or progression. The underlying genetic changes that result in a bladder tumor occur in the entire urothelium, making the whole lining of the urinary system susceptible to tumor recurrence.

Risk factors for recurrence and progression include the following[62, 63] :

• Female sex
• Larger tumor size
• Multifocality
• Larger number of tumors
• High tumor grade
• Advanced stage
• Presence of CIS

The time interval to recurrence is also significant. Patients with tumor recurrences within 2 years, and especially with recurrences within 3-6 months, have an aggressive tumor and an increased risk of disease progression.

Approximately 80-90% of patients with bladder cancer present with painless gross hematuria. Most patients with this classic presentation should be considered to have bladder cancer until proof to the contrary is found. 

Hematuria is not the only manifestation of an underlying bladder cancer. Irritative bladder symptoms such as dysuria, urgency, or frequency of urination occur in 20-30% of patients with bladder cancer. Although irritative symptoms may be related to more advanced muscle-invasive disease, carcinoma in situ (CIS) is the more likely cause. Therefore, patients presenting with unexplained or refractory irritative symptoms should be considered for cystoscopy and urine cytology. The threshold for doing so should be especially low in persons who smoke or have other risk factors.

Patients with advanced disease can present with pelvic or bony pain, lower-extremity edema from iliac vessel compression, or flank pain from ureteral obstruction.

Non ̶ muscle-invasive bladder cancer is typically not found during a physical examination. In rare cases, a mass is palpable during abdominal, pelvic, rectal, or bimanual examination. A bimanual examination may be considered part of the staging of such lesions. In women, a bimanual pelvic examination is done; in men, a bimanual examination is performed with one hand per rectum and the other on the lower abdominal wall.

Attention to the anterior vaginal wall in women and the prostate in men may reveal findings that suggest local extension of bladder cancer. Assessment of fixation of the bladder to the surrounding pelvic sidewall is also important when planning definitive management for locally advanced tumors that may not be surgically resectable.

Any patient with gross or microscopic hematuria should undergo urologic evaluation, as hematuria is the most common clinical manifestation in patients presenting with bladder cancer.[64]  All patients with gross hematuria should undergo a hematuria workup consisting of a cystoscopy, computed tomography (CT) urogram, and cytology. In patients with microscopic hematuria (≥3 red blood cells per high-power field), the American Urological Association (AUA) guideline recommends stratification as low, intermediate, or high risk to determine the workup strategy. High-risk patients undergo the standard evaluation of cystoscopy with CT urogram. Intermediate-risk patients are evaluated with cystoscopy and renal ultrasound. Low-risk patients undergo repeat urinalysis in 6 months.[65]

Urine studies

Urine studies include the following:

• Urinalysis with microscopy
• Urine culture to rule out infection, if suspected
• Voided urinary cytology
• Urinary tumor marker testing

Urinalysis is performed to detect hematuria or infection. Microscopic hematuria from bladder cancer may be intermittent; therefore, a repeat negative result on urinalysis does not exclude the diagnosis.

Cytology

All patients with gross hematuria should undergo cystoscopy, upper tract imaging, and urinary cytology (preferably barbotage urine for cytology). It is no longer recommended to use urine cytology in the initial evaluation of patients with microscopic hematuria unless the patient has risk factors for carcinoma in situ (CIS). Additionally, cytology can be used in patients with microhematuria who have irritative urinary symptoms after a negative workup.[65]    

Urinary cytology is most helpful in diagnosing high-grade tumors and CIS. Low-grade, noninvasive tumors may be missed by routine cytologic analysis.

Endoscopic biopsies are used to establish the diagnosis and determine the extent of the cancer. However, a study by Cha et al found that immunocytology outperforms urine cytology and increases the accuracy of predictive models by a statistically and clinically significant margin for patients with painless hematuria.[66]

Strittmatter et al found that the quality of urinary cytology is impacted by the individual learning curve. Specificity of cytology and sensitivity for low-grade tumors significantly changed when performed by a local cytologist at the beginning of the learning period. This suggests that in the diagnosis of bladder cancer, the cytologist’s level of experience has an important impact on the clinical value of urinary cytology.[67]

Findings

Because cytology is the most reliable urine test for detecting bladder cancer, a positive cytology finding should be treated as indicating cancer somewhere in the urinary tract until proven otherwise. If cystoscopy findings are negative in the setting of positive cytology findings, further evaluation of the urinary tract is required. The upper urinary tract should be evaluated with contrast imaging and possibly ureteroscopy. Cystoscopy with bilateral retrograde pyelography and bilateral ureteral washings should be performed. Additionally, in men the prostatic urethra should be examined.

Most patients with CIS have coexisting papillary cancer. In general, the papillary tumor is diagnosed first, and CIS is discovered during the evaluation and treatment of the papillary tumor. Only 10% of patients with bladder cancer have a pure CIS. The combination of CIS and papillary transitional cell carcinoma (TCC) is associated with a higher risk of recurrence and progression.

In cases of pure CIS, urinary cytology may lead to the diagnosis. CIS exfoliates cells that have an unusual appearance and are easy to identify via cytologic examination, prompting further evaluation. Unfortunately, even findings from urine cytology may be normal in some patients; in these cases the diagnosis is made only when the urologist maintains a high level of suspicion for CIS and obtains random bladder biopsy specimens from patients with worrisome symptoms. However, if the urinary cytology is performed properly, this should happen rarely.

Cystoscopy

Cystoscopy is one of the first tests that should be completed in a patient presenting with signs and symptoms suspicious for bladder cancer. Unfortunately, one study found that only 13% of patients with hematuria and risk factors for bladder cancer underwent cystoscopy.[65] Drawbacks of the procedure are that it is invasive and relatively expensive.[68]  In addition, flat urothelial lesions such as CIS may be difficult to distinguish from normal bladder tissue, and bleeding caused by the procedure can reduce visibility.

Use of adjunctive endoscopic techniques, such as blue light cystoscopy with hexaminolevulinic acid (HAL), may improve the accuracy of cystoscopy. HAL is instilled intravesically and remains in the bladder for one hour before cystoscopy. This allows malignant cells, which have higher intracellular accumulation of the photoactive porphyrins, to appear pink or red while the nonmalignant tissue appears blue.[64] Cytologic analysis of voided urine is frequently used as an adjunctive test to aid in identifying occult cancers.

Virtual cystoscopy can help detect many bladder tumors, but it is more expensive than cystoscopy and has lower sensitivity and specificity. Therefore, it does not play a role in surveillance at this time.

For more information, see Cystoscopy in Bladder Carcinoma.

Imaging studies

Imaging studies of the upper urinary tract are an integral part of the hematuria workup. CT scans of the abdomen and pelvis with contrast are recommended. Two commonly used alternative techniques are magnetic resonance imaging (MRI) and renal ultrasonography. A retrograde pyelogram can also be done to assess the upper tracts.[64]

Intravenous pyelography (IVP) was the traditional standard for upper tract urothelium imaging; however, it is a poor modality for evaluating the renal parenchyma. Few centers in the United States perform IVP today, although the test is still included in the National Comprehensive Cancer Network (NCCN) guidelines as an acceptable modality for imaging the upper tract collecting system.[1]  European Association of Urology (EAU) guidelines recommend CT urography as more informative than IVP for upper urinary tract tumors.[69]

The bladder urothelium is not well visualized with routine imaging studies, including CT and MRI. Small tumors are easily missed on images produced by these modalities. Irregular areas on images, which may appear to represent mucosal abnormalities, are often artifacts of incomplete bladder filling; delayed images following contrast administration can better visualize actual filling defects. CIS is not visible on images from any current radiographic study.

Biomarker testing

Newer molecular and genetic markers, including detection of mutations in genes such as RAS, FGFR3,PIK3CA, and TP53, and methylation pathways in urinary sediment,[70] may help in the early detection and prediction of urothelial carcinoma. At this time, however, no urinary assay has been shown to effectively replace urine cytology and cystoscopy, with or without biopsy, for the diagnosis of bladder cancer. Nevertheless, marker assays may be useful adjuncts to urine cytology and cystoscopy. 

However due to high cost and low specificity, use of urine-based tumor markers is not recommended by the AUA or the EAU as part of the microhematuria workup.[64]  NCCN guidelines state that urinary markers may be useful during surveillance of bladder cancer, but whether these markers are helpful in the detection and management of non–muscle-invasive bladder tumors remains unclear.[1]

Blood tests

No blood tests are specific for bladder cancer. In patients with CIS, however, a general evaluation is necessary prior to initiating therapy with intravesical bacillus Calmette-Guérin (BCG).

On the complete blood count (CBC), the presence of anemia or an elevated white blood cell (WBC) count warrants further investigation for an explanation.

The chemistry panel should include liver function studies. Although BCG is administered intravesically, systemic absorption of this agent can produce acute hepatitis. Performing baseline liver function tests before initiating therapy and repeating these tests during the course of therapy is important to help prevent serious adverse events and to determine when therapy should be stopped. In patients with suspected metastasis to liver or bone, liver function tests and measurement of the bony fraction of alkaline phosphatase should be performed.

Kidney function should be evaluated prior to the initiation of therapy because patients with marginal or abnormal kidney function may have an obstruction or some type of renal disease that may worsen with intravesical therapy. Kidney function can be evaluated with serum creatinine measurements or technetium scans of the kidneys.

Urinalysis is used routinely to evaluate for the presence of red blood cells (RBCs), WBCs, and protein and to assess for urinary tract infection. The presence of RBCs in the urine mandates an evaluation by a urologist to investigate for any serious disease. American Urological Association (AUA) guidelines recommend against relying on dipstick testing alone to diagnose microhematuria, and instead advise following up a positive dipstick test with a formal evaluation; the AUA defines microhematuria as “≥3 red blood cells per high-power field on microscopic evaluation of a single properly collected urine specimen." Workup of microhematuria should be based on history and physical exam findings while taking into consideration the patient's individual risk factors for genitourinary malignancy.[65]

Gross hematuria always requires a careful assessment with imaging studies of the entire urinary tract (CT urography) and cystoscopy. However, prior to performing an endoscopic examination or initiating any therapy, a urine culture should be performed to confirm that the urine is free of evidence of infection. Although microhematuria may be present in healthy persons, 13-34.5% of patients with gross hematuria and 0.5-10.5% of patients with microscopic hematuria will be diagnosed with bladder cancer on initial evaluation.[65]

Voided urine cytology is the standard noninvasive method for diagnosis in the detection of bladder carcinoma. Cytology is used to assess morphologic changes in intact cells. Exfoliated urothelial cells are viewed using microscopy. In some urothelial cancers, cellular clumping, a high nuclear-to-cytoplasmic ratio, nucleoli, and atypia are seen.

As with any type of cytologic examination, the experience and skill of the cytopathologist is extremely important. Many hospital laboratories lack the personnel and technology necessary to accurately perform this type of study. Good reference laboratories are available if local facilities cannot provide this service.

At least 100 mL of a freshly voided specimen is usually sufficient for urine cytology. The first morning sample should not be used, because cells sitting in the urine overnight tend to become distorted and are difficult to analyze. If the urine is very dilute, the number of cells may be insufficient, necessitating a larger urine volume.

Bladder washings can be obtained by placing a catheter into the bladder and vigorously irrigating with saline (ie, barbotage). Bladder wash cytology yields more tumor cells in the sample and is more sensitive in identifying cancer, especially for high-grade tumors, but it also yields a higher false-positive rate than voided urine cytology.[71]

Sensitivity and specificity

Unfortunately, the sensitivity of cytology is low, with various studies reporting values between 11% and 76%.[72] Sensitivity depends largely on the degree of tumor differentiation. High-grade tumors with marked pleomorphism and distinctly abnormal nuclear features are identified more accurately.

Small and/or well-differentiated tumors are less likely to exfoliate cells because intercellular attachments are better preserved and the degree of morphologic departure from normal is smaller, complicating cytologic recognition.[73] This results in poor sensitivity in low-grade and early-stage cancers.

Several other factors affect the sensitivity of cytology, including specimen quality, number of exfoliated cells, and pathologist expertise. However, the overall low sensitivity of cytology is due to its low sensitivity in detecting low-grade bladder tumors.[74] Urine cytology is associated with a significant false-negative rate, especially for low-grade carcinoma (10-50% accuracy rate). The false-positive rate is 1-12%, although cytology has a 95% accuracy rate for diagnosing high-grade carcinoma and CIS.

Urine cytology is often the test used for diagnosis of CIS. Suggestive urine cytology findings encourage the urologist to perform a bladder biopsy. With a properly collected urine sample that is promptly placed into fixative, CIS is detected in 70-75% of cases.

Instrumentation may cause reactive cellular changes, contributing to variability in interpretation. False-positive reports of malignant cells are uncommon, but ambiguous reports of atypical cells are frequent.

Improving accuracy

Perform urine cytology at the same time as cystoscopy, although its routine use for screening is controversial. If the cystoscopic examination yields normal findings but the urine cytology result is positive, further evaluation should include an upper tract study and random biopsies of the bladder. Obtain biopsy samples of the prostatic urethra in men.

Fluorescence in situ hybridization (FISH) may improve the sensitivity and specificity of routine cytology. The US Food and Drug Administration (FDA) has approved a FISH assay for the detection of recurrent bladder cancer in voided urine specimens from patients with a history of bladder cancer, as well as for the detection of bladder cancer in voided urine specimens from patients with gross or microscopic hematuria but no previous history of bladder cancer.[75]

Cytoimmunologic techniques have been developed using cytokeratin 20 as a target molecule. This assay may be more sensitive than conventional cytology, although the ability to detect low-grade tumors tends to be poor in all cytologic examinations. In contrast, the positive predictive value in patients with CIS tends to be around 75%.

Noninvasive urine markers can offer an alternative to the standard means of detecting bladder cancer or can be used as an adjunct to cystoscopy.[76] Over 30 urinary biomarkers have been reported for use in bladder cancer diagnosis, but only a few are commercially available.[77]

The EAU guidelines on non–muscle-invasive bladder cancer state that most of these tests are more sensitive than cytology but are less specific, and none have been accepted for diagnosis or follow-up in routine urologic practice or in guidelines.[69]  NCCN guidelines generally agree with the EAU guidelines but note that urinary biomarker tests approved by the FDA may be considered for use in monitoring for recurrence; however, this is a category 2B recommendation (ie, based on lower-level evidence).[1]

See Urine Tumor Markers in Bladder Cancer Diagnosis for more information on this topic.

Cystoscopy is the primary modality for the diagnosis of bladder carcinoma because of its low risk and because biopsy specimens can be taken and papillary tumors resected during a single procedure. The EAU guidelines on non–muscle-invasive bladder cancer state that cystoscopy should be performed in all patients with symptoms of possible bladder cancer and that no noninvasive test can take its place.[69]

However, cystoscopy may be an embarrassing procedure for the patient because of exposure and handling of the genitalia. The procedure must therefore be performed with respect, and the patient should remain exposed only as long as necessary to complete the evaluation.

Men are most easily evaluated with a flexible cystoscope. In women, cystoscopy can be performed as described for men, using a flexible cystoscope, although, because the female urethra is relatively straight, a rigid cystoscope may be used instead.

See Cystoscopy for more information on this topic.

In the setting of findings that are negative for cystoscopy and urinary cytology but positive for FISH, 2 possible scenarios arise. One is that the FISH result is falsely positive. The other is that it is an anticipatory positive result; in such cases, the patient has a 30% chance of developing a bladder tumor over 2 years. Patients in this category should undergo surveillance with increased frequency (see Table 1, below).

Table 1. Clinical Findings and Recommended Action in Patients with Negative Cystoscopy (Open Table in a new window)

In North America, South America, Europe, and Asia, more than 90% of bladder cancers are UCs. Approximately 5% are squamous cell carcinomas (SCCs), and less than 2% are adenocarcinomas.

Carcinoma in situ

The typical visual appearance of CIS is that of a flat carcinoma extending along the surface of the bladder. This is in contrast to a papillary tumor, which extends on a stalk into the lumen of the bladder. CIS, by definition, does not invade through the basement membrane into the lamina propria. When it does, the cancer is considered to behave as an aggressive transitional cell carcinoma (TCC) and is managed accordingly.

The histologic pattern of CIS is characterized by bizarre, abnormal cells in the epithelial layer. The cells appear to be those of high-grade cancer; thus, they are readily detected in cytology specimens.

The pathologist may have difficulty distinguishing between cellular atypia and CIS. A consultant should review the slides if the pathologist is uncertain or diagnoses atypia. Upon further review, these cases usually prove to be CIS. The distinction is important because CIS requires therapy while atypia can be managed with observation. Finally, some pathologists attempt to grade CIS; however, CIS is not graded. An associated papillary tumor would be graded as low or high grade.

For more information, see Pathology of Urinary Bladder Squamous Cell Carcinoma and Pathologic Findings in Small Cell Bladder Carcinoma.

Upper tract imaging is necessary for the hematuria workup. The imaging modality chosen should be able to visualize the kidneys and the urothelium.

American Urological Association Best Practice Policy recommends CT scanning of the abdomen and pelvis with contrast, with preinfusion and postinfusion phases.[78] This evaluation is ideally performed with CT urography, using multidetector CT, or it can be performed with a single-detector CT-scan study followed by an excretory radiographic study of the kidneys, ureters, and bladder (KUB) to obtain images similar to those produced with intravenous pyelography.

Conduct retrograde pyelography in patients in whom contrast CT scanning cannot be performed because of azotemia or a severe allergy to intravenous contrast.

Ultrasonography is also commonly used in the diagnosis of bladder cancer. However, urothelial tumors of the upper tract and small stones are easily missed. For patients who are unable to receive contrast, NCCN guidelines state that a renal ultrasound can be used in addition to retrograde ureteropyelogram as a substitute to CT with contrast.[1]  EAU guidelines state that ultrasonography is useful for identifying obstruction in patients with hematuria. It can detect renal masses, hydronephrosis, and bladder intraluminal masses but cannot rule out all potential causes of hematuria. It cannot reliably exclude the presence of upper tract urothelial carcinomas and cannot replace CT urography.[69]

The tumor, node, and metastasis (TNM) system developed by the International Union Against Cancer and the American Joint Committee on Cancer Staging is used to stage bladder cancer.[79] Ta and T1 tumors and CIS were once considered superficial bladder tumors. T2, T3, and T4 tumors were traditionally described as invasive bladder cancer. However, urologic oncologists now recommend avoiding the term superficial bladder cancer to describe Ta, T1, and CIS tumors because it is a misnomer and tends to group together patients who may require different treatments and who may have different prognoses.

Urothelial carcinoma is histologically graded as low grade or high grade. CIS is characterized by full mucosal thickness and high-grade dysplasia of the bladder epithelium and is associated with a poorer prognosis. Ta, T1, and CIS are categorized as non–muscle invasive while T2-T4 are muscle invasive. [1]

Primary tumor (T) classification for bladder cancer is as follows:

• CIS - Carcinoma in situ, high-grade dysplasia, confined to the epithelium
• Ta - Papillary tumor confined to the epithelium
• T1 - Tumor invasion into the lamina propria
• T2 - Tumor invasion into the muscularis propria: T2a, superficial muscularis propria; T2b, deep muscularis propria
• T3 - Tumor involvement of the perivesical fat: T3a, microscopic invasion; T3b, macroscopic invasion
• T4 - Tumor involvement of adjacent organs: T4a, invasion of prostatic stroma, seminal vesicles, uterus, or vagina; T4b, invasion of pelvic or abdominal wall

Node (N) classification for bladder cancer is as follows:

• N0: No regional lymph node metastasis
• N1: Metastasis in a single lymph node in true pelvis
• N2: Metastasis in multiple regional lymph nodes in true pelvis
• N3: Metastasis in common iliac  lymph node(s)

Distant metastasis (M) classification for bladder cancer is as follows:

• M0: No distant metastsis
• M1a: Non regional lymph nodes
• M1b: Other distant metastasis

See Bladder Cancer Staging for more information on this topic.

More than 70% of all newly diagnosed bladder cancers are non–muscle invasive, approximately 50-70% are Ta, 20-30% are T1, and 10% are CIS. Approximately 25% of affected patients have muscle-invasive disease at diagnosis. Approximately 5% of patients present with metastatic disease, which commonly involves the lymph nodes, lung, liver, bone, and central nervous system. 

In order to clinically stage a patient with muscle-invasive bladder cancer the following needs to be completed: CT or MRI of the abdomen and pelvis, chest imaging, CBC, and chemistry panel with alkaline phosphatase.[80] Bone imaging is recommended only if there is concern for bone metastasis, which could be indicated by bone pain or an elevated alkaline phosphatase.[1] Currently, routine PET scanning is not recommended during the initial staging workup.[80]   

Metastasis

As many as 50% of patients with muscle-invasive bladder cancer may have occult metastases that become clinically apparent within 5 years of initial diagnosis and around 5% will have distant metastasis at the time of initial diagnosis.[80] Most patients with overt metastatic disease die within 2 years despite chemotherapy. Approximately 25-30% of patients with only limited regional lymph node metastasis discovered during cystectomy and pelvic lymph node dissection may survive beyond 5 years. Metastasis can occur through lymphatic spread, most commonly affecting the pelvic lymph nodes, or through hematogenous spread to the liver, lung, or bone.[80]

Grade

Stage and grade are critical to the likelihood of cancer recurrence and progression in persons with bladder cancer who are treated with local therapy.

In 2004, the International Society of Urologic Pathologists and World Health Organization adopted low-grade or high-grade designations. Papillary urothelial neoplasia of low malignant potential (PUNLMP) has also been added as a designation.[5]

CIS, which is defined as a flat, high-grade, noninvasive cancer, is an exception to the above concept. Although some are tempted to consider CIS a premalignant condition, in reality it is an aggressive form of cancer that is detected prior to invasion. Therefore, aggressive management and surveillance are warranted. Likewise, the opportunity to affect CIS-associated mortality is significant because this type of cancer may respond to conservative therapy. If left untreated, however, CIS can lead to an invasive bladder cancer.

The treatment of non–muscle-invasive (Ta, T1, carcinoma in situ [CIS]) and muscle-invasive bladder cancer should be differentiated. Treatments within each category include surgical and medical approaches.[81] European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines for non–muscle-invasive cancer strongly recommend stratifying risk of recurrence and progression and using risk tables to determine appropriate treatment.[1, 69]

The two principal treatment choices in muscle-invasive bladder cancer are radical cystectomy and transurethral resection of bladder tumor (TURBT) followed by concurrent radiation therapy and systemic chemotherapy (trimodality therapy). Each choice has its advocates.

Chedgy and Black propose that radical cystectomy should be considered the gold-standard treatment for muscle-invasive bladder cancer. They cite recommendations from European and United States guidelines, as well as published literature showing a 75% 5-year cancer-specific survival for all stages of bladder cancer treated with cystectomy, while noting that the published literature on trimodality therapy shows evidence of inferior survival and frequent treatment failure, with almost one-third of patients eventually requiring a salvage cystectomy.[82]

Nevertheless, Chedgy and Black consider cystectomy and trimodality therapy to be complementary. They observe that many patients considered ineligible for radical cystectomy may be candidates for trimodality therapy, especially if radiosensitization is performed with 5-fluorouracil and mitomycin.[82]

In contrast, Mitin recommends considering trimodality therapy as the first option for patients with muscle-invasive bladder cancer, with cystectomy reserved for patients who are unable or unwilling to undergo bladder preservation or for salvage in the case of local recurrence. Mitin cites literature demonstrating similar or better outcomes compared with cystectomy and excellent quality of life, with low rates of radiation-induced adverse effects.[83]

Trimodality therapy carries a significant local recurrence rate, however, which necessitates thorough and frequent cystoscopic follow-up. Local recurrence requiring salvage cystectomy is usually identified within the first 3 years. Morbidity and mortality rates with salvage cystectomy are remarkably similar to those with first-line radical cystectomy, but reconstructive options with salvage cystectomy may be limited by the presence of irradiated bowel, which may be unacceptable for a continent reservoir or a neobladder creation.[83]

In the future, treatment selection for muscle-invasive bladder cancer is likely to be based on testing of tumors for biomarkers that indicate treatment sensitivity. Patients with resistant tumors would be offered upfront cystectomy, while those with chemoradiation-sensitive tumors would be offered bladder-preserving therapy, with regimens selected on the basis of genetic analysis.[83] For example, presence of the MRE11A single-nucleotide polymorphism rs1805363 has been associated with worse cancer-specific survival after radiation therapy, with a gene-dosage effect observed, but not after cystectomy.[84]

Immunotherapy and chemotherapy

Patients with low-grade, low-stage disease may receive expectant treatment or may benefit from a single instillation of intravesical chemotherapy. Both EAU and NCCN guidelines also recommend 1 immediate instillation of chemotherapy as the entire adjuvant treatment for patients at low risk of recurrence and progression.[1, 69]

Bacillus Calmette-Guérin (BCG) immunotherapy or other intravesical chemotherapies may be used for patients with recurrent disease or those at intermediate risk. Patients at high risk, with T1–high grade or CIS, are advised to undergo intravesical BCG immunotherapy because of the substantial likelihood of disease recurrence and progression.[85, 86, 87, 88, 89, 90]

The EAU guidelines recommend that patients with intermediate- and high-risk tumors receive intravesical BCG after TURBT to reduce the risk of tumor recurrence. For optimal efficacy, BCG must be given on a maintenance schedule; 3-year maintenance is more effective than 1-year to prevent recurrence of high-risk tumors, but not of intermediate-risk tumors.[69]

In 2016, the US Food and Drug Administration (FDA) granted accelerated approval of atezolizumab, the first cancer immunotherapy that acts as an inhibitor of programmed cell death ligand 1 (PD-L1), for the treatment of urothelial carcinoma. Nivolumab, another PD-L1 inhibitor, was approved by the FDA in 2017. For more information, see Chemotherapeutic Regimens for Metastatic Bladder Cancer, below.

Surgery and radiation therapy

Endoscopic TURBT is the first-line intervention to diagnose, stage, and treat visible tumors. TURBT is not effective for CIS, because the disease is often so diffuse and difficult to visualize that complete surgical removal may not be feasible. It is critically important to surgically remove all non–muscle-invasive disease prior to beginning intravesical therapy. When a combination of papillary tumor and CIS is present, the papillary tumor is removed before treatment of the CIS is initiated.

The EAU guidelines recommend the use of fluorescence-guided resection, as it is more sensitive than conventional white-light cystoscopy for detection of tumors.[91, 92, 93] The added detection rate with fluorescence-guided cystoscopy is 20% for all tumors and 23% for CIS.[94] The FDA has approved the use of blue-light cystoscopy with 5-aminolevulinic acid (Cysview) in patients suspected or known to have non–muscle-invasive bladder cancer on the basis of prior cystoscopy.[95]

As many as 20% of patients initially diagnosed with CIS may have unrecognized invasion beyond the lamina propria. Thus, they may not respond to intravesical therapy. These patients are candidates for radical cystectomy or radiation therapy and/or chemotherapy. Radiation therapy with or without chemotherapy is of limited benefit in patients with pure CIS but can be useful in some patients with muscle-invasive transitional cell carcinoma (TCC).

The criterion standard for the treatment of patients with stage T2-T4 disease is radical cystoprostatectomy for men and anterior pelvic exenteration for women. Additionally, all patients should undergo bilateral pelvic lymphadenectomy.

Level 1 evidence supports the use of preoperative (neoadjuvant) chemotherapy in patients with muscle-invasive bladder cancer. In addition, a series of studies have shown substantial benefit for adjuvant chemotherapy in these patients. Booth and Tannock have noted that few patients in North America receive neoadjuvant therapy, however, and suggest that neoadjuvant or adjuvant therapy should be provided to all patients with muscle-invasive bladder cancer who are sufficiently fit to receive it.[96]

Lymph node dissection

Much controversy exists regarding the optimal extent of the lymph node dissection that should accompany cystectomy. It is clear that at minimum, a meticulous standard dissection should be performed.

While a number of retrospective studies demonstrate no difference in overall survival with standard versus extended lymph node dissection, a growing body of evidence suggests that more extended node dissection may improve survival in both lymph node–positive and lymph node–negative disease. The first prospective, randomized trial to address this question, sponsored by the Southwest Oncology Group (SWOG), is currently enrolling patients.[97]

Small cell carcinoma

The treatment of localized small cell carcinoma is neoadjuvant chemotherapy followed by radical cystectomy or external beam radiation therapy. Chemotherapy using a platinum-based protocol is applied to metastatic disease. In addition, adjuvant therapy may be used in cases of stage III and IV disease that were treated with radical cystectomy.[50, 61, 98]

Adenocarcinoma and lymphoma

Adenocarcinomas respond poorly to radiation and chemotherapy. Radical cystectomy is the treatment of choice. Lymphomas may be effectively treated with chemotherapy or radiation.

Squamous cell carcinoma

For patients with squamous cell carcinoma (SCC), the main treatment is cystectomy because these tumor tend to be chemoresistant. Adjuvant radiation therapy has been reported in patients with locally advanced disease or positive margins.

See Bladder Cancer Treatment Protocols for more information on this topic. Go to Oncology Decision Point for expert commentary on bladder cancer treatment decisions and related guidelines.

Lifestyle measures

Smoking cessation decreases the risk of tumor recurrence and progression and improves overall health. Increased water intake has been advocated because it may help to dilute carcinogens and decrease the exposure of the urothelium to them, but conclusive benefit has not been shown. Multivitamin or vitamin A supplementation has also been advocated, but data do not fully support this practice.[99]

Immunotherapy and chemotherapy

Bacillus Calmette-Guérin (BCG)

Intravesical instillation of BCG is used in the treatment of high-risk Ta, T1, and CIS urothelial carcinoma of the bladder. Immunotherapy with BCG is the most effective intravesical therapy for CIS and T1 tumors. It is less effective in reducing the 5-year recurrence rate for low-grade and low-stage urothelial carcinoma (see Table 2, below).

Table 2. Recurrence and Progression Rates at 5 Years for Ta, T1, and CIS TCC of the Bladder Treated With BCG (Open Table in a new window)

The intravesical instillation of either BCG vaccine or chemotherapy is initiated approximately 2-4 weeks following endoscopic resection of any visible papillary tumors or bladder biopsies. By that time, the bladder has usually healed enough to avoid systemic distribution of the vaccine organism.

See Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer for more information on this topic.

Gene therapy

In December 2022, nadofaragene firadenovec (Adstiladrin) became the first gene therapy approved for adults with bladder cancer. It is indicated for high-risk BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with CIS, with or without papillary tumors. Nadofaragene firadenovec is a non-replicating adenoviral vector–based gene therapy that delivers a copy of a gene encoding a human interferon-alfa 2b (IFNα2b) to the bladder urothelium. Intravesical instillation results in cell transduction and transient local expression of IFNα2b protein that is anticipated to have antitumor effects. 

Approval was supported by a phase 3, multicenter, open-label, repeat-dose study in adults with BCG-unresponsive NMIBC with Eastern Cooperative Oncology Grouip status of 2 or less. Among 151 patients included in the per-protocol efficacy analyses, 55 (53.4%) of 103 patients with CIS (with or without a high-grade Ta or T1 tumor) had a complete response within 3 months of the first dose and this response was maintained in 25 (45.5%) of 55 patients at 12 months.[100]  

Immunotherapy

Interferon alfa or gamma has been used in the treatment of stages Ta and T1 and CIS urothelial carcinoma, either as single-agent therapy or in combination with BCG.[101] Its role has primarily been in treatment following BCG failure. Early results in nonrandomized, retrospective series have reported a 42% response with tolerable adverse effects after BCG failure. However, no evidence has indicated that retreatment with BCG plus interferon is superior to retreatment with BCG alone.

Patients who have a recurrence within 12 months after 2 courses of BCG (preferably 6+3 treatments) do not benefit from treatment with BCG plus interferon. In addition, in a randomized study of BCG versus BCG plus interferon in BCG-naive high-risk patients, the addition of interferon was equivalent to BCG alone.[102]

Kamat et al found that the results of fluorescence in situ hybridization (FISH) assays can identify patients at risk for tumor recurrence and progression who are undergoing BCG immunotherapy. This information could be useful in counseling patients about alternative treatment strategies.[103]

Patients with BCG-refractory CIS may also be treated with intravesical valrubicin (Valstar), which is approved for this particular indication. However, any patient who has persistent or recurrent disease after BCG should be considered for radical cystectomy, given the high rate of disease progression.

Another option is pembrolizumab (Keytruda), which is indicated for treatment of BCG-unresponsive, high-risk, non–muscle-invasive bladder cancer with CIS with or without papillary tumors in patients who are ineligible for, or have elected not to undergo, cystectomy. Approval was supported by the KEYNOTE-057 study, which showed a complete response rate of 41% in patients who received pembrolizumab. The median duration of response was 16.2 months.[104, 105]

Intravesical docetaxel appears to be a promising agent for BCG-refractory non–muscle-invasive bladder cancer; adding maintenance treatments of docetaxel may increase the duration of recurrence-free survival. Barlow et al reported that 32 of 54 patients with BCG-refractory bladder cancer showed a complete response to 6 weekly treatments of intravesical docetaxel.[106] Median time to recurrence was 39.3 months in responders treated with maintenance docetaxel, compared with 19 months in those who did not receive maintenance therapy.

Surgery

TURBT

Endoscopic TURBT is the first-line means of diagnosing, staging, and treating visible tumors. Electrocautery or laser fulguration of the bladder tumor is sufficient for low-grade, small-volume, papillary tumors. However, the EAU guidelines recommend resection of small tumors (< 1 cm) in a single piece that includes part of the underlying bladder wall.[69]

The EAU and NCCN guidelines offer similar recommendations for surgical treatment.[1, 69] Patients with bulky, high-grade, or multifocal tumors should undergo a second procedure to ensure complete resection and accurate staging 2-6 weeks after the initial TURBT.

Both guidelines state that a second resection should be performed at this time if these or other factors, such as an absence of muscle tissue in the initial specimen, indicate that the initial TURBT was incomplete. Resection of large tumors (> 1 cm diameter) should be performed in fractions, including muscle tissue.[1, 69] Approximately 30% of stage T1 tumors are upgraded to muscle-invasive disease.

Fluorescence-guided resection

The EAU guidelines recommend fluorescence-guided resection, as it is more sensitive than white-light cystoscopy alone for detection of tumors, particularly CIS.[107, 108, 109] The FDA has approved blue-light cystoscopy with hexaminolevulinate (Cysview) as an adjunct to white-light cystoscopy in patients suspected or known to have non–muscle-invasive papillary cancer of the bladder on the basis of a prior cystoscopy. This technique is not a replacement for random bladder biopsies or other procedures used in the detection of bladder cancer and is not for repetitive use.

Blue-light cystoscopy with hexaminolevulinate detects more Ta/T1 bladder cancer lesions than does white-light cystoscopy alone.[107, 108, 109, 110, 111] (See the image below.) Stenzl et al reported that in patients with Ta or T1 tumors, at least one of the tumors was seen only with fluorescent cystoscopy in 16% of patients.[112] Improved detection leads to improved tumor resection, as every tumor detected is resected in the same TURBT.[113]

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.

No further metastatic workup is needed for obviously superficial tumors. Because bladder cancer is a polyclonal field change defect, continued surveillance is mandatory.

See Transurethral Resection of Bladder Tumors for more information on this topic.

Radical cystectomy

Although radical cystectomy is typically reserved for muscle-invasive disease, it is also appropriately used to treat some patients with high-risk, non–muscle-invasive bladder cancer, including CIS. Indications in non–muscle-invasive disease include the following:

• Tumor bulk so substantial that complete eradication of tumor is not feasible endoscopically
• Prostatic urethra involvement
• CIS or T1 high-grade tumor persistence despite adequate intravesical management

Eliminating visible lesions with resection is preferable prior to intravesical BCG, but some CIS lesions may not be readily visible. Blue-light cystoscopy may improve the detection of CIS.[112] Patients who do not respond to BCG instillations often find cystectomy difficult to accept and, instead, want to continue trying various intravesical instillations.

The difficulty of accurately staging CIS preoperatively was demonstrated by Tilki and a group of international investigators.[114] These researchers reported that of 243 patients who were considered to have only CIS before cystectomy, only 117 (48.1%) were found to actually have CIS; 20 patients (8.2%) had no cancer (pT0), and 19 patients (7.8%) had urothelial cancer only. The disease was up-staged in 36% of the patients. The overall 5-year recurrence-free and cancer-specific survival was 74% and 85%, respectively.

From 35-50% of patients who undergo cystectomy for Ta, T1, or CIS are discovered to have muscle-invasive disease, with 10-15% demonstrating microscopic lymph node metastasis. According to the NCCN guidelines, cystectomy should involve at least bilateral node dissection, including iliac and obturator nodes.[1]

Patients with T1 high-grade cancer in association with diffuse CIS are at especially high risk of progression, and they may be treated with early cystectomy based on a decision made by the physician and patient. The EAU guidelines recommend that immediate cystectomy be considered for such patients.[69]

CIS progresses to muscle-invasive disease in upwards of 80% of affected patients, with 20% of patients found to have muscle-invasive disease at the time of cystectomy. High-grade T1 tumors that recur despite BCG have a 50% likelihood of progressing to muscle-invasive disease. Cystectomy performed prior to progression yields a 90% 5-year survival rate. The 5-year survival rate drops to 30-50% in muscle-invasive disease. The EAU guidelines strongly advocate cystectomy in patients with early BCG failure.[69]

Radical cystectomy

The criterion standard for the treatment of patients with stage T2-T4 disease is radical cystoprostatectomy for men and anterior pelvic exenteration for women Additionally, bilateral pelvic lymphadenectomy should be offered.

Cystoprostatectomy involves removal of the bladder, peritoneal covering, perivesical fat, , prostate, seminal vesicles, vasa deferentia, and, sometimes, the membranous or entire urethra. Total urethrectomy is rarely performed concomitantly for primary cancer of the bladder in the male since the vast majority of cases a negative urethral margin can be achieved. Those with a positive urethral margin on final pathology can be considered for a delayed urethrectomy.[80]

Anterior pelvic exenteration consists of cystectomy, urethrectomy, hysterectomy, salpingo-oophorectomy, and partial anterior vaginectomy. Vaginal-sparing techniques can be considered in low stage patients, which will help with the preservation of sexual function.[115] Additionally, there is evidence suggesting that removing the fallopian tubes alone may decrease the risk of ovarian cancer without impacting hormonal function.[116, 117]

In experienced hands, robot-assisted radical cystectomy may offer the advantages of reduced blood loss, opiate requirement, and hospital stay. As this is a relatively new procedure, surgeons performing it need to provide detailed informed consent and a full description of potential complications and outcomes.[118]

Emerging retrospective data from multiple institutions suggest that a longer interval from the time of diagnosis to radical cystectomy can adversely affect pathologic stage and survival.[119] For example, at the University of Pennsylvania, patients who underwent radical cystectomy within 12 weeks of the diagnosis had a lower incidence of advanced pathologic stage (42% vs 84% with extravesical disease), lower incidence of positive lymph nodes, and an increased 3-year survival rate (62% vs 35% with extravesical disease).[120]

Pelvic lymphadenectomy

Approximately 25% of patients undergoing radical cystectomy have lymph node metastases at the time of surgery. Bilateral pelvic lymphadenectomy (PLND) should be performed in conjunction with radical cystoprostatectomy and anterior pelvic exenteration. PLND adds prognostic information by appropriately staging the patient and may confer a therapeutic benefit. Furthermore, AUA guidelines recommend a standard lymphadenectomy, which includes the external and internal iliac and obturator lymph nodes. 

PLND can be performed in a standard or an extended version. The boundaries of a standard PLND include the bifurcation of the common iliac artery and vein superiorly, the genitofemoral nerve laterally, the obturator fossa posteriorly, and the circumflex iliac vein (or node of Cloquet) inferiorly.

Extended PLND includes the lymph nodes in the presacral region and those surrounding the common iliac vessels to the level of the aortic bifurcation. For a supra-extended PLND, dissection can be continued to the level of the inferior mesenteric artery. In rare cases, patients with lymph node metastases have “skip lesions” (ie, positive nodes in the extended dissection with negative pelvic lymph nodes).

The additional benefit of an extended PLND is controversial. On the basis of several retrospective studies, some experts believe that an extended dissection provides additional staging information and offers a survival benefit. However, no randomized trials to date have proved that an extended PLND is more beneficial than the standard procedure. In a randomized trial of extended versus limited lymph node dissection performed in Germany, extended node dissection failed to show a significant improvement in recurrence-free, cancer-specific, or overall survival.[121] A Southwestern Oncology Group (SWOG) prospective, randomized trial comparing standard with extended pelvic lymphadenectomy has completed accrural and should report in 2022.[97]

Urinary diversion

After cystectomy is performed, a urinary diversion must be created from an intestinal segment. Diversions can be incontinent or continent. Contraindications to performing continent urinary diversions are as follows:

• Multiple comorbid health problems
• Chronic renal insufficiency
• Hepatic dysfunction
• Advanced disease stage

Incontinent urinary diversion

Conduits can be constructed from either ileum or colon. The most common incontinent diversion is the ileal conduit (see the image below), which has been used for more than 40 years with excellent reliability and minimal morbidity.

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 this procedure, a small segment of ileum (at least 15 cm proximal to the ileocecal valve) is taken out of gastrointestinal continuity but maintained on its mesentery, with care to preserve its blood supply. The gastrointestinal tract is restored with a small-bowel anastomosis. The ureters are anastomosed to an end or side of this intestinal segment and the other end is brought out as a stoma to the abdominal wall. Urine continuously collects in an external collection device worn over the stoma.

Continent urinary diversion

The most commonly used continent cutaneous urinary diversion is the Indiana pouch (see the image below). Introduced in 1987, the Indiana pouch is a urinary reservoir created from a detubularized right colon and an efferent limb of terminal ileum. The terminal ileum is plicated and brought to the abdominal wall. The ileocecal valve acts as a continence mechanism. The Indiana pouch is emptied with a clean, intermittent catheterization 4-6 times per day.

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.

The orthotopic neobladder is another form of continent urinary diversion. In neobladder diversions (see the image below), various segments of intestine, including the ileum, ileum and colon, and sigmoid colon, can be used to construct a reservoir. The ureters are implanted to the reservoir, and the reservoir is anastomosed to the urethra.

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.

Neobladder diversions have been performed successfully in men for more than 20 years and, more recently, in women. The orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder. Patients have volitional control of urination and void by Valsalva.

A variety of other continent urinary reservoirs have been developed. These vary primarily in the continence mechanisms utilized.

Neoadjuvant chemotherapy in muscle-invasive disease

Cisplatin-based neoadjuvant chemotherapy has become the standard of care in muscle-invasive bladder cancer.[70] Giving chemotherapy prior to radical cystectomy may improve cancer-specific survival, presumably by treating micrometastatic disease and pathologic downstaging.[122] A meta-analysis of 11 trials showed an overall survival rate benefit of 5% in patients who received neoadjuvant chemotherapy.[123]

If locally advanced TCC is suspected, based on clinical staging, the rationale for neoadjuvant chemotherapy prior to cystectomy may be even stronger. In a SWOG multicenter, randomized, prospective study of neoadjuvant therapy with a combination of methotrexate, vinblastine, doxorubicin, and cisplatin, the investigators concluded that neoadjuvant therapy conferred a treatment benefit compared with surgery alone for locally advanced bladder cancer.[124]  Median survival in patients treated with surgery was 46 months as compared to 77 months in patients assigned to receive neoadjuvant MVAC followed by cystectomy. [124]

However, several criticisms of this study exist. The study was underpowered because of slow recruitment (317 patients over 11 y), because 20% of the patients who were to undergo cystectomy alone never had the surgery, and because there was no comparison to neoadjuvant therapy alone or adjuvant therapy. In addition, a study that reevaluated the SWOG data found that surgical factors significantly affected outcomes.[125]

The gemcitabine and cisplatin combination is frequently substituted for the classic MVAC. Studies have shown non-inferiority to the MVAC regimen. The American Urological Association (AUA) states that cisplatin plus gemcitabine is widely accepted by the oncology community as an alternative to MVAC because of its better tolerability.[126]   

A phase III trial that assessed 976 patients with muscle-invasive bladder cancer using neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy found that risk of death was decreased by 16%. Chemotherapy was followed by cystectomy and/or radiotherapy.[127]

Advanced urothelial carcinoma that develops resistance to platinum-based chemotherapy has often also developed resistance to inhibitors of the epithelial growth factor receptor (EGFR) family of receptor tyrosine kinases. However, a review by Mooso et al notes that EGFR family inhibitors such as erlotinib may be of use in patients with no prior chemotherapy in whom EGFR or ERBB2 is over expressed.[128]

Adjuvant chemotherapy in muscle-invasive bladder cancer

Although the evidence supporting adjuvant chemotherapy is less compelling than that for neoadjuvant chemotherapy, some patients may benefıt from adjuvant chemotherapy, such as those who underwent up-front radical cystectomy and have extensive tumor invasion of the bladder wall or lymph node involvement.[70]

The AUA guidelines recommend offering adjuvant cisplatin-based chemotherapy to patients with non–organ-confined (pT3/T4 and/or N+) disease at cystectomy who are eligible for, but have not received, cisplatin-based neoadjuvant chemotherapy.[80]

A phase III trial in 284 patients with pT3 to T4 or node-positive bladder cancer found insignificant improvement in overall survival with adjuvant cisplatin-based chemotherapy given within 90 days after cystectomy, compared with deferral of chemotherapy until relapse: after a median follow-up of 7 years, 66 of 141 patients (47%%) in the immediate chemotherapy arm had died, compared with 82 out of 143 (57%) in the deferred chemotherapy arm (P=0.13). However, patients who received iimmediate adjuvant chemotherapy had significantly longer progression-free survival (PFS): 5-year PFS was 47.6% in the immediate chemotherapy arm versus 31.8% in the deferred treatment arm (P< 0.0001).[129]

This study did not meet its accrual goal of 644 patients and was terminated early. Nevertheless, it remains the largest randomized trial of adjuvant chemotherapy to date.[70]

First-line, platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma. However, long-term outcomes, including disease-specific and overall survival, remain suboptimal.

Methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is a standard combination regimen for treatment of metastatic bladder cancer. MVAC has an objective response rate of 57-70% and a complete response rate of 15-20%. Median overall patient survival with this regimen is typically 13-15 months, and the 2-year survival rate is 15-20%.[130, 131, 132]

Gemcitabine and cisplatin (GC) is a newer regimen that has been shown to be as effective as MVAC but with less toxicity.[133] In particular, less nephrotoxicity is seen with GC than with MVAC.[134] GC is now considered a first-line treatment for bladder cancer. Unfortunately, about 40-50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy.

Programmed cell death inhibitors

Agents that inhibit programmed cell death 1 (PD-1) protein and its ligands PD-L1 and PD-L2, which are part of immune checkpoint pathways that regulate T-cell activation to escape antitumor immunity, have entered clinical practice as second-line therapy for metastatic urothelial carcinoma, and are beginning to establish a role as first-line agents in patients who are not candidates for cisplatin chemotherapy. Agents in this category include atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab.

Previously, second-line therapy had represented a significant unmet medical need. While vinflunine, a vinca alkaloid, was approved in Europe based on the results of a phase III trial versus best supportive care in the second-line setting, its efficacy is marginal.[135] The median survival for patients treated with second-line therapy such as vinflunine or other agents, including the taxanes and pemetrexed, is only 6-9 months.

Atezolizumab

Atezolizumab (Tecentriq) is the first PD-L1 inhibitor approved for the treatment of urothelial carcinoma. In May 2016, the US Food and Drug Administration (FDA) granted accelerated approval of atezolizumab for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[136] In April 2017, atezolizumab’s indication was expanded to include use as initial treatment of locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin chemotherapy.

Approval of atezolizumab was based on the phase II IMvigor 210 trial (n=310), an open-label, multicenter, single-arm study with two cohorts. In the previously treated patients (cohort 2), the objective response rate (ORR) was 26% for the subgroup with the highest positivity for PD-L1, 18% for the subgroup with lower positivity, and 15% for all patients. Median overall survival was 7.9 months for all patients, 11.4 months for the highest-positivity subgroup, and 6.7 months for the lowest-positivity subgroup. Twelve-month overall survival was 36% for all patients, 48% for the high group, and 30% for the low group.[136]

In the treatment-naive patients (cohort 1), the ORR was 23.5%. Complete responses were seen in 6.7%, and partial responses were seen in 16.8%.[137]

The FDA has also approved a complementary diagnostic, the Ventana PD-L1 (SP142) assay, which can detect PD-L1 protein expression levels on tumor-infiltrating immune cells and help physicians determine which patients may derive the most benefit from treatment with atezolizumab.

In IMvigor 211, a confirmatory phase III study that compared atezolizumab with chemotherapy in patients whose bladder cancer had progressed on at least one prior platinum-containing regimen, overall survival was numerically, but not significantly, longer in the atezolizumab group than in the chemotherapy group (median 15.9 vs 8.3 months, respectively). However, the safety profile of atezolizumab was superior to that of chemotherapy, with lower rates of grade 3-4 treatment-related adverse events (20% vs 43%), and of adverse events leading to treatment discontinuation (7% vs 18%).[138]

Nivolumab

Nivolumab (Opdivo) also gained accelerated approval for advanced or metastatic urothelial carcinoma from the FDA. Approval was based on the CheckMate-275, single-arm, phase II clinical trial (n=270). ORR, confirmed by an independent radiographic review committee using Response Evaluation Criteria in Solid Tumors 1.1, was 19.6% (52/265; 95% confidence index [CI]: 15.0-24.9). Seven patients had complete responses and 46 had partial responses. Estimated median response duration was 10.3 months, with responses ongoing at data cutoff.[139]

The double-blind, randomized phase III CheckMate-274 trial demonstrated the efficacy and safety of adjuvant nivolumab in patients with muscle-invasive urothelial carcinoma after radical surgery (with or without neoadjuvant cisplatin-based combination chemotherapy). Median disease-free survival in the intention-to-treat population was 20.8 months with nivolumab versus 10.8 months with placebo. At 6 months, 74.9% of the 353 patients treated with nivolumab were alive and disease-free, versus 60.3% of the 356 patients treated with placebo (hazard ratio for disease recurrence or death, 0.70; P < 0.001). Among patients with a PD-L1 expression level of 1% or more, those percentages were 74.5% and 55.7%, respectively (hazard ratio, 0.55; 5; P < 0.001).[140]

Avelumab

Avelumab (Bavencio) was also granted accelerated approval in 2017 for advanced urothelial carcinoma that progresses during or following platinum-containing chemotherapy. Approval was based on the JAVELIN solid tumor trial, which comprised 2 cohorts with 44 patients and 200 patients, respectively. The data from both cohorts were pulled together and showed that 161 patients with a follow-up of > 6 months had an overall response rate of 16.1%.[141]

Pembrolizumab

Pembrolizumab (Keytruda) gained approval from the FDA for urothelial carcinoma in May 2017. It is indicated for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy. It is also indicated for patients with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Approval was based on the KEYNOTE-052 trial. As first-line treatment for patients who were ineligible to receive platinum-based chemotherapy, the ORR was 24% at the time of initial phase II data evaluation.[142]

Pembrolizumab is the only drug with data from a phase III trial demonstrating overall survival benefit vs chemotherapy in the second-line setting for metastatic bladder cancer, with an overall response rate of 15-20% in an unselected patient population.[80]  The FDA approval for second-line therapy for advanced urothelial carcinoma was based on an international phase III trial (n=542). ORR was 10.3 months in the pembrolizumab recipients compared with 7.4 months in the chemotherapy group.[143]  

Pembrolizumab plus enfortumab vedotin gained accelerated approval in April 2023 for treatment of locally advanced or metastatic urothelial carcinoma in adults ineligible for cisplatin-containing chemotherapy. Approval was based on the KEYNOTE-869 trial, which showed a 68% ORR and duration of response (DOR) of 2 years with the combination.[144]   

Fibroblast growth factor receptor inhibitors

Erdafitnib

Erdafitinib inhibits fibroblast growth factor receptor (FGFR) phosphorylation and signaling, and thereby decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. FGFRs regulate important biological processes including cell proliferation and differentiation, which are part of a complex signaling pathway in tumorigenesis. 

The FDA granted erdafitinib accelerated approval in 2019 for locally advanced or metastatic urothelial carcinoma that has FGFR2 or FGFR3 genetic alterations and progressed during or following at least 1 line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Approval was based on a multicenter, open-label, single-arm study (n=87) of patients in which the overall response rate was 32.2%, with 2.3% of patients having a complete response and almost 30% having a partial response.[145]

Anti-nectin-4 monoclonal antibodies

Enfortumab vedotin

Enfortumab vedotin is an antibody-drug conjugate (ADC) composed of an anti–nectin-4 monoclonal antibody attached to the cell-killing agent monomethylauristatin E (MMAE). Once the antibody attaches to nectin-4 that is expressed on the tumor, the complex is internalized in the lysosome, which releases MMAE. 

The FDA approved enfortumab vedotin in 2019 for locally advanced or metastatic urothelial cancer in patients who have received a PD-1/L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. Approval was based on the single-arm, phase II EV-201 global trial, which enrolled 125 patients with locally advanced or metastatic urothelial cancer who had received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy. The primary endpoint of confirmed ORR was 44% per blinded independent central review (55/125; 95% CI, 35.1-53.2). Of patients treated with the single agent enfortumab vedotin, 12% (15/125) experienced a complete response and 32% (40/125) experienced a partial response.[146]  

Enfortumab vedotin plus pembrolizumab gained accelerated approval in April 2023 for treatment of locally advanced or metastatic urothelial carcinoma in adults ineligible for cisplatin-containing chemotherapy. Approval was based on the KEYNOTE-869 trial, which showed a 68% ORR and DOR of 2 years with the combination.[144]   

External beam radiation therapy has been shown to be inferior to radical cystectomy for the treatment of bladder cancer. The overall 5-year survival rate after treatment with external beam radiation is 20-40%, compared with a 90% 5-year survival after cystectomy for organ-confined disease. Nevertheless, external beam radiation therapy is used in various countries other than the United States for T2-T3 urothelial carcinoma of the bladder.

Neoadjuvant external beam radiation therapy has been attempted for muscle-invasive bladder cancer. However, no improvement in survival rate has been demonstrated.

In certain centers, a bladder-preserving strategy for T2-T3 urothelial carcinoma is applied using a combination of external beam radiation, chemotherapy, and endoscopic resection. Survival rates associated with this approach are comparable with those of cystectomy in selected patients. This combination has a widespread application that is limited by the complexity of the protocol, its toxicity, and a high peritreatment mortality rate of 4-5%, mostly due to nadir sepsis from the chemotherapy. In comparison, the mortality rate for most modern cystectomy series is 2-3%.

Overall, approximately 30% of patients treated with bladder-preserving therapy experience local recurrence of bladder cancer.[83] A significant number of patients ultimately require salvage cystectomy, which may be associated with decreased options for urinary diversions.

Radical cystectomy

Radical cystectomy has a 2-3% perioperative mortality rate. However, the 6-month mortality may be as high as 7-8% in elderly patients. The two most common late complications are small-bowel obstruction and ureteroenteric stricture (see Table 3, below).

Table 3. Most Common Complications of Radical Cystectomy (Open Table in a new window)

The reported overall complication rate (including early and late complications) for radical cystectomy is approximately 30-40%. However, this may be an underestimation of the true complication rate because of a lack of standardized reporting in published studies.

Many patients who undergo a radical cystectomy have multiple comorbid health risk factors (eg, advanced age, cardiovascular disease, pulmonary disease). Despite these difficulties, this procedure may be performed safely even in patients older than 80 years.

After a radical cystectomy, all men are impotent if the parasympathetic nerves from the pelvic plexus (S2-S4) to the corpora cavernosum are not spared at the time of surgery. A nerve-sparing approach may be associated with potency rates of approximately 50-70%.

Urinary diversion

Complications of urinary diversion include the following:

• Hyperchloremic metabolic acidosis - If the ileum or colon is used
• Urinary tract infections (UTIs)
• Stomal-peristomal inflammation, hernia, or stenosis
• Urinary calculi
• Vitamin B12 deficiency - For diversions affecting the terminal ileum
• Ureterointestinal stenosis leading to hydronephrosis

Orthotopic neobladder complications

Owing to advances in surgical technique, this procedure is commonly used in tertiary centers. Complications include daytime and nighttime urinary incontinence at rates of approximately 5% and 20%, respectively. Urinary incontinence may develop from multiple factors, including injury to the external urethral sphincter, increased urine production from solute absorption, and relaxation of the external sphincter, which is greater at night.

The high rate of disease recurrence and progression in non–muscle-invasive bladder cancer underscores the need for careful follow-up studies. According to the National Cancer Institute, bladder cancer affects approximately 500,000 people in the United States. Because most still have an intact bladder, the number of patients under surveillance approaches this figure.

The EAU guidelines include schedules for follow-up cystoscopy, urinary cytology, and imaging in patients with Ta/T1 tumors, depending on risk of recurrence and progression. For follow-up in patients with no visible tumor in the bladder but positive cytology, the guidelines recommend biopsies and investigation of extravesical locations.[69]

For follow-up after a radical cystectomy for muscle-invasive bladder cancer, NCCN recommendations are as follows[1] :

• Imaging: For the first two years, patients should undergo computed tomography (CT) or magnetic resonance imaging (MRI) urography (imaging of upper tracts plus axial imaging of abdomen and pelvis) every 3-6 months. Chest x-ray or CT every 3-6 months or fluorodeoxyglucose positron emission tomography/CT (FDG PET/CT) (category 2B) is recommended only if metastatic disease is suspected. In years 3 through 5, patients should have abdominal/pelvic CT or MRI annually. Chest  x-ray annually or FDG PET/CT (category 2B) is recommended only if metastatic disease is suspected. After year 5, patients should have annual ultrasound to look for hydronephrosis; after more than 10 years, imaging is needed only if clinically indicated.
• Blood tests: Kidney function testing (electrolytes and creatinine) is recommended every 3-6 months. A complete blood cell count (CBC) and comprehensive metabolic panel (CMP) should be performed every 3-6 months in patients who received chemotherapy. Liver function tests (LFTs) should be performed every 3-6 months. In year 2 through year 5, patients should have annual kidney function testing, LFTs, and vitamin B12 assays. After year 5, patients should have annual monitoring of vitamin B12 levels.
• Urine tests: For the first two years following radical cystectomy, patients should have urine cytology every 6-12 months; consider urethral wash cytology every 6-12 months for patients with high-risk disease (eg, postitive urethral margin, multifocal CIS, prostatic urethal invasion). Cytology should be performed at the time of cystoscopy if bladder in situ. 

For follow-up after a segmental (partial) cystectomy or bladder preservation, the NCCN recommendations are as follows[1] :

• Cystoscopy: Every 3 months for the first two years, every 6 months for years 3 and 4, annually for years 5 through 10. After 10 years, cystoscopy should be performed only if clinically indicated.
• Imaging: Every 3-6 months for the first 2 years, patients with muscle-invasive bladder cancer should undergo CT or MRI urography (imaging of the upper tracts plus axial imaging of abdomen/pelvis), as well as chest x-ray or chest CT. Alternatively, FDG PET/CT (category 2B) may be performed, but only if metastatic disease is suspected. In years 3 through 5, patients should have those imaging studies annually (category 2B). After year 5, imaging is used if clinically indicated.
• Blood tests: In the first year, patients should undergo kidney function testing and LFTs every 3-6 months, along with CBC and CMP if they received chemotherapy. Following the first year, patients should have kidney function testing and LFTs as clinically indicated.
• Urine tests: For the first two years, patients should have urine cytology every 6-12 months. Following year 2, patients should  have urine cytology only if clinically indicated.

See Surveillance for Recurrent Bladder Cancer for more information on this topic.

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)

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]

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

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

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.

The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the standard treatment for metastatic bladder cancer. No proven role exists for adjuvant chemotherapy. MVAC has substantial toxicity, which must be weighed against the expected benefit. The major dose-limiting toxicity is myelosuppression.

Newer combination regimens show response rates and median survival comparable to those for MVAC but with less toxicity. Gemcitabine plus cisplatin is now considered a first-line treatment for bladder cancer. Therapy with programmed cell death ligand 1 (PD-L1) inhibitors (eg, atezolizumab, nivolumab, durvalumab, avelumab, pembrolizumab) is now approved by the US Food and Drug Administration (FDA) for advanced urothelial carcinoma. Erdafitinib is the first fibroblast growth factor receptor (FGFR) inhibitor approved by the FDA for urothelial carcinoma, in April 2019. The first anti-nectin-4 monoclonal antibody, enfortumab vedotin, was approved for urothelial carcinoma in December 2019. The first gene therapy, nadofaragene firadenovec, was approved in December 2022. 

Class Summary

These agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.

Fluorouracil (Adrucil)

Fluorouracil is a pyrimidine antimetabolite. Several mechanisms of action have been proposed, including inhibition of thymidylate synthase and inhibition of RNA synthesis. This agent is also a potent radiosensitizer. Although not approved by the FDA for this indication, it is often used as a treatment for bladder cancer,., commonly in Cisplatin/Fluorouracil combinations.

Methotrexate (Trexall, Rasuvo, Otrexup, Xatmep)

Methotrexate inhibits dihydrofolate reductase (DHFR), causing a block in the reduction of dihydrofolate to tetrahydrofolate. This inhibits the formation of thymidylate and purines and arrests DNA, RNA, and protein synthesis.Common toxicities include mucositis and myelosuppression. It is often used as a treatment for bladder cancer, although that is not an FDA-approved indication.

Gemcitabine (Gemzar)

Gemcitabine is a pyrimidine analog. After intracellular metabolism to its active nucleotide, it inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Although it does not have FDA approval for this indication, it is often used as a treatment for bladder cancer. Gemcitabine is used in combination with cisplatin for the treatment of advanced or metastatic bladder cancer. It is also used as an intraveiscal treatment.

Pemetrexed (Alimta)

Pemetrexed disrupts the folate-dependant metabolic processes important for cell replication, inhibits the enzymes involved in folate metabolism and DNA synthesis, and inhibits protein synthesis. Although it does not have FDA approval for this indication, it is often used for the treatment of metastatic bladder cancer. Folic acid and vitamin B12 are typically given prior to initiation of treatment. Dexamethasone is also given with pemetrexed, to minimize cutaneous reactions.

Class Summary

Vinca alkaloids act on the M and S phases of mitosis, inhibiting microtubule formation and inhibiting DNA/RNA synthesis.

Vinblastine

A vinca alkaloid with a cytotoxic effect (as a result of causing mitotic arrest), vinblastine binds to a specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation. Although not FDA approved for this indication, vinblastine is often used as a treatment for bladder cancer in combination with a chemotherapy regimen.

Vinblastine is approved for intravenous use only; the FDA has issued a black box warning regarding possible death with intrathecal administration. Vinblastine is a moderate vesicant and extravasation should be avoided.

Class Summary

Anthracycline antineoplastics inhibit DNA and RNA synthesis by steric obstruction. They intercalate between DNA base pairs and trigger DNA cleavage by topoisomerase II.

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline antineoplastic that causes DNA strand breakage through effects on topoisomerase II and direct intercalation into DNA, which causes DNA polymerase inhibition. It has a labeled indication for the treatment of bladder cancer. The largest benefit this agent has compared with other intravesical chemotherapeutic agents is its low cost and ability to decrease tumor recurrence.This drug has several black box warnings, including bone marrow suppression, myocardial toxicity, and secondary malignancy.

Valrubicin (Valstar)

Valrubicin is a semisynthetic analog of doxorubicin that inhibits incorporation of nucleosides into nucleic acids. It is indicated for intravesicular treatment of bladder carcinoma in situ (CIS) that is refractory to treatment with bacillus Calmette-Guérin (BCG).

Class Summary

These agents inhibit cell growth and proliferation. They inhibit DNA synthesis by the formation of DNA cross-links. Alkylating agents can have serious adverse effects, including bone marrow suppression, anaphylactic-like reactions, ototoxicity, renal toxicity, and vomiting.

Cisplatin

Cisplatin is a platinum-containing compound that exerts an antineoplastic effect by covalently binding to DNA, with preferential binding to the N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. The platinum complex also can bind to nuclear and cytoplasmic protein. Cisplatin has black box warnings, including anaphylactic-like reactions, ototoxicity, and renal toxicity.

Carboplatin

Carboplatin is a platinum alkylating agent that interferes with the function of DNA by producing interstrand DNA cross-links. It can be used in combination with paclitaxel for the treatment of bladder cancer, which is an off-label indication. Carboplatin has black box warnings, including bone marrow suppression, anaphylactic reactions, and vomiting.

Ifosfamide (Ifex)

Ifosfamide is a nitrogen mustard alkylating agent that inhibits DNA and protein synthesis. Although not FDA approved for this indication, ifosfamide is often used as a treatment for metastatic bladder cancer.

Thiotepa (Tepadina)

Thiotepa is an alkylating agent that inhibits DNA, RNA, and protein synthesis by producing cross-links between DNA strands. It is available as a powder for reconstitution and administration by injection. Thiotepa is indicated for the treatment of superficial papillary bladder cancer.

Class Summary

These agents prevent cell growth and proliferation. They work by enhancing tubulin dimers, as well as by stabilizing existing microtubules and inhibiting their disassembly.

Docetaxel (Taxotere, Docefrez)

Docetaxel inhibits the depolymerization of tubulin, which inhibits DNA, RNA, and protein synthesis. It can be used for the treatment of bladder cancer, which is an off-label indication. It has several black box warnings, including bone marrow suppression, fluid retention, and hypersensitivity reactions. Its use is not recommended in certain patients with hepatic impairment. Patients receiving docetaxel treatment should be premedicated with corticosteroids the day before administration to help reduce fluid retention and hypersensitivity reactions.

Class Summary

PDL1 is expressed on the surface of activated T cells under normal conditions. PDL1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PDL1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

Atezolizumab (Tecentriq)

Monoclonal antibody to programmed cell death ligand-1 protein (PDL1). It blocks the interaction between PDL-1 and its ligands. It is indicated for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy, or have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Nivolumab (Opdivo)

Monoclonal antibody to programmed cell death ligand-1 protein (PDL1). It blocks the interaction between PDL-1 and its ligands. It is indicated for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Avelumab (Bavencio)

Avelumab is an anti-PD-L1 IgG1 monoclonal antibody.  It is indicated for locally advanced or metastatic urothelial carcinoma (UC) in patients who have disease progression during or following platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Pembrolizumab (Keytruda)

Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is indicated as first-line treatment for locally advanced or metastatic urothelial carcinoma (UC) in patients who are not eligible for cisplatin-containing chemotherapy. It is also indicated for patients with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Additionally, pembrolizumab is indicated for treatment of BCG-unresponsive, high-risk, nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors in patients who are ineligible for, or have elected not to undergo cystectomy. It is also indicated in combination with enfortumab vedotin for locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy. 

Class Summary

Fibroblast growth factor receptor (FGFR) regulate important biological processes including cell proliferation and differentiation, which are part of a complex signaling pathway in tumorigenesis.

Erdafitinib (Balversa)

Erdafitinib inhibits FGFR phosphorylation and signaling, and thereby, decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. It is indicated for locally advanced or metastatic urothelial carcinoma that has FGFR2 or FGFR3 genetic alterations and progressed during or following at least 1 line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Class Summary

Nectin-4 is a cell adhesion molecule that is expressed on many solid tumors.

Enfortumab vedotin (Padcev, enfortumab vedotin-ejfv)

Enfortumab vedotin is an antibody-drug conjugate (ADC) composed of an anti-nectin-4 monoclonal antibody attached to the cell-killing agent, monomethylauristatin E (MMAE). Once the antibody attaches to nectin-4 that is expressed on the tumor, the complex is internalized in the lysosome, which releases MMAE. Enfortumab vedotin is indicated for locally advanced or metastatic urothelial cancer in patients who have received a PD-1/L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. It is also indicated in combination with pembrolizumab for locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy. 

Class Summary

Non-replicating adenoviral vector-based gene therapy delivers a copy of a gene encoding a human interferon-alfa 2b (IFNα2b) to bladder urothelium. Intravesical instillation results in cell transduction and transient local expression of IFNα2b protein that is anticipated to have antitumor effects. 

Nadofaragene firadenovec (Adstiladrin)

Indicated for high-risk Bacillus Calmette Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. Instilled via bladder instillation every 3 months.