Bladder Cancer is the fifth most common cancer in the United States, accounting for 55,000 new cancer diagnoses and 12,000 cancer-related deaths each year in this country. The most common presenting symptom is painless hematuria (blood in urine) and this is considered a major warning sign of cancer that should be evaluated. Some patients will also or alternatively present with irritative voiding symptoms such as frequency, urgency, or incontinence. Bladder cancer is diagnosed through urine cytology (similar to a pap smear of the urine sample) and cystoscopy and biopsy. During cystoscopy the urethra is numbered with a local anesthetic and a soft, flexible telescope is introduced allowing inspection of the internal lining of the bladder.

Bladder cancer can be caused or exacerbated by carcinogens that are filtered out of the blood stream by the kidneys and concentrated into the urine. The bladder acts as the storage organ for the urine allowing for prolonged exposure of the carcinogens to the lining of the bladder. Smoking and employment in the chemical, dye, textile or rubber industries can increase the risk of developing bladder cancer, although in many cases the eact cause cannot be determined, and many patients have none of these factors. Other factors that can increase the risk of bladder cancer include chronic bladder infection or longstanding indwelling catheter, chronic phenacetin exposure, prior treatment with cytoxan (a chemotherapeutic agent), and pelvic radiation therapy.

Most bladder tumors are called transitional cell carcinomas (>90%), developed from the transitional lining of the bladder. The following discussion will relate to this most common type of bladder cancer.

Bladder cancer rarely runs in families, although there is one well described syndrome, the Lynch syndrome, in which family members can develop colonic polyps, colon cancer, endometrial cancer, ovarian cancer, and cancer of the bladder or ureter. Families in which a constellation of these cancers are found should be evaluated for this possibility.

Bladder cancer is staged by a pelvic examination performed under anesthesia combined with a biopsy of the tumor. This is done with the cytoscope, which is used to remove the tumor and underlying portion of the wall of the bladder. Parts of the bladder are scraped out and cauterized. The main distinction with bladder cancer is between superficial bladder tumors (primarily confined to the lining of the bladder-stages Ta and carcinoma in situ) and invasive bladder cancer (invading into the muscle wall of the bladder-stage T2, T3, and T4). There is also an intermediate category in which the tumor is microinvasive (stage T1). Bladder tumors are also graded as to their apparent aggressiveness based upon their appearance under the microscope.

The stages of bladder cancer are:

• Ta:
  A papillary tumor confined to the lining of the bladder and growing into the lumen of the bladder.
• Carcinoma in situ (CIS):
  potentially aggressive cancer cells are present, but still confined to the lining of the bladder
• T1:
  Microinvasive tumor with relatively high malignant potential
• T2:
  Tumor invading into the muscle coat of the bladder but not breaking through
• T3:
  Tumor invading into the muscle coat and breaking through the back wall of the bladder
• T4:
  Tumor invading into adjacent organs or fixed into the sidewall of the pelvis

Bladder cancer can also spread to the lymph nodes in the pelvis, which marks it as a more aggressive cancer, and it can spread through the blood stream to the lung, liver, or bones. Patients with high-grade disease will often require evaluation with a CT scan and CXR, and in some instances additional studies such as bone scan, to accurately stage the cancer.

Treatment of bladder cancer

• Low risk superficial disease (low grade, stageTa):
  Patients with low grade, superficial disease are at relatively low risk for progression to more serious forms of invasive bladder cancer (only 10-20%), and this form of bladder cancer is rarely lethal. However, these bladders often behave like a lawn with weeds as they can grow additional tumors through the subsequent months or years (perhaps due to prior exposure to carcinogens). These patients are managed initially with bladder biopsy to remove all of the visible cancer, and then they are followed with an office cystoscopy and cytology every three months for at least a year, and every six months subsequently, unless frequent recurrences are found. In the latter case, intravaesical treatments can be considered (see below), in an effort to reduce the risk of recurrence or progression. As with all patients with bladder cancer, the entire lining of the urinary tract is also at risk, and these patients should undergo kidney X-rays such as an IVP every few years.
• High risk superficial bladder cancer (high grade Ta, carcinoma in situ, or microinvasive disease-T1):
  Patients with this form of superficial bladder cancer are not only at risk of recurrence within the bladder, some of these tumors can progress to more invasive and potentially lethal disease. Hence, these patients are at increased risk long-term and require diligent care and follow-up. After biopsy to remove the tumor most such patients will be offered intravesical therapy. For this the patient returns once a week for 6 weeks for installation of BCG or chemotherapy directly into the bladder. The bladder is temporarily catheterized and emptied, the treatment is placed into the bladder, and the catheter is removed. The patient then is asked to hold the treatment in place by not voiding for at least two hours and the agent will treat the lining of the bladder and reduce the risk of recurrence or progression. The most commonly used agent is BCG, which is actually a bacteria in the tuberculosis family. BCG has been altered over many years to be less aggressive and the treatment is considered very safe, although patients should call if they develop a fever after treatment. BCG incites an immune reaction within the bladder wall and this is thought to account for its effectiveness. In addition to the intravesical therapies, patients are followed closely with cystoscopy and cytology every three months and a kidney X-ray is obtained on a yearly basis. Patients who recur with muscle invasive disease despite the BCG treatments may need to move on to more radical therapies (see below), while those that recur with high grade tumors, CIS, or microinvasive disease are at high risk of developing potentially lethal disease. Again, bladder removal should be considered, although some patients may opt for additional intravesical treatments with BCG and/or interferon or chemotherapeutic agents such as mitomycin C or valrubicin. The risk of recurrence of bladder cancer can also be reduced by stopping smoking (continuing smoking may be like pouring gasoline on a fire), increasing fluid intake, by pursuing a healthy, low fat diet, and through the use of vitamins such as A, B6, C, E and zinc (one preparation of these vitamins is called Oncovite and is available over the internet).
• Muscle invasive disease (stage T2 or T3):
  Patients with muscle invasive disease are at risk for spread of the cancer to other parts of the body and will need to consider more invasive treatments as this can be a lethal form of the disease. Traditionally, these patients have been treated with removal of the bladder (radical cystectomy), and this is still considered the gold standard for the management of this group of patients. In men this involves removal of the bladder and prostate and in women the removal of the female reproductive organs (uterus and ovaries) in addition to the bladder. The urinary tract can then be reconstructed in three ways:
  1. Neobladder:
     A pouch is made from the intestines and connected to the urethra allowing the patient to void in a relatively normal manner. Wearing of a bag and catherization is not required and this is considered the Cadillac of urinary diversions. It is the preferred form of diversion in the appropriate circumstances, but requires a relatively healthy patient who is well motivated, as the recovery from surgery is somewhat more involved.
  2. Indiana pouch:
     A pouch is made from the intestines and connected to the skin near the belly button by a very small conduit with a small stoma that can be readily covered with a band aid. The pouch fills internally and does not leak. The patient then catheterizes the pouch every 3-4 hours letting the urine drain into the commode. A bag is not required and this form of diversion also provides a very high quality of life.
  3. Ileal conduit:
     The urine is brought to the skin through a stoma that drains continuously and requires the patient to wear a small bag that must be emptied periodically. This is the simplest form of diversion that can be performed quickly in the operating room allowing the patient to recover from surgery in the most expedient manner. This form of diversion is often preferred in older patients or those with other major medical problems, or in sedentary patients less concerned about body image.
• Other options for patients with muscle invasive disease include partial cystectomy, radiation therapy, and a combination of chemotherapy and radiation therapy.
  All of these options allow for preservation of the natural bladder but come at the cost of either an increased risk of cancer recurrence or an increased burden of therapy. Also, many patients managed in these ways will eventually require bladder removal as the remaining bladder remains at high risk long-term. Nevertheless, these options should be reviewed and understood before making a final decision about treatment.
• Locally advanced or metastatic disease (stages T4, nodal positive disease, or metastatic disease):
  Patients with bladder cancer that is fixed into the pelvis and not resectable and those with spread of cancer into the lymph nodes or to other organ systems are traditionally treated with chemotherapy as their primary mode of therapy. A variety of chemotherapeutic agents are used including cis-platin, taxol and related agents, and gemcitabine. After several courses of therapy have been administered the patient is reassessed for response to therapy, and the bladder is also monitored carefully. Chemotherapy is administered by our Medical Oncologists at The Cardinal Bernardin Cancer Center.

Summary:

Each patient with bladder cancer should be counseled to understand the stage of the cancer and its malignant potential, and it should be recognized that this is a highly variable group of patients, some with low risk and some with potentially lethal cancer. The reasonable options for treatment should be reviewed, and treatment should be individualized taking into account patient age and general medical condition, the stage and grade of the cancer, and patient preferences. Quality of life considerations must be weighed heavily, while at the same time providing effective and safe therapy. We hope that this brief review of the current diagnosis, staging and therapy of bladder cancer is informative for you and your family members. Our urologic oncology team is always available to discuss any questions or problems with you, and to answer any questions that you may have about your disease.

• Robert C. Flanigan, MD
• Marcus Quek, MD, PhD
• Mila Yap, RN
• Kathy Marchese, RN