Bladder cancer is the most common malignancy involving the urinary system. It originates from the cells that are on the surface of the inner lining of the bladder that are called transitional cells. Much less commonly, urothelial cancers can arise in the renal pelvis, ureter, or urethra.

Bladder Cancer Statistics 

Bladder cancer is the 4^th most common type of cancer in men, while it is less common in women. Based on the American Cancer Society, it is estimated that in 2021 there are going to be almost 84,000 new cases and 17,000 deaths with a male to female ratio of 3:1. The majority of patients diagnosed over the age of 55, with mean age being 73 years. Caucasians have double the risk of developing bladder cancer compared to African Americans while the disease is less common among Hispanics, Asians and Native Americans. 

What Causes Bladder Cancer? 

The most common causes of bladder cancer and cancer of the upper track including renal pelvis, ureters and urethra are environmental and specifically carcinogens that are excreted in the urine.  Chemical carcinogens like smoking cigarettes and industrial exposure are the most common causes. Others are hair dye, paint components, diesel exhaust, and printing. Certain occupations have higher risk, such as metal workers, rubber industry workers, leather, textile and electrical workers, miners, painters and cement workers. There is also genetic predisposition for those individuals who have Lynch syndrome also known as hereditary nonpolyposis colorectal cancer syndrome as well as Cowden disease. Other conditions that increase the risk of bladder cancer is prior chemotherapy use like cyclophosphamide, prior radiation exposure, for example those being treated for prostate or cervical cancer. Chronic bladder infections, including schistosomiasis, chronic indwelling catheter use and chronic cystitis are leading to inflammation, irritation and eventually cancer.

What are Early Symptoms of Bladder Cancer? 

Bladder Cancer most commonly present with blood in the urine. Other alerting symptoms are flank pain, lower abdominal pain, cramping, frequent urinary infections, urinary frequency, nocturia or dysuria depending on where is the initial cancer located. In more advanced stages patients could have weight loss, anorexia and symptoms related to the sites of metastasis, such as pain when metastasized in bones. Rarely, patients are asymptomatic and bladder cancer diagnosis is an incidental finding.

 

How does my doctor know I have Bladder Cancer?

The work up and eventually diagnosis of bladder cancer is based on the presentation. Cystoscopy is the gold standard procedure when patients present with hematuria. For tumors that are originating in the renal pelvis or ureters the standard approach is bilateral ureteroscopy with biopsies especially if the cystoscopy is normal. Those procedures are combined with urine cytology as that could detect small tumors that are not visible with the endoscopies. For those patients with diagnosed urothelial cancer will need to undergo staging scans that will include CT of chest with contrast and / or  CT abdomen/pelvis or CT urogram. However, those with compromised kidney function will need to have MR urogram. Ultimately tissue diagnosis via direct biopsy (during endoscopy) or CT guided biopsy (if cancer in metastatic site) will lead to the final diagnosis that will be confirmed based on the pathology report.

What does Classification and Staging of my Bladder Cancer mean?

The most common histology is urothelial or transitional cell carcinoma, that could be either pure or mixed with variants such as nested variant, micropapillary, plasmacytoid, sarcomatoid or squamous differentiation. Other histologies are small cell carcinoma, adenocarcinoma, squamous cancer. While most common information is provided for bladder cancer, this is often interchangeable for cancer originating in upper track including renal pelvis, ureters and urethra.

The standard staging system that is being used for bladder cancer is the TNM system.  Based on the American Joint Committee on Cancer (AJCC) TNM stands for T for tumor, N for nodes and M for metastasis. Specifically T describes the size of the original tumor and whether it has grown through the bladder wall or invades nearby tissues, N indicates whether the tumor has spread to the local or distant nodes while M indicates whether the cancer had metastasized. Bladder cancer could present in various stages, with Stage 1 being the very early stage that usually managed by the urologists. Stage 2 and 3 is local or locally advanced bladder cancer while stage 4 is when cancer has already spread and is metastatic. The TNM stage is also being used for cancer of the upper track and urethra.

What are treatments for Bladder Cancer?

The treatment options for bladder cancer depend on the stage of the disease. Patients should always consider enroll in clinical trials that are available to them. The information below is primarily for patients who have the most common histology that is urothelial cancer or mixed histology with urothelial being the predominant one.

Non Muscle Invasive Bladder Cancer is being managed with transurethral resection of the bladder tumor (TURBT). For low grade tumors, no therapy is indicated after TURBT. For high grade tumors, after TURBT patients should undergo intravesical therapy with BCG followed by maintenance. Due to BCG shortage, in same cases gemcitabine is being offered. Patients who are BCG refractory could be treated with intraesical mitomycin or gemcitabine. Pembrolizumab has been approved for BCG refractory disease however clinical trials should be offered when available.  

Muscle Invasive Bladder Cancer or patients with locoregional disease that are surgical candidates and can be operated with curative intent, should be offered clinical trials as there is a surge of those in this setting. As of 2021, the standard of care for cisplatin eligible patients, is neoadjuvant chemotherapy with cisplatin based chemotherapy followed by cystectomy. For those who have residual disease T3, Nx, adjuvant nivolumab has been FDA approved based on prolonged disease free survival however overall survival date are not available yet. If they underwent cystectomy without neoadjuvant therapy and are cisplatin eligible, then cisplatin based chemotherapy should also be offered. Patients who are cisplatin ineligible and surgical candidates should undergo cystectomy with lymph node dissection and could be offered post operatively nivolumab if they have T2 and above disease or the standard of care to this date which is carboplatin based chemotherapy. Important to point out that with the introduction of immunotherapy for urothelial cancer there are several ongoing studies in which immunotherapy has been offered prior to surgery either as single agent but most commonly in combination chemotherapy and often is continued postoperatively with the hope to improve outcomes. Interestingly at this point and time, the goal is to offer neoadjuvant therapy (immunotherapy and more) in the cisplatin ineligible individuals.

There are several bladder preservation protocols for those who are not surgical candidates or are refusing radical cystectomy and those include combination of systemic therapy with radiation after maximum resection with TURBT. Those systemic therapies vary from single or combination chemotherapies depending on kidney function and performance status while again clinical trials studying the role of immunotherapy or combination of chemotherapy and immunotherapy with radiation are undergoing.

Significant progress has been made for the treatment of bladder cancer in the metastatic setting. The information below is for urothelial cancer originating not only in the bladder but also upper track, ureters and urethra. As of 2021, newly diagnosed patients with advanced, unresectable bladder cancer are offered cisplatin based chemotherapy if they are eligible, while carboplatin remains the standard of care in those who are not able to receive cisplatin. Immunotherapy (pembrolizumab, atezolizumab) in the first line setting is approved only for the cisplatin ineligible patients who are PD-L1 positive or platinum ineligible patients regardless of the PD-L1 status. Similarly, immunotherapy agents (pembrolizumab, avelumab, nivolumab) are approved in the second line irrespective to the PD-L1 status.

While taxanes used to be the next drug of choice, the treatment approach has changed since the approval of enfortumab vedotin , the antibody drug conjugate (ADC) for Nectin 4. Similarly, sacituzumab govitecan is another ADC for trop-2 also recently approved for bladder cancer after progression on platinum based chemotherapy and immunotherapy. Patients who have FGFR 2 or 3 mutation based on next generation sequencing should also be offered the only approved to date FGFR inhibitor, erdafitinib for urothelial cancer. 

Important to mention is that all these newly approved agents for advanced bladder cancer are now being studied in earlier settings (neoadjuvant, adjuvant  and early metastatic) as single agents and in combination. Therefore is critical for patients to be offered and encouraged to participate in the relevant clinical trials, again with ultimate goal to improve outcomes and advance the field. 

Who are the people that research Bladder Cancer at our affiliate UCLA? 

The Medical Director of the Bladder Cancer Program is Alexandra Drakaki, MD, PhD. She is the principal Investigator of the bladder cancer clinical trials at UCLA and TRIO-US. Part of the GU Oncology team and sub-investigators in those trials are Dr. Sandy Liu and Dr. John Shen. 

The Surgical Director of the Bladder Cancer Program is Karim Chamie, MD, who is also the principal investigator of the early stage bladder cancer clinical trials. Members of the urologic oncology team who care for patients with bladder cancer are Dr. Allan Pantuck, Dr. Mark Litwin, Dr. Christopher Saigal and Dr. Brian Shuch. Last but not least is Arnold Chin, MD, PhD who is a clinician scientist and is running a lab with special interest and in small cell bladder cancer. Dr. Chin’s focus in this cancer subtype lead to the design of an investigator initiating immunotherapy based combination study.

Part of the Team caring for patients with bladder cancer are the Radiation Oncologist, Dr. Amar Kishan and Dr. Albert Chang.

The excellent care provided to this patient population would have not been possible without the expertise in diagnosis that is made by the specialized GU pathologists and Radiologists at UCLA.