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 2016 is projected to be over 16,000, 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

Following a period of stagnation in the development of new therapies for advanced bladder cancer, novel targeted and immunotherapeutic agents have demonstrated promising outcomes in clinical trials and their clinical investigation and the development of molecular profiling approaches is an area of active investigation and intense interest.

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.

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 TCC 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 GNT, NAT, Rb1, and PTEN, 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 percent of deaths from bladder cancer by age.1 Survival differs between races and is lower in blacks than in whites, Hispanics, and Asian Pacific Islanders.

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/Cysview-guided 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, 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 thepresence 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.

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 tests have been developed to detect complement factor H-related protein in the urine of bladder cancer patients.

Complement factor Hrelated 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 three 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-Guérin (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 low-grade 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.

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 carefully considered. 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.

Articles

Clinical Articles

This is the "Introduction" section of the current issue of Evolving Paradigms In Bladder Cancer.

Evolving Paradigms In Bladder Cancer: Introduction

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.

Radiation therapy is used to kill cancer cells by exposure to highenergy x-rays or other forms of radiation. There are two 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 for 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 examples of clinical trials that are currently recruiting participants. In highly selected cases with T1 bladder cancer with limited lamina propria invasion and no CIS, observation only may also be suitable.13

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. Patients with poor performance or extensive comorbid disease may choose TURBT 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.

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.

This is the "Current Treatment Strategies" section of the current issue of Evolving Paradigms In Bladder Cancer.

Evolving Paradigms In Bladder Cancer: Current Treatment Strategies

The cell type from which a bladder cancer arises may be used to determine treatment strategies based on 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 survival 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.

This is the "Prognosis and Treatment" section of the current issue of Evolving Paradigms In Bladder Cancer.

Evolving Paradigms In Bladder Cancer: Prognosis and Treatment

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.35,36 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.

Based on reports from a phase I study with the antiPD-L1 antibody atezolizumab (MPDL3280A)

in patients with metastatic bladder cancer demonstrating tumor shrinkage in 43% of patients with PD-L1-positive metastatic urothelial bladder cancer, the agent received a breakthrough therapy designation by the FDA.

Recently updated results from the phase II IMvigor210 trial

of atezolizumab in heavily pretreated patients with locally advanced or metastatic urothelial carcinoma reported a promising median overall survival (OS) of 7.9 months in the overall study population, and 11.9 months among patients whose tumors expressed medium and high levels of PDL1.

Testing for PD-L1 status 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).16 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.

FGFR3 is a fibroblast growth factor receptor (FGFR) that is commonly mutated or overexpressed in bladder cancer, resulting in increased cell proliferation. FGFR3 mutation is strongly associated with low-grade and low-stage bladder tumors and is linked to a favorable disease course with low features of clinical malignancy. Overexpression of wild-type FGFR3, however, is associated with invasive bladder cancers and activates Ras/ mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, which are involved in cell proliferation and survival. FGFR3 can be detected in urine and is currently being developed into an assay for bladder cancer detection and prognosis.

Matrix metalloproteinases (MMPs) are ECM degradation enzymes that play important roles in tumor cell invasion and metastasis. MMP2 has been studied for its role in invasive urothelial carcinoma due to its ability to degrade components of the bladder&rsquo;s ECM, including type IV collagen, gelatin, and laminin. High levels of MMP expression measured by RT-PCR correlated with worse survival in patients with urothelial carcinoma.

Another study measured MMP2 protein expression by ELISA in serum samples in patients with urothelial carcinoma and determined that MMP2 expression was predictive of recurrence and advanced disease.

Currently, MMP2 measurement in urine is being developed as a marker of disease prognosis.

This list of candidate biomarkers is by no means exhaustive. Several other molecular markers are also under investigation for bladder cancer, including hyaluronic acid, DNA methylation markers, gene expression signatures, cytokeratins, prothymosin alpha, soluble Fas, Reg1, p53, Rb, Ki67, and more.

This is the "Emerging Biomarkers" section of the current issue of Evolving Paradigms In Bladder Cancer.

Evolving Paradigms In Bladder Cancer: Emerging Biomarkers

Sunitinib is a tyrosine kinase inhibitor that blocks the vascular epidermal growth factor receptor (VEGFR), which plays an important role in angiogenesis and tumor growth. A report found that sunitinib treatment in patients with metastatic bladder cancer results in a clinical response after recurrence.

Investigators at the University of Michigan are studying the effect of sunitinib treatment following BCG delivery in patients with high-risk nonmuscle-invasive bladder cancer (Sutent trial). While about half of patients with nonmuscle-invasive disease experience a complete response to BCG therapy alone at 3 months, up to one-third of these patients develop recurrent or progressive disease. The Sutent trial will evaluate complete response at 3 months and 6 months, as well as recurrence at 3 years, following combination treatment with BCG and sunitinib.

Cabozantinib is another receptor tyrosine kinase inhibitor that targets VEGFR and slows angiogenesis. Previous studies have demonstrated its use in the treatment of medullary thyroid cancer, prostate cancer, and ovarian cancer. A phase II study being conducted at the National Cancer Institute (NCI) is investigating its use in advanced and/or metastatic urothelial carcinomas. Overall response rate is the primary outcome of the study.

In addition to single-agent cabozantinib, a recently initiated phase I trial will also evaluate combination regimens of cabozantinib with immune checkpoint inhibitor therapy in patients with advanced or metastatic bladder cancer or other genitourinary tumors.

Patients will receive either single-agent cabozantinib, or the agent in combination with the PD-1 antibody nivolumab alone, or the agent in combination with both nivolumab and ipilimumab. Primary endpoint is the dose-limiting toxicity for each of these combinations.

Pazopanib is a tyrosine kinase inhibitor that blocks VEGF and is currently being studied in kidney cancer. Combination treatment with pazopanib and paclitaxel was shown to be favorable in a phase I trial. Therefore, an ongoing phase II trial is evaluating pazopanib and weekly paclitaxel in patients with first recurrence following chemotherapy and with TCC of the urothelium, with objective response rate according to response evaluation criteria in solid tumors (RECIST) as the main outcome.

Outcomes from this trial have been reported for the first 28 evaluable patients and indicate activity of the combination regimen, with an overall response rate of 50%, including 11% complete responses. The median progression-free survival (PFS) was 6 months, and median OS was 8 months.

Alisertib is a selective, small molecule inhibitor of aurora kinase A, a protein involved in mitosis and cell proliferation. Overexpression of aurora kinase A has recently been reported in bladder cancer, and dysregulation of spindle checkpoints is common in urothelial carcinoma. The Fondazione IRCCS Istituto Nazionale dei Tumori, Milano will conduct a randomized, phase II trial to study the effects of alisertib plus or minus paclitaxel versus placebo plus paclitaxel on the 2-month response rate and PFS of patients with relapsed or refractory TCC of the bladder and urothelial tract.

Erlotinib is a reversible tyrosine kinase inhibitor that acts upon epidermal growth factor receptor (EGFR), which is commonly mutated and overexpressed in several types of cancer. EGFR activates the PI3K-AKT-mTOR and Ras-MAPK pathways, which regulate cell growth. Erlotinib is most well-known for its use in the treatment of nonsmall cell lung cancer (NSCLC) and pancreatic cancer. A multicenter, randomized, phase II trial will begin recruiting in October 2014 to investigate the effect of pretreatment with erlotinib versus placebo before surgery (TURBT) on tumor cell growth in patients with bladder cancer. Patients with stages T1-T3 bladder cancer, as well as patients with recurrent bladder cancer, will be eligible for the study. The main outcome will be phosphorylation of EGFR in the bladder tissue adjacent (normal appearing) to the tumor.

Afatinib is a second-generation tyrosine kinase inhibitor that irreversibly inhibits human epidermal growth factor receptor 2 (HER2) and EGFR, both of which play crucial roles in cancer cell growth and survival. Similar to EGFR, HER2 is a protein that is commonly overexpressed in cancer and is associated with more aggressive disease. The University of Chicago is conducting a trial to study the effect of afatinib treatment on PFS in patients with refractory urothelial cancer. Patients enrolled in this study have cancers that are unable to be removed surgically and that have progressed following treatment with standard first-line chemotherapy. Similar to the erlotinib study, investigators expect that treatment with afatinib may retard tumor cell growth and/or promote cancer cell death.

Dovitinib is a receptor tyrosine kinase inhibitor that binds strongly to FGFR3, which plays a role in cell proliferation. FGFR3 is commonly mutated in bladder cancer, leading to its constitutive activation and resulting in aberrant cell proliferation. A multicenter, phase II trial is assessing the use of oral dovitinib in BCG-refractory urothelial carcinoma patients harboring tumors with FGFR3 mutations or overexpression and who are ineligible for or refusing cystectomy. The primary outcome of the study is the proportion of patients with a complete response 6 months following treatment with dovitinib.

Ramucirumab is a monoclonal antibody with high specificity for the extracellular domain of the vascular endothelial growth factor receptor tyrosine kinase VEGFR-2 that mediates broad inhibition of VEGFR-2 and thus angiogenesis. Data from a randomized phase II study have shown that adding ramucirumab to docetaxel significantly increased PFS of patients with advanced urothelial carcinoma with progression after platinum therapy (22 weeks vs 10.4 weeks on docetaxel alone).

The addition of ramucirumab to docetaxel is currently being investigated in a large, randomized phase III trial (RANGE) in patients with urothelial cancer who failed previous therapy.

Patients with advanced bladder cancer are also eligible for a phase I trial that is evaluating the combination of ramucirumab with the immunotherapeutic agent pembrolizumab, which targets PD-1.

Everolimus is an mTOR inhibitor that has been used in the treatment of several cancers, including breast, pancreatic, and kidney. mTOR is a serine/threonine protein kinase in the PI3K pathway that is involved in cell growth, proliferation, motility, and survival. It also plays a role in protein synthesis and transcription. Patients with tumors containing activating mutations in mTOR maybe particularly responsive to treatment with mTOR inhibitors, as suggested by the case report of a patient with advanced bladder cancer who experienced an exceptional response of 14 months duration to a combination of everolimus and pazopanib. Whole exome sequencing revealed the simultaneous presence of two activating mTOR mutations in the urothelial carcinoma of this patient.

Three fully accrued trials are currently evaluating everolimus in bladder cancer. These include a multicenter, randomized, phase II trial investigating everolimus alone or everolimus plus paclitaxel as first-line therapy in cisplatin-ineligible patients with advanced urothelial carcinoma.

The primary outcome is response rate (complete response, partial response, or stable disease) at 4 months from initiation of treatment.

The second study is a phase I trial investigating the safety of standard chemotherapy (gemcitabine and cisplatin) plus everolimus at different dose levels in patients with advanced urothelial cancer. The addition of everolimus to cisplatin has previously been shown to enhance the killing of cancer cells, thus suggesting its therapeutic potential in cancer treatment. The primary outcome of this study is doselimiting toxicity for everolimus in combination treatment with gemcitabine and cisplatin.

The third study is a phase I/II study at Memorial Sloan Kettering Cancer Center investigating different doses of oral everolimus paired with intravesical delivery of gemcitabine in patients with primary or secondary carcinoma in situ of the bladder and who are refractory to BCG. Dose-limiting toxicity and the maximum tolerated dose will be assessed for this combination therapy as part of the phase I portion of the trial. The primary outcome of the phase II portion of the trial is the proportion of patients who experience complete response at 1 year following initiation of therapy.

The mTOR inhibitor temsirolimus showed clinical efficacy in the French, multicenter, phase II VESTOR study in patients with relapsed bladder cancer.71 Among 36 evaluable patients, 50% experienced nonprogression at 2 months, defined as the sum of partial response, complete response, and stable disease.72 Additional analyses are ongoing to identify mutations that may predict sensitivity to temsirolimus.

Nanoparticle albumin-bound rapamycin (Nab-rapamycin; ABI009) is an mTOR inhibitor that is currently being studied for its use in the treatment of nonmuscle-invasive bladder cancer. Patients included in the study have either recurrent nonmuscle-invasive TCC of the bladder or are refractory to BCG treatment. This study is a phase I/II trial. Phase I primary outcomes are safety and tolerability, while the phase II outcome is complete response rate.

BCG therapy is the most commonly used immunotherapy in bladder cancer treatment. BCG is a live, attenuated strain of Mycobacterium bovis and is the only therapy approved by the FDA for carcinoma in situ of the bladder. Cystectomy is often accompanied by BCG intravesical therapy in patients with bladder cancer because it has been shown to reduce the risk of recurrence and tumor progression.

Several agents mentioned in this section are supplements of BCG therapy.

Checkpoint inhibitors are monoclonal antibodies directed against inhibitory immune receptors or their ligands. These so-called checkpoints control T-cell activation and normally maintain selftolerance and prevent autoimmunity; however, their upregulation in cancers can prevent an anticancer immune response. The use of checkpoint inhibitors can therefore augment the ability of the patient&rsquo;s immune system to eliminate tumor cells, resulting in long-lasting responses. Key checkpoints that are pursued therapeutically include the PD-1 and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathways.

Ipilimumab is an antiCTLA-4 antibody that has shown promise as a neoadjuvant therapy for patients with clinically localized bladder cancer undergoing radical cystectomy. Data have become available from a multicenter phase II trial evaluating the combination of chemotherapy (gemcitabine, cisplatin) with ipilimumab in the treatment of metastatic urothelial carcinoma.

The overall response rate among 36 treated patients was 23%, including five complete responses, and median PFS was 8 months.

Atezolizumab is an antibody against PD-L1, a ligand for the PD-1 pathway. When the body encounters a foreign antigen, there is a proliferative response of antigen-specific CD8+ T cells in the lymph nodes and spleen. The PD-1 pathway reduces proliferation of these T cells upon binding of PD-L1 to the PD-1 receptor. Neutralizing PD-L1 restores the accumulation of CD8+ T cells that can counteract tumor cells. Phase I and II study results with atezolizumab in patients with advanced or metastatic bladder cancer have demonstrated tumor shrinkage in 43% of patients42 and an OS of 11.9 months in patients PD-L1expressing tumors, respectively.

The phase II study also reported high response rates to the agent among heavily pretreated patients with metastatic urothelial carcinoma, who had progression on platinum-based chemotherapy; overall responses were 15% in the entire cohort, and 18% and 27%, respectively, in patients with &ge;1% and &ge;5% tumor PD-L1 expression.

Two phase III trials of atezolizumab are currently recruiting patients with bladder cancer,

and an open-label, single-arm, phase IV expanded access study has been initiated to provide atezolizumab to patients with locally advanced or metastatic platinum-resistant urothelial carcinoma.

The phase III IMvigor211 trial will compare the efficacy of atezolizumab with chemotherapy in patients with platinum-resistant advanced or metastatic bladder cancer, with OS as the primary outcome measure.

The second phase III trial, IMvigor010, is investigating efficacy and safety of adjuvant atezolizumab compared with observation in patients with PD-L1positive muscle-invasive bladder cancer who are at high risk for recurrence after cystectomy. The primary efficacy endpoint of this trial is disease-free survival.

Nivolumab is an antibody against PD-1, which is currently being studied by Bristol-Myers Squibb in a phase II trial in patients with metastatic or unresectable bladder cancer, with objective response rate per RECIST as the primary endpoint. This trial has completed accrual.

A second phase I/II clinical trial is evaluating nivolumab in several cancers, including advanced or metastatic triple-negative breast cancer (TNBC), gastric cancer, pancreatic adenocarcinoma, small cell lung cancer, and bladder cancer. This trial compares treatment with nivolumab alone versus nivolumab plus ipilimumab and evaluates the objective response rate up to 17 months following treatment.

The antiPD-1 antibody pembrolizumab showed promising results in patients with advanced or metastatic urothelial carcinoma who participated in the phase I KEYNOTE-12 study in patients with advanced solid tumors, with updated results reporting an overall response rate of 25% in 28 evaluable patients, and of 38% in patients with PD-L1&ndash;positive tumors; the 12-month PFS rate was 19%.

The phase III KEYNOTE-45 study comparing pembrolizumab with chemotherapy in patients with advanced urothelial cancer has completed accrual; primary outcomes are OS and PFS, with follow-up of up to 27 months.

The ongoing phase II KEYNOTE-52 trial is evaluating overall response rate to pembrolizumab in patients with advanced or metastatic urothelial cancer ineligible for cisplatin therapy.

A second phase II trial will assess pembrolizumab as maintenance therapy after initial chemotherapy,

and a third phase II monotherapy study (KEYNOTE-057) will investigate the agent in patients with high-risk nonmuscle invasive bladder cancer.

Patients with bladder cancer are also eligible for the expansion phase of a phase I/II study of pembrolizumab in combination with the small molecule kinase inhibitor PLX3397.

Phase I study data have also become available for the antiPDL1 checkpoint agent avelumab, with a reported overall response rate of 15.9% in patients with refractory metastatic urothelial carcinoma, including one complete response.

The disease control rate was 59.1%. Of patients with PD-L1expressing tumors, 70% were progression-free at 12 weeks, compared with 45.5% of patients with PD-L1&ndash;negative cancers.

The phase III JAVELIN Bladder 100 study will compare avelumab to best supportive care in patients with locally advanced or metastatic urothelial cancer as maintenance treatment following first-line chemotherapy.

ALT-801 is a recombinant fusion protein of interleukin-2 (IL-2) and soluble T-cell receptor directed against an antigen driven by the tumor suppressor p53. Tumor cells presenting p53/major histocompatibility complexes (MHC) are bound by ALT-801, resulting in the IL-2 moiety of the fusion protein stimulating natural killer (NK) cells and T-cell cytotoxic immune responses against the tumor cells. Data from a phase Ib/II trial evaluating the addition of ALT-801 to either gemcitabine alone or to the combination of gemcitabine and cisplatin in patients with muscle-invasive or metastatic urothelial cancers have shown clinical activity of the agent.92,93 The overall response rate was 35%, and complete responses were seen in both treatment groups. A second phase I/II study is studying the addition of ALT-801 to gemcitabine in patients with nonmuscle-invasive bladder cancer who have failed BCG therapy.

ALT-803 is a fusion protein complex of superagonist interleukin-15 (IL-15) and a soluble, dimeric IL-15 receptor alpha Fc fusion protein. ALT-803 binds to the IL-2/IL-15 receptor beta-common gamma chain receptor on NK and CD8+ T cells, activating these immune cells and inducing their expansion. A phase Ib/II, multicenter study is determining the effect of combination therapy with BCG and ALT-803 in patients with nonmuscle-invasive bladder cancer who have not received prior BCG therapy. Safety, maximum tolerated dose, and recommended dose are the primary outcomes.

CG0070 is an oncolytic adenovirus that encodes granulocyte macrophage-colony stimulating factor (GM-CSF). This virus selectively infects tumor cells and replicates in them, potentially leading to tumor cell lysis. At the same time, the GM-CSF expressed by the virus may stimulate cytotoxic T-cell responses against tumor cells. A dose-escalation study of intravesical CG0070 in patients with superficial bladder cancer who had failed BCG therapy demonstrated a 64% and 23% complete response rate among patients receiving multiple and a single dose.

Outcomes from the ongoing fully accrued phase II/III efficacy trial of CG0070 in nonmuscle-invasive bladder cancer (BOND) are expected in 2018.

Patients included in the study have TCC, bladder cancer, carcinoma in situ, or carcinoma in situ with papillary tumors. The phase II outcome of this study is the proportion of patients achieving complete response 9 months after treatment. The phase III outcome is the proportion of patients with durable complete response 15 months following treatment.

A second phase III trial of CG0070 (BOND2) is evaluating the agent in patients with high-grade nonmuscle invasive bladder cancer who failed BCG therapy and refused cystectomy.

NY-ESO-1 is a cancer-testis antigen found in normal testis and overexpressed in many tumor types. An NY-ESO-1 peptide vaccine has been developed to stimulate the immune system to mount antitumor responses to cells expressing NY-ESO-1 antigen, resulting in tumor cell lysis. A phase I trial is being conducted to evaluate the safety and dosing schedule for NY-ESO-1 vaccine therapy with or without sirolimus treatment in patients with solid tumors expressing NY-ESO-1, including recurrent and stage IV bladder cancers. Secondary outcomes will measure NYESO-1specific cellular and humoral immunity.

HS-410 is an allogenic urothelial bladder cancer cell vaccine that expresses a recombinant, secretory heat shock protein gp96 fused with an Fc domain from an immunoglobulin (Ig). HS-410 administration results in continuous secretion of gp96-Ig in irradiated tumor cells, which enhances presentation of tumor-associated antigens to cytotoxic T cells and induces an antitumor response. Results from the phase I portion from a phase I/II trial investigating administration of HS-410 in patients with nonmuscle-invasive bladder cancer have become available, demonstrating safety and tolerability of the agent, and suggesting clinical activity, with 7/10 patients remaining recurrence free after 1 year.

The ongoing phase II portion of the study is fully enrolled and will evaluate if disease-free survival is improved 1 year after treatment with BCG combined with HS-410 compared with placebo.

PANVAC is a viral cancer vaccine that expresses mucin-1 (MUC1) and TRIad of COstimulatory Molecules (TRICOMTM), proteinsoverexpressed by many cancers. When cancer cells become infected with PANVAC, MUC-1, and TRICOM are expressed and presented along with other tumor-associated antigens. The immune system associates these proteins with viral proteins and mounts a response to them, potentially killing tumor cells. A randomized, phase II study is investigating whether or not the addition of PANVAC to BCG therapy has improved disease-free survival over the course of 5 years compared with BCG therapy alone. Patients included in the study have high-grade nonmuscle-invasive bladder cancer and have failed prior BCG therapy.

MAGE-A3 is a peptide cancer vaccine comprised of a peptide from the human melanoma antigen A3, which is expressed in a variety of cancer types, including bladder cancer. MAGE-A3 acts as an immunostimulant by inducing a cytotoxic T-cell response against tumor cells that express MAGE-A3. A randomized, placebo-controlled, phase II trial is evaluating the safety and efficacy of MAGE-A3 plus the vaccine adjuvant AS-15 in patients with MAGE-A3+ muscle-invasive bladder cancer after cystectomy. The primary outcome of the study is disease-free survival 5 years following cystectomy.

This is the "Emerging Therapies" section of the current issue of Evolving Paradigms In Bladder Cancer.

Evolving Paradigms In Bladder Cancer: Emerging Therapies

Bladder cancer affects thousands of people in the United States. While treatable, many bladder cancers recur and require additional procedures and/or treatment regimens. There are many clinical trials focused on improving treatment options for patients with bladder cancer, and particular emphasis is being placed upon discovering treatments for patients with recurrent bladder cancer. While no new treatments have been approved for bladder cancer in over 10 years, molecular profiling of tumors, which has proven beneficial for improving treatment strategies in several different tumor types, is likely to unveil novel biomarkers that may be targeted in bladder cancer patients.

Several clinical trials are currently in progress to identify biomarkers for the detection of bladder cancer and the likelihood of disease recurrence.

The results of these studies, as well as those of ongoing therapeutic clinical trials, are eagerly anticipated by physicians and patients alike and will hopefully advance bladder cancer therapeutics and patient outcomes.

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This is the "Conclusion and References" section of the current issue of Evolving Paradigms In Bladder Cancer.

Bladder Cancer

Evolving Paradigms In Bladder Cancer: Introduction

Evolving Paradigms In Bladder Cancer: Current Treatment Strategies

Evolving Paradigms In Bladder Cancer: Prognosis and Treatment

Evolving Paradigms In Bladder Cancer: Emerging Biomarkers

Evolving Paradigms In Bladder Cancer: Emerging Therapies

Evolving Paradigms In Bladder Cancer: Conclusion and References