Bladder Cancer

Picture of bladder cancer.

The urinary bladder, or the bladder, is a hollow organ in the pelvis. Most of it lies behind the pubic bone of the pelvis, but when full of urine, it can extend up into the lower part of the abdomen. Its primary function is to store urine that drains into it from the kidney through tube-like structures called the ureters. The ureters from both kidneys open into the urinary bladder. The bladder forms a low-pressure reservoir that gradually stretches out as urine fills into it. In males, the prostate gland is located adjacent to the base of the bladder where the urethra joins the bladder. From time to time, the muscular wall of the bladder contracts to expel urine through the urinary passage (urethra) into the outside world.

The bladder is controlled by the autonomic nervous system, which signals the muscles in the bladder wall to contract or relax, allowing urine to be stored or released. The amount of urine the bladder can hold varies depending on the person's age, gender, and overall health. The normal volume of the full bladder is about 400 ml-600 ml or about 2 cups.

The bladder consists of several layers of tissue.

The innermost layer of the bladder, which comes in contact with the urine stored inside the bladder, is called the "mucosa" and consists of several layers of specialized cells called "transitional cells," which are almost exclusively found in the urinary system of the body.

These same cells also form the inner lining of the ureters, kidneys, and a part of the urethra. These cells form a waterproof lining within these organs to prevent the urine from going into the deeper tissue layers. These cells are also termed urothelial cells, and the mucosa is termed the urothelium.

The middle layer is a thin lining known as the "lamina propria" and forms the boundary between the inner "mucosa" and the outer muscular layer. This layer has a network of blood vessels and nerves and is an important landmark in terms of the staging of bladder cancer (described in detail below in the bladder cancer staging section).

The outer layer of the bladder (the "muscularis") comprises the "detrusor" muscle. This is the thickest layer of the bladder wall. Its main function is to relax slowly as the bladder fills up to provide low-pressure urine storage and then to contract to compress the bladder and expel the urine during the act of passing urine.

Outside these three layers (adventitia) is a variable amount of fat that lines and protects the bladder like a soft cushion and separate it from the surrounding organs such as the rectum and the muscles and bones of the pelvis.

Bladder cancer is an uncontrolled abnormal growth and multiplication of cells in the urinary bladder, which have broken free from the normal mechanisms that keep uncontrolled cell growth in check. Invasive bladder cancer (like cancers of other organs) has the ability to spread (metastasize) to other body parts, including the lungs, bones, and liver.

Bladder cancer invariably starts from the innermost layer of the bladder (for example, the mucosa) and may invade the deeper layers as it grows. Alternatively, it may remain confined to the mucosa for a prolonged period. Visually, it may appear in various forms. The most common is a shrub-like appearance (papillary), but it may also appear as a nodule, an irregular solid growth, or a flat, barely perceptible thickening of the inner bladder wall (see details in subsequent sections).

Bladder cancer is classified based on the appearance of its cells under the microscope (histological type). The type of bladder cancer has implications in selecting the appropriate treatment for the disease. For example, certain types may not respond to radiation and chemotherapy as well as others. The histological type of cancer may also impact the extent of surgery required for maximizing the chances of a cure. In addition, physicians often describe bladder cancer based on its position in the wall of the bladder. Noninvasive bladder cancers occur in the inner layer of cells (transitional cell epithelium) but do not penetrate deeper layers. Invasive cancers penetrate into the deeper layers such as the muscle layer. Invasive cancers are more difficult to treat.

The more common types of bladder cancer are as follows:

• Urothelial carcinoma (previously known as "transitional cell carcinoma") is the most common type and comprises 90%-95% of all bladder cancers. This type of cancer has two subtypes: papillary carcinoma (growing finger-like projections into the bladder lumen) and flat carcinomas that do not produce fingerlike projections. Urothelial carcinoma (transitional cell carcinoma) is strongly associated with cigarette smoking.
• Adenocarcinoma of the bladder comprises about 1%-2% of all bladder cancers and is associated with prolonged inflammation and irritation. Most adenocarcinomas of the bladder are invasive.
• Squamous cell carcinoma comprises 1%-2% of bladder cancers and is also associated with prolonged infection, inflammation, and irritation such as that associated with longstanding stones in the bladder. In certain parts of the Middle East and Africa (for example, Egypt), this is the predominant form of bladder cancer and is associated with chronic infection caused by Schistosoma worm (a blood fluke, that causes schistosomiasis, also termed bilharzia or snail fever).
• Other rare forms of cancer found in the bladder include small cell cancer (arising in neuroendocrine cells), pheochromocytoma (rare), and sarcoma (in muscle tissue).

Cigarette smoking causes about 50% of all bladder cancers. The longer and heavier the exposure, the greater the chances of developing bladder cancer. The toxic chemicals in cigarette smoke, many of which are known cancer-causing substances (carcinogens), travel in the bloodstream after being absorbed from the lungs; the kidneys filter the chemicals into the urine. Then they contact the cells in the inner lining of the urinary system, including the bladder, and cause changes within these cells that make them more prone to developing into cancer cells. Quitting smoking decreases the risk of developing bladder cancer but takes many years to reach the level of people who have never smoked. However, as time passes after the quit date, the risk progressively decreases. Given the above, patients with bladder cancer need to stop smoking completely since the chances of cancer coming back after treatment are higher in those people who continue to smoke.

People who smoke also have a higher risk of many other types of cancer, including

• acute leukemia and cancers of the lung, lips, mouth, larynx, esophagus, stomach, and pancreas.

Age and family history are other risk factors as is the male sex. About 90% of people with bladder cancer are over age 55, though in exceptional cases the disease may surface in the third or fourth decade of life. Men are more prone to developing bladder cancer probably due to a higher incidence of smoking and exposure to toxic chemicals. A close relative with a history of bladder cancer may increase the predisposition for the development of this disease.

Exposure to toxic chemicals such as arsenic, phenols, aniline dyes, and arylamines increases the risk of bladder cancer. Dye workers, rubber workers, aluminum workers, leather workers, truck drivers, and pesticide applicators are at the highest risk.

Radiation therapy (such as that for prostate or cervical cancer) and chemotherapy with cyclophosphamide (Cytoxan) increase the risk for the development of bladder cancer. Moreover, it may also delay the diagnosis of bladder cancer in patients who have blood in their urine, since the patient and/or physician may incorrectly blame bladder irritation caused by the chemotherapy or radiation (radiation cystitis) as the cause of the bleeding.

Long-term chronic infections of the bladder, irritation due to stones or foreign bodies, and infections with the blood fluke prevalent in certain regions of the world (as mentioned earlier) are some other factors that predispose to bladder cancer.

The most common symptom of bladder cancer is bleeding in the urine (hematuria). Most often the bleeding is "gross" (visible to the naked eye), episodic (occurs in episodes), and is not associated with pain (painless hematuria). However, sometimes the bleeding may only be visible under a microscope (microscopic hematuria) or may be associated with pain due to the blockage of urine by the formation of blood clots.

There may be no symptoms or bleeding for prolonged periods between episodes, lulling the patient into a false sense of security ("I don't know what the problem was, but it is fine now!"). Some types of bladder cancer may cause irritative symptoms of the bladder with little or no bleeding. The patients may have the desire to urinate small amounts in short intervals (increased urinary frequency), an inability to hold the urine for any length of time after the initial desire to void (urgency), or a burning sensation while passing urine (dysuria). These symptoms occur more commonly in patients with high-grade, flat urothelial cancers called "carcinoma in situ" or "CIS" (described subsequently in the section on the staging of bladder cancer).

Other problems may cause blood to appear in the urine; for example, infections, kidney stones, and kidney disease, so it is important to have a physician check for the exact cause of blood in the urine.

Rarely, patients may have signs and symptoms of the more advanced diseases such as

• a distended bladder (due to obstruction by a tumor at the bladder neck),
• an inability to pass any urine,
• pain in the flanks (due to obstruction of urine flow from the kidney to the bladder by the growing tumor mass in the bladder),
• bone pains,
• foot and/or ankle swelling, or
• cough/blood in the phlegm (due to the spread of cancer cells to bones or lungs).
• Unexplained weight loss

Bladder cancer is most frequently diagnosed by investigating the cause of bleeding in the urine that a patient has noticed. The following are investigations or tests that come in handy in such circumstances:

• Urinalysis: A simple urine test that can confirm that there is bleeding in the urine and can provide an idea about whether an infection is present or not. It is usually one of the first tests that a physician requests. It does not confirm that a person has bladder cancer but can help the physician in short-listing the potential causes of bleeding.
• Urine cytology: A health care professional performs the test on a urine sample that is centrifuged. Then a pathologist examines the sediment under a microscope. The idea is to detect malformed cancerous cells that may pass into the urine from cancer. A positive test is quite specific for cancer (for example, it provides a high degree of certainty that cancer is present in the urinary system). However, many early bladder cancers may be missed by this test so a negative or inconclusive test does not effectively rule out the presence of bladder cancer.
• Ultrasound: An ultrasound examination of the bladder can detect bladder tumors. It can also detect the presence of swelling in the kidneys in case the bladder tumor is located at a spot where it can potentially block the flow of urine from the kidneys to the bladder. It can also detect other causes of bleeding, such as stones in the urinary system or prostate enlargement, which may be the cause of the symptoms or may coexist with a bladder tumor. An X-ray examination may rule out other causes of symptoms.
• CT scan/MRI: A CT scan or MRI provides greater visual detail than an ultrasound exam and may detect smaller tumors in the kidneys or bladder than can be detected by an ultrasound. It can also detect other causes of bleeding more effectively than ultrasound, especially when intravenous contrast is used.
• Cystoscopy and biopsy: This is probably the single most important investigation for bladder cancer. Since there is always a chance to miss bladder tumors on imaging investigations (ultrasound/CT/MRI) and urine cytology, it is recommended that all patients with bleeding in the urine, without an obvious cause, should have a cystoscopy performed by a urologist as a part of the initial evaluation. This entails the use of a thin tube-like optical instrument connected to a camera and a light source (cystoscope). A healthcare provider passes it through the urethra into the bladder and the inner surface of the bladder is visualized on a video monitor. Small or flat tumors that may not be visible on other investigations are visible by this method, and a piece of this tissue can be taken as a biopsy for examination under the microscope. This method effectively diagnoses the presence and type of bladder cancer. In addition, healthcare professionals may perform fluorescence cystoscopy at the same time; fluorescent dyes are placed in the bladder and are taken up by cancer cells. These cancer cells are visible (fluoresce) when blue light is shined on them through the cystoscope and thus becomes visible, thereby making identification of cancer cells easier with this technique.
• Newer biomarkers like NMP 22 and fluorescent in-situ hybridization (FISH) are currently in use to detect bladder cancer cells by a simple urine test. UroVysion, BTA, and the ImmunoCyt test are among the newer diagnostic tests. However, they have not yet achieved the level of accuracy to replace cystoscopy and cytology in the diagnosis and follow-up of bladder cancer.

Bladder cancer is staged using the tumor node metastases (TNM) system developed by the International Union Against Cancer (UICC) in 1997 and updated and used by the American Joint Committee on Cancer (AJCC). In addition, the American Urologic Association (AUA) has a similar staging system that varies slightly from that used by the AJCC. The combination of both staging systems appears below. This staging gives your physician a complete picture of the extent of the person's bladder cancer.

The T stage refers to the depth of penetration of the tumor from the innermost lining to the deeper layers of the bladder. The T stages are as follows:

• Tx - Primary tumor cannot be evaluated
• T0 - No primary tumor
• Ta - Noninvasive papillary carcinoma (tumor limited to the innermost lining or the epithelium)
• Tis - Carcinoma in situ (flat tumor)
• T1 - Tumor invades connective tissue under the epithelium (surface layer)
• T2 - Tumor invades the muscle of the bladder
  • T2a - Superficial muscle affected (inner half)
  • T2b - Deep muscle affected (outer half)
• T3 - Tumor invades perivesical (around the bladder) fatty tissue
  • T3a - Microscopically (visible only on examination under the microscope)
  • T3b - Macroscopically (for example, visible tumor mass on the outer bladder tissue)
• T4 - Tumor spreads beyond fatty tissue and invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall

The presence and extent of involvement of the lymph nodes in the pelvic region of the body near the urinary bladder determine the N stage. The N stages are as follows:

• Nx - Regional lymph nodes cannot be evaluated
• N0 - No regional lymph node metastasis
• N1 - Metastasis in a single lymph node < 2 cm in size
• N2 - Metastasis in a single lymph node > 2 cm, but < 5 cm in size, or two or more lymph nodes < 5 cm in size
• N3 - Metastasis in a lymph node > 5 cm in size and/or to lymph nodes along the common iliac artery

The metastases or the M stage signifies the presence or absence of the spread of bladder cancer to other organs of the body.

• Mx - Distant metastasis cannot be evaluated (This stage is not used by some clinicians.)
• M0 - No distant metastasis
• M1 - Distant metastasis

A healthcare professional then assigns a stage:

• Stage 0a Ta N0 M0
• Stage 0is Tis N0 M0
• Stage 1 T1 N0 M0
• Stage 2 T2 N0 M0
• Stage 3 T3 N0M0
• Stage 4 T4 N0 M0, or any T, N1 or above M0 , or any T, any N, M1

The proper staging of bladder cancer is an essential step that has a significant bearing on the management of this condition. The implications of the bladder stage are as follows:

• It helps select the proper treatment for the patient. Less aggressive treatment manages superficial disease (Ta/T1/Tis) as compared to invasive disease (T2/T3/T4).
• Invasive tumors have a higher likelihood of spreading to lymph nodes and distant organs as compared to superficial tumors.
• The chances of cure and long-term survival progressively decrease as the bladder cancer stage increases.
• Staging allows the proper classification of patients into groups for research studies and the study of newer treatments.

A pathologist examines the tumor specimen under a microscope to determine the grading of bladder cancer. It is a measure of the extent to which the tumor cells differ in their appearance from normal bladder cells. If the cancer looks similar to normal bladder tissue, it is referred to as "differentiated" or a "low-grade tumor." If the cancerous tissue looks very different from healthy tissue, it is called "poorly differentiated" or a "high-grade tumor." High-grade cancers are more aggressive than low-grade ones and have a greater propensity to invade the bladder wall and spread to other parts of the body. 

Stage and grade of bladder cancer play a very important role not just in deciding the treatment that an individual patient should receive but also in quantifying the chances of success with that treatment. 

The initial surgical procedure that a patient undergoes after the diagnosis of bladder cancer is established is usually a transurethral resection of a bladder tumor or "TURBT." Healthcare professionals perform TURBT with the help of special instruments attached to a cystoscope (mentioned earlier in the section on investigations) which involves cutting out the tumor and removing it from the bladder with the help of an electrical cautery device.

Doctors perform this surgery through the normal urinary passage and do not involve an external cut on the body. It is the initial treatment of bladder cancer as well as a staging procedure since the specimen retrieved from the surgery is sent to a pathologist who gives his/her diagnosis as to the depth of invasion of the tumor in the bladder wall (T stage) as well as the grade (high/low). Further treatment depends on the findings of this initial surgery as well as the other staging investigations and is covered in the sections to follow. TURBT is the most common treatment for bladder cancer.

Superficial bladder cancer is cancer that has not invaded the muscle wall of the bladder and is confined to the inner lining of the bladder. This cancer is also termed non-muscle-invasive bladder cancer. The T stage is Ta, T1, or Tis (also known as carcinoma in situ or "CIS"). After the initial TURBT or biopsy in the case of CIS, the subsequent treatment in these cases may involve observation with regular follow-up with cystoscopy examinations of the bladder, instillation of medications in the bladder, or in certain cases, surgical removal of the bladder (radical cystectomy).

Small low-grade, superficial bladder cancers may not require aggressive management after the initial TURBT and may be simply followed up by doing repeated cystoscopy examinations at regular intervals (usually every three months for the initial two years and then at increasing intervals). Some physicians will use fulguration (laser or electricity) to treat biopsy areas or other small areas that may contain bladder cancer cells.

It is very important to note that 30%-40% of these tumors tend to recur and these recurrences may not be associated with any symptoms. Hence, it is imperative to stick to a regular follow-up protocol to ensure that the disease does not go out of control. A single dose of a chemotherapy medication (for example, mitomycin C [Mutamycin]) put inside the bladder immediately after a TURBT can decrease the chances of recurrence within the first two years after surgery.

High-grade, larger, multiple, or recurrent superficial bladder cancers may require additional treatment after the initial TURBT. One of the most effective and widely used medications is the Bacille Calmette Guerin, commonly referred to as BCG. It is a modified form of Mycobacterium bovis, the bacterium that causes tuberculosis in cattle. Healthcare professionals instill BCG into the bladder in the form of a solution using a catheter placed in the urinary passage. It acts by stimulating the immune system of the body to act against the cancerous bladder cells and prevent their growth and development. It decreases the chances of recurrence of bladder cancer as well as its invasion into the muscle layer of the bladder. However, it is only partially effective in achieving these objectives, and its use does not obviate the need for regular follow-up. It is usually administered in six initial doses at weekly intervals followed by a "maintenance" schedule of three weekly doses repeated every three months that is usually recommended for at least one year but may be needed for as long as three years.

Patients who do not respond to BCG treatment, have recurrent bladder cancer in spite of treatment or have medical issues which preclude the use of BCG may require other forms of treatment. These include bladder instillation of immunotherapy agents such as interferon or chemotherapy medicines like valrubicin (Valstar), mitomycin C, epirubicin (Ellence), or doxorubicin (Adriamycin). In general, these medications are not as effective as BCG and help only a small minority of patients who have not responded to BCG.

Patients who have an aggressive form of high-grade superficial bladder cancer and those who have not responded or who have recurrent bladder cancer in spite of the treatments mentioned above receive a more aggressive form of treatment. This is usually in the form of a major surgical procedure called radical cystectomy. Cystectomy entails the removal of the bladder and the prostate and diverting of the urinary stream using parts of the intestine.

Patients diagnosed and treated for superficial bladder cancer need regular follow-ups to detect recurrences and treat them effectively. The following is a typical follow-up protocol:

• Cystoscopy and urine cytology every three months for two years, every six months for the next two to three years, and annually thereafter
• Imaging study (CT scan/intravenous urogram) of the kidneys and ureters once every year (especially for high-grade tumors/those associated with CIS)

Cystoscopy and cytology detect recurrence in the bladder itself while CT/IVU detects a tumor in the kidneys and ureters. Patients with bladder cancer are more likely to get upper urinary tract (kidney and ureter) tumors that arise from the inner lining of these organs and share a common origin with bladder tumors. The risk of upper urinary tract recurrence depends on the stage and grade of the initial disease and the response of the tumor to BCG. Individuals with recurrent high-grade bladder tumors can have a risk of developing a tumor in the upper tract.

Commercially available tumor markers that test urine samples for evidence of bladder tumor recurrence are also being used in follow-up protocols. However, their exact role is undefined as of now, and they are not an adequate substitute for cystoscopy and cytology. Some of these tests and markers are NMP 22, BTA Stat, BTA Trak, and UroVysion.

Surveillance is an important part of bladder cancer management, as it allows for early detection and treatment of cancer recurrence or progression. Patients should be vigilant about attending all scheduled surveillance appointments and reporting any new symptoms or concerns to their healthcare provider.

Muscle-invasive bladder cancer generally requires a more aggressive treatment plan than superficial bladder cancer. The standard and most effective treatment is the surgical removal of the bladder and diversion of the urinary stream using intestinal segments. This procedure, known as radical cystectomy, is a major operation; the doctor and patient should have a thorough discussion about the risks, complications, and benefits prior to this surgical procedure.

In short, the procedure entails the removal of the bladder, prostate, seminal vesicles, and the fatty tissue around the bladder through an incision made in the abdomen. The surgery also includes the removal of lymph nodes in the pelvis on both sides of the bladder to detect their involvement with cancer. This helps in deciding further management after surgery, including the need for chemotherapy. Patients who undergo a thorough lymph node dissection have a better chance of cure as compared to patients who either do not receive one or undergo a less extensive dissection.

Radical cystectomy can be performed via open surgery, laparoscopy, or with robotic assistance. The outcomes in terms of cancer control and cure rates do not differ between these different approaches. However, the use of laparoscopic and robotic approaches significantly decreases blood loss during surgery, decreases the need for blood transfusions, and may help in early recovery by decreasing postoperative pain at the surgical site. An additional advantage of the robot is that it permits an enhanced magnification of the surgical field with three-dimensional vision, which helps to enhance surgical precision. It is very important to note that all these approaches can achieve comparable results in terms of cancer control in the hands of surgeons skilled and experienced in a particular modality. So, the comfort factor and experience of an individual surgeon in a particular approach should play a major role in the patient's decision regarding the selection of the approach for surgery.

The physician must divert the urine to another way of exiting the body once the bladder has been removed. There are three popular ways of doing that. All of them require the use of segments of the intestine that are still connected to their blood supply but have been disconnected from the gastrointestinal tract.

• An ileal conduit is the most extensively used form of urinary diversion. It is also the simplest and the least time-consuming form of diversion and has the least chance of complications in the short and long term. This entails the use of an intestinal segment, one end of which is connected inside the body to the ureters that drain urine into it from the kidneys, while the other end is brought out to the level of the skin and is covered by an external appliance (a "urostomy bag"). The urine from the kidneys continuously drains into the bag through the ureters and the "ileal conduit." A patient can empty the bag at regular intervals or when it is nearly full by opening a tap-like attachment at the lower end of the bag. The major advantage of this procedure is that is relatively straightforward to perform with the least chance of complications. The disadvantages include the need to wear a bag all the time and the resultant negative impact that may occur on body image. This procedure is also termed incontinent diversion.
• Orthotopic neobladder entails the creation of a new bladder ("neobladder") with the help of an intestinal segment and connecting it to the natural urinary passage so that a person may be able to pass urine "more normally." The major advantage of this procedure is that it avoids the need to wear a bag, and the patient can pass urine in a more natural fashion. However, this is a more difficult procedure with a longer recovery period and may lead to some short-term and long-term complications, including persistent urinary leakage and inability to pass urine requiring the use of self-intermittent catheterization (passage of a tube into the urinary passage to empty the bladder). The ileal conduit rather than the neobladder may best serve some senior patients and those with certain medical conditions that affect the function of the kidneys or impair their ability to self-catheterize.
• Continent catheterizable pouch (for example, "Indiana pouch") is a form of neobladder that is not connected to the normal urinary passage but instead has an opening or a "stoma" at the level of the skin on the abdomen through which a catheter can be passed to empty it periodically. This has a valve-like mechanism that prevents the leakage of urine through this opening thereby precluding the need to wear a bag. It is used in patients desirous of and fit for a continent urinary system while being unsuitable for an orthotopic neobladder due to certain circumstances such as cancer at the point where the bladder joins the urethra. This procedure is also termed continent diversion.

Radical cystectomy (open, laparoscopic, or robot-assisted) combined with one of the three urinary diversion methods is the gold standard for the treatment of muscle-invasive and selected cases of high-grade superficial bladder cancer. Certain patients, however, may be unfit or unwilling to undergo this surgery. Segmental or partial cystectomy is rarely done. Bladder cancer is so often multifocal in the bladder that such an approach is rarely effective. These patients can often undergo a combination of extensive TURBT, chemotherapy, and radiation in an attempt to cure or control the disease without the need to remove the urinary bladder surgically. Most experts believe that this regime may not be as effective as a radical cystectomy, but it is an option for unfit/unwilling patients. Radiation to the bladder can, however, lead to its own set of problems and complications, including radiation damage to the bladder and rectum that give rise to bleeding and irritative symptoms ("radiation cystitis" and "radiation proctitis").

Patients who are diagnosed with metastatic bladder cancer (M stage - M1; cancer which has spread to other parts of the body) are usually treated with chemotherapy. Chemotherapy may also be used in cases of "locally advanced" bladder cancer (T stage - T3 and above and/or N stage - N1 and above) in an attempt to decrease the chances of cancer coming back after radical cystectomy. This is "adjuvant chemotherapy." Another strategy entails administering "neoadjuvant chemotherapy" by giving these medications before radical cystectomy in an attempt to improve the results of surgery and decrease the size of the tumor before the operation.

Chemotherapy has the potential to control metastatic bladder cancer and increase the chances of cure when used in a neoadjuvant or adjuvant setting along with surgery. However, chemotherapy has its own set of side effects that some individuals find intolerable.

The time-honored chemotherapy regimen for bladder cancer is the MVAC. It is a combination of four medications given in the cyclical form.

• M: Methotrexate 
• V: Vinblastine
• A: Doxorubicin 
• C: Cisplatin 

Oncologists currently prescribe MVAC in a "dose-dense" fashion. This means the patient takes the drugs more frequently than was previously done in the accepted treatment schedule, as well as taking growth factors to help the blood counts recover faster from the effects of the chemotherapy drugs. The older schedule for MVAC therapy is no longer recommended according to the National Comprehensive Cancer Network.

Some patients with heart disease may not be in a condition to receive Adriamycin and may receive CMV instead (CMV = MVAC without Adriamycin)

An alternative regimen is a combination of gemcitabine and cisplatin. Physicians use this more often nowadays since some studies have shown that it is equally effective as the MVAC regime with fewer side effects. However, about 40%-50% of patients have medical issues that preclude the use of this therapy.

Cisplatin, which is the main medication in all these regimens, is not given to patients who have abnormal kidney function. In this case, doctors may substitute it with carboplatin (Paraplatin), which, however, is not as effective as cisplatin-based chemotherapy.

Chemotherapy is an ever-changing method to reduce or eliminate cancer cells; it is best for patients to discuss this therapy with their doctors. Variations in chemotherapy treatments occur among clinicians and one patient’s therapy may be quite different from that of another patient. In addition, healthcare professionals may introduce newer compounds at any time that may be advantageous to use instead of conventional chemotherapy agents.

A few cancer treatment centers use, in addition to chemotherapy and endoscopic resection, external radiation beam therapy to treat patients. However, the protocol is complex with toxicity and high pretreatment mortality (death) rates mainly due to sepsis from the chemotherapy. External beam radiation therapy is mainly used in other countries; it is infrequently used in the United States as a primary treatment. Its use to reduce pain from metastases of bladder cancer, especially to the bones, is still of value.

Immunotherapy drugs, such as pembrolizumab, also are used treatadvanced or metastatic bladder cancer. These drugs block a molecule known as PD-L1 that leads to increased immune system (T-cell) activation and decreased tumor size; you should discuss with your doctors what individual treatments are best for your current condition. Additional treatments for metastatic bladder cancer include targeted therapy. Targeted therapy uses drugs designed to attack cells that express certain molecular markers. Erdafitinib is a targeted therapy drug that is given to people whose tumors have been shown to contain genetic alterations in the genes known as FGFR2 or FGFR3. Enfortumab vedotin (Padcev), is a type of drug known as an antibody-drug conjugate. It is used to treat locally advanced (unresectable) or metastatic urothelial carcinoma in people who have also received a PD-1 or PD-L1 immune checkpoint inhibitor and platinum-based chemotherapy, as well as for those who cannot receive cisplatin-based chemotherapy and have already received one or more treatments. 

The most important factors that affect the prognosis (or the chances of control and cure) of bladder cancer are the stage and grade of the tumor. The lower the stage and grade, the better the outlook. Other factors such as number, size, the pattern of recurrence (if any), response to initial treatment like BCG, coexistent carcinoma in situ, and certain genetic mutations also play a role. The table below is based on the National Cancer Institute's database:

The 5-year relative survival rates for bladder cancer are as follows:

• 97% for carcinoma in situ of the bladder alone (abnormal cells found in the tissue lining the inside of the bladder)
• 71% for localized bladder cancer (cancer is in the bladder only)
• 39% for regional bladder cancer (cancer has spread beyond the bladder to nearby lymph nodes or organs)
• 8% for metastatic bladder cancer (cancer has spread beyond the bladder to a distant part of the body)

For low-risk superficial bladder cancer (Ta, low grade), the chances of recurrence are about 50% five years after the initial diagnosis. This necessitates regular follow-up, even in these low-risk tumors. However, unlike the more aggressive variants of bladder cancer, the chances of progression (for example, chances of the tumor invading the deeper layers of the bladder) are minimal. Typically, these tumors, even when they recur, do so in the same stage and grade as the original tumor and do not compromise the life expectancy of the patient.

High-risk superficial tumors are those that are high-grade, T1 tumors and are associated with extensive areas of carcinoma in situ. Multiple tumors, large tumors, and those that recur despite BCG treatment are also at an increased risk for recurrence and progression. These tumors have a recurrence rate in the range of 50%-70% at one and five years, respectively. They are also much more likely to invade the deeper layers. Doctors need to manage these tumors more aggressively since they have the potential to invade and spread to other parts of the body thereby shortening the life expectancy of the patient.

The best way to prevent bladder cancer is to avoid exposure to agents that cause the disease.

• People who don't smoke are three to four times less likely to get bladder cancer as compared to smokers. Continuing to smoke after the diagnosis of bladder cancer portends a poorer outcome and increases the chance of the disease coming back after treatment.
• Avoidance of occupational exposure to cancer-causing chemicals such as aniline dyes may also be important.
• Despite research in this area no medication or dietary supplement has been conclusively demonstrated to decrease the risk of bladder cancer in normal individuals.
• However, recent studies of patients taking atorvastatin to lower cholesterol have suggested the drug may lower the risk of prostatic cancer and by inference, bladder cancer, but this needs further study.

A number of online resources are available for bladder cancer patients to gain more insight into this disease and its management. Bladder Cancer Advocacy Network (http://www.bcan.org) is one such resource that provides a downloadable patient information handbook and links to patient support groups.

The National Cancer Institute (http://www.cancer.gov) also provides bladder cancer information.

The European Organization for Research and Treatment of Cancer (http://www.eortc.be/tools/
bladdercalculator) features a calculator that predicts the chances of recurrence and progression of superficial bladder cancer after initial treatment based on certain tumor characteristics.