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Bladder cancer is the fourth most prevalent cancer in the United States and is estimated to account for 7% of all new cancer cases in 2014.

Though many bladder cancers are nonmuscle-invasive and successfully treated with local resection and/or adjuvant intravesical therapy,

the number of deaths from bladder cancer in 2014 is projected to be over 15,000, a number that has remained relatively unchanged since the 1970s.

These deaths are largely due to the high rate of disease relapse in bladder cancer patients, who require additional procedures in order to manage their disease. Between 50% and 70% of patients with superficial bladder cancer will experience recurrence, and 10% to 15% of those patients will progress to muscle-invasive disease.

The anatomical structure of the bladder is shown in

. While substantial improvements have been achieved in treatments for other cancers, such as lung cancer, breast cancer, and melanoma, no new therapies have been approved for bladder cancer in more than 20 years.

In this article, we provide a general overview of bladder cancer as a disease, highlighting current therapeutic strategies as well as potential new avenues for advancing bladder cancer therapy.

Figure 1. Anatomical structure of the bladder.

Bladder cancer can arise from any part of the bladder wall (

). The most common type of bladder cancer is transitional cell carcinoma (TCC), which accounts for 90% of all bladder cancers. TCC arises from the transitional epithelium, comprised of cells in the inner lining of the bladder that expand and contract, and is usually caused by exposure to environmental carcinogens that pass through the urinary tract. Other types of bladder cancer include squamous cell carcinoma (1%-2%), adenocarcinoma (1%), sarcoma (<1%), and small cell (<1%).

The biggest risk factor for bladder cancer is smoking, which accounts for about half of TCC cases and triples the risk of developing bladder cancer.

Exposure to other carcinogens in the workplace or ingestion of arsenic is also associated with a higher risk for bladder cancer, as is age >55 years, male sex, and white race. Chronic bladder infections and a family or personal history of bladder cancer predisposes individuals to the development of bladder cancer. Individuals with mutations in the genes encoding

, or those who have Lynch syndrome are also at a higher risk for bladder cancer (

Patients with bladder cancer typically present with symptoms such as gross/macroscopic hematuria or microscopic hematuria, a frequent urge to urinate (sometimes without needing to do so), painful urination, and/or lower back pain. Those patients with advanced disease may experience pelvic/bony pain, lower extremity edema, and/or flank pain. Rarely, a palpable mass may also be detected.

Diagnostic tests are performed by a urologist before patient referral to a urological surgeon or a medical oncologist.

illustrates the 5-year survival rates of bladder cancer by race. Survival is lower in blacks than in whites, Hispanics, and Asian Pacific Islanders.

Figure 2. Cancer arising from bladder wall.

Guidelines for the diagnosis and staging of bladder cancer have been developed by the National Comprehensive Cancer Network (NCCN) and are well accepted (

The gold standard for detection of bladder cancer and suspicious lesions is biopsy by cystoscopy. In this procedure, the urologist inserts a camera-guided, flexible tube into the urethra of the patient and uses surgical instruments in the cystoscope to remove a section of suspicious tissue or tumor. This biopsy is then analyzed by a pathologist to determine staging.

Blue light (Hexvix/Cysviewguided fluorescence) cystoscopy may be used in addition to standard white light cystoscopy for a more thorough screen for bladder cancer detection.

Imaging and urine testing are less invasive methods that are also used to diagnose bladder cancer. Imaging tests include computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasound, intravenous pyelogram (IVP), and CT urogram. Urine cytology is also commonly used for bladder cancer detection. A major limitation of urine cytology is insensitivity; a negative reading does not absolutely rule out the presence of bladder cancer. However, its noninvasive approach and ease of processing has maintained its high level of use.

Several other noninvasive urine tests have been developed to detect bladder cancer biomarkers.

Figure 3. 5-year bladder cancer survival.

Two assays have been developed for the detection of nuclear mitotic apparatus protein (NMP22), an enzyme-linked immunosorbent assay (ELISA) and the BladderChek immunochromatography method. NMP22 is overexpressed in bladder cancer cells and aids in cell division by facilitating proper chromosome segregation. One drawback of NMP22 for bladder cancer detection is its varying sensitivity and false-positive results.

The bladder tumor antigen (BTA) TRAK ELISA and the BTA stat test have been developed to detect complement factor H-related protein in the urine of bladder cancer patients.

Complement factor H-related protein is expressed by bladder cancer cells and is supposed to promote degradation of other complement factors.

BTA TRAK and BTA stat are more sensitive than cytology; however, specificity of these assays is compromised by a history of urinary tract foreign body, bowel interposition segment, other genitourinary cancer, and benign genitourinary conditions. Patients with hematuria, proteinuria, infection, stones, and inflammation have also experienced false-positive results from these tests. Because of these characteristics, BTA TRAK and BTA stat have not been widely utilized.

Two mucin-like proteins as well as a high molecular weight form of carcinoembryonic antigen (CEA) have been reported as specific markers of bladder cancer that can be detected in the urine.

ImmunoCyt utilizes fluorescently labeled monoclonal antibodies against these 3 proteins for adjunct bladder cancer detection.

While ImmunoCyt has improved sensitivity compared with cytology, especially in lower-stage and lower-grade tumors,

it has not been used widely as an independent clinical marker of bladder cancer, due to varying sensitivity in detecting disease recurrence in patients receiving bacillus Calmette-Gu&eacute;rin (BCG) therapy. However, the combination of ImmunoCyt and cytology resulted in a sensitivity of 100% in patients receiving BCG therapy.

Other drawbacks of ImmunoCyt include a high level of variability between observers and up to a 17% failure rate because of inadequate cellularity in the specimens.

Aneuploidy for chromosomes 3, 7, and 17 and loss of locus 9p21 are common in bladder cancer.

The UroVysion fluorescence in situ hybridization (FISH) assay has been developed to detect these genetic aberrations. It has been used to detect new bladder cancer as well as recurrent bladder cancer.

UroVysion has shown promising ability to predict future recurrences in the presence of a negative cystoscopy, especially for high-risk tumors, such as pT1 and carcinoma in situ (CIS).

However, due to varying sensitivity based on tumor grade, it has not been used as an independent surveillance tool for nonmuscle-invasive disease. Due to its high cost, need for trained personnel, need for intact cells, and limited use in lowgrade tumors, the use of UroVysion has been limited. Nevertheless, it seems to be useful as an adjunct to cytology and cystoscopy in bladder cancer follow-up.

Figure 4. NCCN algorithm for bladder cancer diagnosis and staging.

Importantly, rather than relying on one test for the detection of bladder cancer, urologists will usually combine multiple tests for the best probability of finding disease if it is present.

For example, cystoscopy, though a frequently used and relied upon method for cancer detection, is not always able to detect carcinoma in situ or some small papillary tumors.

In these cases, imaging and/or urine testing may be the most useful tests for bladder cancer diagnosis.

In order to determine the best treatment strategy for each patient with bladder cancer, tumor stage is taken into account. Following detection, a pathologist is consulted to provide tumor staging. Staging is performed using the TNM system, in which T indicates the growth and invasion of the tumor, N indicates lymph node status, and M indicates presence of metastases.

demonstrates pictorially the different stages of bladder cancer. Carcinoma in situ, a &ldquo;flat tumor,&rdquo; is the smallest and least invasive stage of bladder cancer. A tumor of stage Ta is a small tumor that affects only the bladder epithelium. T1 indicates tumor invasion into the lamina propria, subepithelial connective tissue. Carcinoma in situ, Ta, and T1 bladder cancers are described as nonmuscle-invasive bladder cancers because they have not grown into the layers of muscle in the bladder wall. Tumors in stages T2, T3, and T4 are muscle-invasive bladder cancers.

Stage T2 bladder cancers have invaded the superficial (T2a) or deep muscle (T2b) of the bladder wall. Cancers in stage T3 move beyond the muscle layers and into the perivesical tissue, either microscopically or macroscopically. Finally, stage T4 bladder cancers invade into neighboring organs, such as the prostate, uterus, vagina, abdominal wall, rectum, or pelvic wall.

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Introduction: Evolving Paradigms in Bladder Cancer

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Based upon the stage of disease, which is indicative of invasiveness, different treatment regimens have been adopted and are included in guidelines developed by the NCCN.

Bladder cancer is treated by surgery, chemotherapy, immunotherapy, radiation therapy, or a combination of these modalities.

Surgery is employed in nearly every bladder cancer treatment strategy. Transurethral resection of bladder tumor (TURBT) is used to treat early bladder cancer. It is performed using a cystoscope inserted through the urethra. A wire loop on the end of the cystoscope is used to remove the cancer or burn it away using an electric current, a process called fulguration.

Cystectomy is another procedure in which part of or the entire bladder is removed. Partial (segmental) cystectomy is performed in patients with low-grade tumors localized to one area of the bladder. In addition to the tumor itself, nearby lymph nodes are removed. Following this surgery, patients are able to urinate normally, but possibly will do so more often.

Radical cystectomy, in which the entire bladder is removed, is employed in patients with muscle-invasive disease. In addition to the bladder, any nearby lymph nodes and organs in which cancer has been detected are removed. The prostate is usually removed in men, and the uterus is sometimes removed in women.

During radical cystectomy, the surgeon provides a new way for urine to leave the body. A bag may be carried outside of the patient&rsquo;s body to collect urine, or part of the small intestine may be used to create a pouch inside of the patient&rsquo;s body (ileal conduit).

Chemotherapy is a treatment that is designed to kill cancer cells or prevent them from dividing. Chemotherapeutic agents may be delivered locally or systemically. For example, lower stages of bladder cancer may be treated with intravesical chemotherapy, in which chemotherapeutic agents are delivered directly into the bladder via catheter. Agents that are frequently used to treat bladder cancer intravesically are mitomycin and thiotepa; others include valrubicin, doxorubicin, and gemcitabine. Alternatively, bladder cancers that have progressed outside of the bladder into nearby organs or distant metastatic sites may be treated with systemic chemotherapy in the attempt to kill both the local tumor as well as tumor cells that have spread to other sites. Chemotherapy may be delivered as single agents or as a combination of agents.

Immunotherapy is a strategy for cancer treatment in which the patient&rsquo;s immune system is stimulated to target cancer cells. Natural or synthetic agents are delivered to enhance, redirect, or restore the immune system&rsquo;s ability to eradicate aberrant tumor cells. One immunotherapy that is utilized for early-stage bladder cancers is Bacillus Calmette-Guerin (BCG), a live, attenuated strain of Mycobacterium bovis. BCG is delivered intravesically directly into the bladder, activating local immune cells and killing tumor cells. Interferon is another intravesical, immunotherapeutic agent that is commonly used in treating bladder cancer. Interferons stimulate the immune system and program immune cells to kill cancer cells. The most common interferon applied to bladder cancer therapy is interferon alpha.

BCG indicates Bacillus Calmette-Guerin; CIS, carcinoma in situ; PC, partial cystectomy; RC, radical cystectomy; RT, radiation therapy; TURBT, transurethral resection of the bladder

Radiation therapy is used to kill cancer cells by exposure to highenergy x-rays or other forms of radiation. There are 2 types of radiation therapy: external and internal. External radiation therapy directs radiation from a source outside of the body to a localized area of the body. Internal radiation uses a radioactive agent that is sealed within needles, catheters, seeds, or wires that are placed in proximity to or into the cancer.

Bladder cancer treatment is based primarily on tumor stage.

describes treatments that are recommended to patients with nonmuscle-invasive disease (CIS and T1), muscle-invasive disease (T2, T3, and T4), and metastatic disease (T4). For carcinoma in situ and stage T1 bladder cancers, TURBT is performed with fulguration and is followed by intravesical chemotherapy or intravesical BCG immunotherapy. Alternatively, partial or radical cystectomy may be performed, or the patient may choose to enroll in a clinical trial.

for clinical trials that are currently recruiting participants.

Patients with stage T2, T3, or T4 bladder cancers may be treated in a number of ways. Because the disease is muscle-invasive, more radical approaches are usually employed to combat the cancer. For stage T2 tumors, partial or radical cystectomy is performed and is usually accompanied by neoadjuvant chemotherapy. Maximal TURBT with concurrent chemotherapy and radiation is another treatment option for patients with T2 bladder cancer. Those patients with poor performance or extensive comorbid disease may choose TURBT alone, chemotherapy alone, or chemotherapy plus radiation. Finally, patients may enroll in clinical trials of experimental therapies.

Treatment of stage T3 and nonmetastatic T4 bladder cancer is usually radical cystectomy with or without neoadjuvant chemotherapy. Similar to patients with T2 bladder cancer, maximal TURBT with concurrent chemotherapy and radiation may be used to treat patients with T3 or nonmetastatic T4 bladder cancer. TURBT alone, chemotherapy alone, or chemotherapy plus radiation, or clinical trial participation are also available options.

Table 2. Clinical Trials Currently Recruiting Participants

Metastatic T4 bladder cancer is treated primarily with chemotherapy. Palliative therapy, including urinary diversion, external beam radiation therapy, and/or cystectomy, is another option to alleviate symptoms and improve quality of life. Clinical trials of new cancer drugs or strategies are available for all patients with stage T4 bladder cancer.

 Current Bladder Cancer Treatment Strategies Based Upon Stage

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di Martino E, Tomlinson DC, Knowles MA. A decade of FGF receptor research in bladder cancer: past, present, and future challenges.

Kanayama H, Yokota K, Kurokawa Y, Murakami Y, Nishitani M, Kagawa S. Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer.

Gohji K, Fujimoto N, Ohkawa J, Fujii A, Nakajima M. Imbalance between serum matrix metalloproteinase-2 and its inhibitor as a predictor of recurrence of urothelial cancer.

References for Evolving Paradigms in Bladder Cancer

Evolving Paradigms in Bladder Cancer: References

This article is part III of a series. View parts I,II:

While the stage of bladder cancer is influential in determining treatment strategy, a number of other factors may also affect a patient&rsquo;s treatment regimen. These include the type of bladder cancer, location of the tumor, the number of tumors, tumor size, tumor grade, age and health, recurrence status, and tumor biomarkers.

The cell type that a bladder cancer arises from may be used to determine treatment strategies based upon methods used to successfully treat other cancer types with the same parent cell. For example, squamous cell carcinomas in the bladder may be treated with fluorouracil (5-FU), taxanes, and/or methotrexate, because these agents are effective in other squamous cell carcinomas. Squamous cell carcinoma may also be treated with cystectomy and/or radiation therapy. Adenocarcinomas may be treated with partial or radical cystectomy, and chemotherapy treatment regimens must be personalized for these tumors because conventional chemotherapy for bladder cancer is ineffective against this tumor type. Small cell bladder tumors are treated with neoadjuvant therapies used for other small cell cancers with or without cystectomy and/or radiation therapy. Finally, sarcomas of the bladder are treated as other sarcomas. Tumors with mixed histology are treated as pure urothelial carcinoma of the bladder, taking into account their worse prognosis.

Tumor location, number, size, and grade are all important determinants of bladder cancer treatment. These factors help determine which cancers are at low, medium, and high risk for recurrence. Grade is a measure of how abnormal the cancer cells appear histologically compared with normal bladder cells. Higher grades correlate with higher risk for recurrence, lending these tumors to more aggressive therapies to prolong or prevent recurrence. Larger tumors and higher numbers of tumors also indicate higher risk for recurrence. Finally, tumor presence in the bladder alone or also in neighboring organs or distant metastases affects a patient&rsquo;s treatment regimen. For example, localized bladder tumors may be treated with TURBT plus intravesical therapy, while metastatic disease is treated with systemic chemotherapy.

Age, general health, and disease history will also factor into a patient&rsquo;s treatment regimen. Older age or coexisting medical conditions may result in higher probability of complications from bladder cancer treatments, which should be taken into consideration when selecting a treatment regimen. Additionally, if a patient has recurrent disease, repeating first-line chemotherapeutic or intravesical treatment strategies are not likely to be beneficial. The physician may therefore recommend a different approach that is congruent with a patient&rsquo;s specific tumor.

Biomarker discovery in bladder cancer is a young field but one that has exciting implications for detecting bladder cancer and measuring patient response to treatment. While several potential molecular markers for prediction of clinical response and outcome have been identified recently, there is still not a single marker or group of markers that is reliable enough to replace standard clinical parameters used to determine treatment course. However, most of the potential molecular markers identified have not been tested in enough patients of varying grade and stage to demonstrate their prognostic value.

Hopefully, with future multiinstitutional studies, some of these markers will be validated as independent, prognostic markers in bladder cancer. Several of these promising molecular markers are described in more detail below.

While the stage of bladder cancer is influential in determining treatment strategy, a number of other factors may also affect a patientâ€™s treatment regimen.

Other Factors Affecting Prognosis and Treatment in Bladder Cancer

This article is part IV of a series. View parts I,II, and III:

There is a significant need for biomarkers throughout the course of bladder cancer diagnosis and different treatment regimens. Because assays and markers have limitations in their clinical use, other candidate biomarkers are being identified for potential use in bladder cancer diagnosis as well as treatment response, recurrence, and survival following TURBT, TURBT plus intravesical therapy, radical cystectomy, radiation therapy, and systemic chemotherapy. Biomarkers may be classified as chromosomal alterations or DNA/nucleotide-based markers, cDNA microarray mRNA expression analysis or gene expression signatures, proto-oncogenes or oncogenes, tumor-suppressor genes, cell cycle regulators, or extracellular matrix (ECM) adhesion molecules.

Many candidate biomarkers are originally detected by immunohistochemistry (IHC). Other methods for biomarker detection include enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (RT-PCR), FISH, and more specialized assays.

A select group of potential biomarkers being investigated for clinical application in bladder cancer:

Urothelial carcinoma demonstrating absence of PD-L1 staining (20&times;).

Urothelial carcinoma demonstrating marked membranous PD-L1 staining (20&times;).

Programmed death ligand 1 (PD-L1) is a coinhibitory repressor that negatively regulates T-cell responses. It is highly expressed in several cancers, including bladder cancer, and has been associated with localized stage advancement of urothelial carcinoma and attenuation of responses to BCG therapy.

Results from a phase I study of an antibody directed against PD-L1 in patients with metastatic bladder cancer were released in May 2014. The antibody was reported to have shrunk tumors in 43% of patients with PD-L1-positive metastatic urothelial bladder cancer, achieving a breakthrough therapy designation by the US Food and Drug Administration (FDA).90 Testing for PD-L1 status is not yet available for bladder cancer patients but is likely to be beneficial in determining patients who may benefit from anti-PD-L1 therapy.

BLCA-4 is a nuclear matrix protein transcription factor that has been identified as an abundant bladder cancer-specific protein. Its overexpression has been determined to induce cell proliferation and the production of mediators involved in invasion and angiogenesis.

An investigational ELISA assay using urine samples is in development for BLCA-4 detection in individuals with a high risk for bladder cancer.

Telomerase is an enzyme that maintains chromosomal integrity by preserving telomeric DNA that would otherwise be degraded during rapid cell division of cancer cells.

This enzyme is present in more than 80% of all cancer cells while not expressed in most healthy cells, indicating its potential for success as a bladder cancer biomarker. Telomerase reverse transcriptase mRNA is detected in exfoliated cells in urine by telomerase reverse transcriptase assays or a PCR-based telomeric repeat amplification protocol (TRAP).

Telomerase has also been detected using IHC and has been found to independently associate with reduced recurrence-free survival and the development of invasive disease in patients treated with BCG therapy following TURBT.

Thus, telomerase expression may be useful for identifying patients who are at higher risk for recurrence and who might benefit from radical cystectomy.

Fibronectin is a glycoprotein that is expressed in cells, plasma, and the ECM and has been reported to be associated with bladder cancer. Bladder tumor fibronectin (BTF) is an assay that is being developed to measure urinary fibronectin for the detection of bladder cancer. One study has shown that BTF predicts residual tumor load following TURBT with high sensitivity (91.4%) and specificity (87.8%) in patients with suspected bladder cancer. Further investigation is under way to develop this assay and gain FDA approval.

Survivin is a protein that inhibits apoptosis by blocking caspase activation. It has been detected by mRNA and protein in urine samples nearly exclusively in patients with bladder cancer compared with healthy individuals and has also been shown to be expressed by malignant epithelium.

Survivin has been reported as superior to NMP22 and cytology for bladder cancer detection, demonstrating better sensitivity, specificity, and both positive and negative predictive values.

However, a drawback of survivin measurements in the urine is the release of survivin by the healthy prostate.

Measuring the proportion of survivin that originates from the prostate may be challenging in men of varying prostate sizes.

is a fibroblast growth factor receptor (FGFR) that is commonly mutated or overexpressed in bladder cancer, resulting in increased cell proliferation.

There is a significant need for biomarkers throughout the course of bladder cancer diagnosis and different treatment regimens. 

Bladder Cancer

Introduction: Evolving Paradigms in Bladder Cancer

Current Bladder Cancer Treatment Strategies Based Upon Stage

Evolving Paradigms in Bladder Cancer: References

Other Factors Affecting Prognosis and Treatment in Bladder Cancer

Emerging Biomarkers for Bladder Cancer

Emerging Therapies in Clinical Trials for Bladder Cancer

Evolving Paradigms in Bladder Cancer: Conclusion