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Information for Physicians, Healthcare Providers, and Researchers

Overview and epidemiology

Bladder cancer is a common urologic cancer characterized by the highest recurrence rate of all cancers. Nine out of every ten patients diagnosed with bladder cancer are >55 years old (mean age at diagnosis: 70 years). The overall lifetime risk for presenting with bladder cancer is 2.4%. Currently, there are >500,000 bladder cancer survivors residing in the USA alone. In European countries the incidence rate for urinary bladder cancer is 17 cases per 100,000 persons, while the attributable mortality rate is 4.5 cases per 100,000 persons. In the USA, the incident rate is notably higher at 20.5 cases per 100,000 persons. Both in Europe and the USA the annual number of deaths attributed to bladder cancer is 4.4 per 100,000 persons.Bladder cancer develops in both men and women. In men bladder cancer is the fourth most common cancer. Older men (>65 years old) are 3 to 4 times more likely to develop bladder cancer than their female counterparts.

At diagnosis, approximately 70% of the bladder cancer patients have tumors which are either non-muscle-invasive or carcinomas in situ (see: Bladder cancer staging). The rest (approximately 30%) of incident bladder cancer cases have tumors, which are muscle-invasive. This includes patients with tumors which have invaded nearby organs and structures of the pelvis, and also patients diagnosed with distant metastases (approximately 4%), primarily to the lungs, liver, and bone (see: Clinical signs and symptoms).

Histological types of bladder cancer

Five known histological types of bladder cancer exist, arising as tumorous growths in the inner tissue lining of the urinary bladder wall. The most frequent type of bladder cancer, found in excess of 90% of all newly diagnosed patients, is Transitional Cell Carcinoma (TCC). TCC arises from abnormal growths of the innermost bladder lining, known as the urothelium, or transitional epithelium. TCC is identified as either non-muscle-invasive bladder cancer if tumorous growth is confined to the transitional epithelium, or as muscle-invasive bladder cancer if the tumor has infiltrated the bladder's muscle or deeper tissue layers, such as the fatty connective tissue. Due to perpetration into the deeper tissue layers, invasive bladder cancer is more likely to penetrate nearby structures and organs, as well as to metastasize to distant organs, such as liver, lungs, and bone. As a result, muscle-invasive bladder cancer is more difficult to treat (see: Treatment strategies). TCC presents as either papillary or flat carcinomas. Papillary carcinomas are well-differentiated nodular projections of the transitional epithelium into the hollow cavity of the urinary bladder. In contrast, flat carcinomas develop within the bladder lining. When confined to the transitional epithelium, flat carcinomas are identified as carcinoma in situ (CIS). If timely treatment is neglected, though, both papillary and flat carcinomas (particularly CIS) can develop into muscle-invasive bladder cancer.

Squamous Cell Carcinoma (SCC) accounts for 5% of bladder cancer cases. The majority of SCCs are invasive cancers. SCCs are most often found in patients with chronic parasitic bladder infections, such as Schistosomiasis. Other types of bladder cancer are even more rare. Adenocarcinomas account for 1% of cases, and Small Cell Carcinomas, arising from neuroendocrine cells, account for 0.5% of cases. Sarcomas of the bladder have been reported but are extremely rare. Finally, other rare bladder cancer types include secondary malignancies, mesenchymal tumors, lymphomas, and lymphoepithelial variants.

Etiology and prevention

The exact etiology of bladder cancer is multifactorial and still under investigation. However, several risk factors for bladder cancer have been identified. Four fifths of bladder cancer cases are attributed to environmental exposures, including exposures to cigarette smoking, industrial chemicals, dietary supplements, and contaminated drinking water. Avoidance and or modification of these risk factors may prevent onset and/or progression of bladder cancer. The remaining one fifth of cases is attributed to patient clinical and genetic factors.

The most prominent environmental risk factor for bladder cancer is cigarette smoking. Smoking history is documented in approximately 50% of bladder cancer patients. Disease risk is correlated with both duration and intensity of smoking history, with no differential risk between genders. A second environmental risk for bladder cancer is occupational and/or other exposures to industrial chemicals (ie aromatic amines and aniline dies) used in the paint, textiles, rubber, and leather industries. Additional suspected occupational hazards which have been associated with increased disease risk are occupational exposures to hair dyes (ie hair-dressers) and diesel fumes (ie occupational drivers). Consumption of dietary supplements containing aristolochic acid have also been associated with an increased risk of bladder cancer. Finally, consumption of arsenic in drinking water, such as from contaminated well water sources, is also associated with increased cancer risk.

Age and gender are the most prominent patient factors associated with bladder cancer risk. Bladder cancer risk increases with advancing age, as nine out of 10 patients are >55 years at diagnosis (mean age: 70 years). In particular, males aged >65 years are 3 to 4 times more likely to develop bladder cancer than their female counterparts. In addition, chronic urinary tract infections - e.g. from parasitic infections such as schistosomiasis, or long-term indwelling urethral catheters - increase bladder cancer risk. Other patient clinical risk factors include a personal history of bladder birth defects, prior urothelial cancer, and/or prior radiation therapy or chemotherapy (ie cyclophosphamide use). A family history of bladder cancer also increases individual's risk of developing the disease. While investigations of genetic variants causing tumor progression are underway, accumulating evidence has indicated that mutations in both tumor suppressor genes (ie RB1 and TP53) and oncogenes (ie FGFR and RAS) are implicated in bladder cancer development.

Clinical signs and symptoms

In approximately 90% of patients the primary symptom of bladder cancer is painless hematuria, with or without accompanying anemia. All patients presenting with painless gross hematuria ought to be considered as probable bladder cancer cases until proof of an alternative diagnosis is established. Disease progression causes changes in bladder habits. Irritative voiding symptoms occur in approximately 25% of patients, including increased voidance frequency, painful urination, and dysuria. With advanced disease urinary obstruction occurs, and pyuria may follow. A palpable pelvic mass may be detectable upon clinical examination in advanced tumors. The growing pelvic mass results in pelvic pain. Edema in the lower extremities follows. Distant metastasis of disease is usually to the liver, lungs, and bone. Bone metastases cause pain in the bones and joints. Loss of appetite and weight loss (cancer cachexia) characterize terminal stage of disease.

Current diagnostic approaches

The cornerstone for the diagnosis of bladder cancer is a thorough medical history, including exposures to bladder cancer risk factors. Upon suspicion of bladder cancer, urine analysis and cystoscopy are conducted. Cystoscopy is used to visually evaluate the inner bladder lining. Fluorescence cystoscopy, also known as blue light cystoscopy, is an alternative approach. It entails porphyrins to be absorbed by cancerous cells which then fluoresce, facilitating the evaluation of the bladder lining for suspect lesions.

Specimens are collected during a following Transurethral Resection of the Bladder Tumor (TURBT). Histopathological analyses of these samples determine the invasiveness and grade of the suspected tumor (see: Bladder cancer staging). Low grade tumors are well-differentiated growths with best therapeutic response. In contrast, high grade tumors are undifferentiated growths which are likely to metastasize and have poorer response to treatment (see: Disease prognosis).

Patients' acceptance of cystoscopy is often limited by the procedure's invasiveness. The diagnostic capability of cystoscopy is dependent upon urologists' experience. Flat lesions may impede bladder lining evaluations of even highly skilled urologists. Voided urine cytologic analysis is thus used as an adjunct diagnostic approach for detecting cancer cells. More recently, adjuvant non-invasive urinary tumor marker tests for detecting primary or recurrent bladder cancer have been developed (see: Novel biomarkers for bladder cancer).

Imaging techniques determine tumor size, as well as the degree of dissemination of bladder cancer to nearby structures, including lymph nodes, and distant organs. Intravenous pyelography is used primarily in limited resource settings. In cases where its use is contraindicated due to suspected allergic reactions to venous dyes, retrograde pyelography is used instead. Particularly CIS flat lesions are often non-detectable even with these approaches and diagnosis must be confirmed by endoscopic biopsy. CT urogram, as well as abdominal CT, is optimal for assessing cancer dissemination to nearby and distant organs, particularly when combined with CT-guided needle biopsy. Alternatively, abdominal and pelvic MRI with contrast imaging elucidates tumor spread to lymph nodes and nearby organs. In advanced disease, metastasis to the lungs may be ascertained with chest radiography. In the event of bone pain, metastasis to bone tissue is best displayed with bone scans (PET scan).

Staging of disease

Staging of disease is used for clinical decision-making of optimal treatment. Staging is also used to predict patient's prognosis for disease progression (see: Disease prognosis). The Tumor Node Metastasis (TNM) classification is applied for disease staging. The TNM system is based on tumor size and infiltration into deeper bladder tissue layers (Tumor), dissemination to lymph nodes (Nodes), and metastasis to distant organs (Metastasis). TNM Stages range from T0 through T4. TNM stages Ta through T1 are non-muscle-invasive tumors, while stages T2 through T4 refer to muscle-invasive tumors.

According to the TNM system, Ta stage refers to non-muscle-invasive papillary carcinomas, while Tis growths are non-muscle-invasive flat superficial carcinomas (carcinoma in situ, CIS). T1 tumors are non-muscle-invasive subepithelial tumors which have penetrated the underlying lamina propria, but not the muscle layer. In particular, superficial or non-muscle-invasive bladder cancers are those which have penetrated, albeit not completely, the lamina propria, but not the bladder muscularis propria. T2 tumors are invasive tumors which have infiltrated the muscularis propria. More advanced disease stages include T3 tumors, which entail perivesical invasion, and T4 tumors involving invasion into neighboring pelvic structures and organs, or metastasis to distant organs, primarily including lungs, liver, and bone.

Disease prognosis

Disease prognosis depends primarily on bladder cancer type and stage, tumor grade, and other concomitant patient health conditions (see: Recurrence and Surveillance). The 5-year survival rate diminishes markedly with advancing stage of disease. In particular, while T1 tumors are associated with a relative 5-year survival rate of 88%, this rate is limited to 46% and 15% in T3 and T4 tumors, respectively.

Treatment strategies

Optimal treatment for bladder cancer depends upon tumor type, stage, grade, number of foci, and infiltration into deeper bladder tissue layers, as well as presence of distant metastasis and other concomitant health conditions (see: Recurrence and Surveillance).

For early stage non-invasive bladder cancer, TURBT is the treatment strategy of choice. TURBT entails the removal of non-invasive lesions with a resectoscope during cystoscopy. Despite treatment, risk factors for recurrence in other parts of the bladder and/or urothelium of the urogenital tract include tumor size, type, and grade, as well as number of tumor foci and presence of CIS (See Recurrence and surveillance).

For invasive and/or disseminated bladder cancer, radical cystectomy with extended lymph node dissection is the treatment of choice, depending on tumor invasion to nearby structures and organs. Radical cystectomy entails the surgical formation of diversions for urinary voidance through either ileal or colonic conduits, catheterizable pouches or neobladders.

Adjuvant intravesical therapies include immunotherapy and chemotherapy. In early stage bladder cancer, intravesical immunotherapy with Bacille Calmette Guerin is often administered as adjuvant treatment following TURBT. Adjuvant intravesical chemotherapy, primarily with mitomycin C, epirubicin or doxorubicin, may also be used in early stage disease. Advanced bladder cancer requires systematic (intravenous) administration of chemotherapeutic agents.

Treatment options for recurrent bladder cancer include surgery (with or without chemotherapy and biologic therapy) or combination chemotherapy. Palliative treatment options include radiation therapy (see: Recurrence and surveillance).

Recurrence and surveillance

Bladder cancer has the highest recurrence rate of any malignancy. The European Organization for Research and Treatment of Cancer (EORTC) scoring system is used to predict the short-term (1-year) and long-term (5-year) risks of disease recurrence and progression in non-muscle invasive bladder cancer patients. The EORTC scoring system is based on 6 clinical and pathological factors, including tumor size, number of tumor foci, tumor stage and grade, prior tumor recurrence, and presence of CIS.

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Based on the EORTC scoring system, the European Association of Urology has proposed a three-tier system for predicting bladder cancer recurrence and progression. The EORTC risk tables define low-, intermediate- and high-risk groups separately for bladder cancer recurrence and progression. In particular, based on the EORTC scoring system low, intermediate, and high risk patients have a probability of 5-year recurrence rates of 31%, 46%, and 78% respectively. The corresponding values for low, intermediate and high risk patients for 5-year disease progression are 0.8%, 6% and 45%, respectively. The EORTC tables are applied in medical practice to predict disease prognosis and to facilitate clinical-decision making for optimal treatment schemes (see: Treatment strategies).

As a result of high bladder cancer recurrence rates, the efficacious surveillance of disease recurrence, and timely therapeutic management, is vital for optimal patient outcomes. Recurrence occurs more frequently in non-muscle invasive (78%), as compared to muscle-invasive (7%) tumors. The recommended surveillance schedule for non-muscle invasive bladder cancer patients with Ta tumors and at low risk for recurrence and progression is a cystoscopy at 3 months. If findings are negative, the following cystoscopy is recommended 9 months later, and then annually for 5 years. TaT1 patients at high risk for recurrence and progression (including those with CIS) should have cystoscopy and urinary cytology at 3 months. If found negative, then the following cystoscopy and cytology should be repeated every 3 months for a period of 2 years, and every 6 months thereafter until 5 years, and annually thereafter. Annual imaging of the upper tract in this patient group is recommended. For patients with regional or distant metastases, annual abdominal and pelvic CT scanning, as well as chest radiography, is performed to monitor disease progression.

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To date, detection of disease recurrence heavily relies on invasive cystoscopy that is required throughout the surveillance schedule during each follow-up visit. The annual health care costs for bladder cancer surveillance in the USA alone exceed 2.2 billion USD. Novel non-invasive approaches, such as the use of urinary biomarkers, are under evaluation for clinical use for both monitoring and detecting disease recurrence in bladder cancer patients (see: Novel biomarkers for bladder cancer and The TransBioBC Project).

Novel Biomarkers for Bladder Cancer

Currently, blood or urine tests specific for bladder cancer have not been documented. Hence, novel biomarkers for bladder cancer may be useful non-invasive adjunct tests to both urine cytology and cystoscopy for diagnosing disease or monitoring disease recurrence and/or progression. Urinary biomarkers for bladder cancer aim to be used in either a) patients with signs and symptoms of primary bladder cancer, or b) to detect disease recurrence in bladder cancer survivors.

Current FDA approved urinary biomarkers tests for bladder cancer include BTA tests, ImmunnocytTM, NMP22 Bladder Chek®, and UroVysionTM. In particular, the BTA test detects bladder tumor associated antigen in urine. The ImmunnocytTM detects the presence of carcinoembryonic antigen (CEA) and mucin in cells of urine samples. NMP22 Bladder Chek® identifies elevated levels of protein NMP22 in urine. UroVysionTM detects chromosomal changes associated with bladder cancer cell development. Additionally, the utility of detecting telomerase in urine of suspected bladder cancer patients is currently under investigation in an on-going clinical trial.

Although approved by the FDA, the aforementioned urinary biomarkers have not yet been incorporated in official clinical guidelines for bladder cancer surveillance and monitoring. There is mounting evidence that molecular markers may serve as a primary screening tool for EORTC low risk bladder cancer patients, as well as predict tumor progression in high risk patients. Molecular markers can risk stratify bladder cancer patients receiving treatment, and in particular intravesical therapies. Using markers to identify patients who are likely to fail intravesical therapy would be useful for providing alternative, albeit more radical, treatment strategies so as to prevent disease progression.

The TransBioBC Project: Novel biomarkers for bladder cancer

The TransBioBC project mission is to assess the utility of novel urinary bladder cancer biomarkers in clinical practice. The objective of the TransBioBC project is to translate existing findings on promising proteomic biomarkers, in combination with robust technologies, for the development of non-invasive urine tests for diagnosing bladder cancer and monitoring disease recurrence, particularly in non-muscle invasive bladder cancer patients. Hence, the TranBioBC project targets to meet a very clear clinical need in bladder cancer management: the development of biomarker assays to be used for a) diagnosis of bladder cancer and b) detection of disease recurrence, particularly among non-muscle invasive bladder cancer patients. Non-muscle invasive bladder cancer patients represent the largest bladder cancer subtype and also the group that would benefit most from improvement in recurrence monitoring procedures, as existing approaches are invasive. The project uniquely integrates leading bladder cancer clinical experts with experts on proteome analysis and high throughput immunoassay development in an implementation-oriented workflow. Strict monitoring of assay analytical performance and properly collected and well-characterized clinical samples from existing sufficiently powered patient cohorts are combined to define added value.

The specific impact of the TransBioBC non-invasive biomarker classifier would primarily be to reduce the number of surveillance cystoscopies performed during the monitoring of bladder cancer patients for disease recurrence. The evident benefit for the patient is better patient stratification based on non-invasive molecular risk factors, hence allowing a tailored surveillance plan (e.g. individualized cystoscopy intervals) based on non-invasive periodic monitoring and early therapeutic measures (e.g. initiation of (neo)-adjuvant therapy). Collectively, the direct outcome expected from the implementation of the validated biomarker classifier will be improved quality of life, through the reduction of invasive monitoring procedures, as well as improvement in overall survival through increased patient compliance and timely detection of bladder cancer and its recurrence.

References

The EORTC Tables are modified from: Sylvester at al. Predicitng reccurence and progression in individual patients with stage Ta/T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur. Urol. 2006: 2006, 49(3), 466-5

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