Bladder Instillations to Treat Bladder Cancer

Bladder cancer is the fourth most common cancer in men, surpassed in incidence only by prostate, lung, and colon cancers. Over 80,000 patients are diagnosed annually and follow-up care for patients with bladder cancer comprises a large part of the practice of urology.  Today’s entry reviews the use immuno-therapeutic and cytotoxic medications that are instilled into the urinary bladder to reduce bladder cancer progression and recurrence.

The incidence of bladder cancer increases with age and is four times more common in men than women and twice as common in Caucasian men than African American men. 80% of newly diagnosed individuals are 60 years of age or older. Excepting skin cancers, bladder cancers are the most frequent recurring cancer, with up to 70% of patients experiencing a recurrence. The good news is that when the disease is diagnosed and treated in early stages, the chances of survival are excellent, highlighting the importance of a timely and accurate diagnosis.

Bladder cancer most often presents clinically with blood in the urine and sometimes with urinary symptoms including urgency, frequency, and pain. On occasion, it is picked up incidentally on imaging studies done for other reasons. Cystoscopy identifies the area of abnormality within the bladder and thereafter the patient undergoes surgical biopsy and removal of the tumor (trans-urethral resection of bladder tumor, a.k.a. TURBT).

Following TURBT, under certain circumstances it is beneficial to use a medication that is instilled in the bladder (intravesical therapy) to help prevent or decrease bladder cancer recurrence and progression. This is especially the case with large tumors, when many tumors are present, with high-grade tumors, or with tumors that have recurred. It is particularly useful for carcinoma-in-situ (CIS), a variant of bladder cancer that is superficial and flat, yet high-grade. The mainstay and “gold standard” of bladder instillation treatment is a form of immunotherapy using tuberculosis vaccine–BCG (bacillus Calmette Guerin)–a live, attenuated (weakened) form of tuberculosis bacteria. There are also several chemotherapy alternatives to BCG that are used via bladder instillation, including mitomycin, gemcitabine and valrubicin.

Bladder cancer has a strong tendency to recur, despite TURBT with complete removal of all visible tumors. This approach can only treat obvious and visible tumors, with the possibility that there are additional tumors present that are not yet visible since bladder cancer is a “field” disease—capable of occurring anywhere within the lining of the urinary tract. One of the rationales for using bladder instillation medication is that it is a liquid formulation that is instilled in the bladder and will bathe and treat all surfaces of the bladder.

I often use the analogy of plucking out dandelions in your lawn by hand as opposed to using a weed spray with respect to the difference between TURBT and using a bladder instillation medication.

Immediate Post-Operative Instillation

After surgical removal of a bladder cancer, there is a possibility of implantation of tumor cells or, alternatively, residual but not visible disease. Immediate bladder instillation of an appropriate medication within 24 hours of the bladder cancer resection is used under certain circumstances to reduce recurrence rates from implantation of tumor cells or from residual, unrecognized disease. The chemotherapy medications are used for this purpose.

Intravesical Treatment Options

BCG 

The use of tuberculosis vaccine (bacillus Calmette-Guerin or BCG) to treat bladder cancer is one of the great success stories in the history of using the immune system to fight cancer. For many years, BCG has been recognized as the standard of care for high-grade, superficial bladder cancer and carcinoma-in-situ (CIS).

BCG is a unique strain of “weakened” mycobacterium bovis (cow tuberculosis bacterium) developed by Albert Calmette and Camille Guerin at the Pasteur Institute in Lille, France in 1921 as a tuberculosis vaccine. At the time of its development, there was a growing recognition of the relationship between the immune system and cancer. In 1929, autopsies in TB patients demonstrated a reduced prevalence of cancers, suggesting that BCG might also have a role in the treatment of cancer.

Early investigators found that mice given BCG were protected against cancers that were implanted. In 1975, Dr. Jean deKernion at UCLA reported a melanoma that had spread to the bladder that was eliminated by direct injection of BCG into the melanoma. In 1976, Dr. Alvaro Morales successfully instilled BCG inside the bladder to treat bladder cancer and after clinical trials it was FDA approved for use within the bladder in 1990…The rest is history.

BCG activates the immune system and triggers an inflammatory response that destroys bladder cancer cells. A good response to BCG immunotherapy requires a patient with an immune system capable of mounting a cellular immune response.

BCG is instilled directly within the urinary bladder. One cycle is a once per week treatment for 6 weeks, referred to as an induction course.  A full course is two cycles, followed by maintenance therapy. Typically, the BCG treatment is initiated several weeks following the bladder tumor resection to allow the bladder time to heal. BCG is placed inside the urinary bladder using a narrow catheter. Retaining it for two hours is ideal and rotating body position is important so that all areas of the bladder are adequately bathed with the BCG.

Low-grade fever, urinary urgency, frequency, burning and blood in the urine are typical side effects, often indicative of the immune response being mounted. Occasionally, flu-like symptoms may occur, including fever, chills, cough, muscle and joint aches. When severe symptoms occur, BCG concentration can be reduced to 1/3, 1/10, 1/30, or even 1/100^th of a dose to prevent escalating side effects.

BCG with Interferon

Interferon alpha-2B is a naturally occurring cytokine protein that is used to treat a variety of cancers (leukemia, lymphoma, melanoma, kidney cancer) and viral infections (hepatitis C and genital warts). Interferon can induce a non-specific cellular and humoral immune response towards cancer cells. The combination of BCG and interferon has been used as a “salvage” alternative prior to proceeding with radical cystectomy (surgical removal of the bladder and diversion of the ureters) for patients with bladder cancer that has not responded to BCG alone.

Mitomycin C

Mitomycin is an antitumor antibiotic that inhibits DNA synthesis by producing DNA cross-links that halt cell replication and eventually cause cell death. Since cancer cells in general divide faster and with less error-correcting than healthy cells, they are more sensitive to this damage. This cell damage slows or stops the growth of cancer cells.

Mitomycin is administered according to the same protocol as BCG, given directly into the bladder through a catheter, and left in the bladder for 1-2 hours. This drug is blue in color and may make one’s urine blue/green in color. This can last up to two days after each dose. It is not uncommon to have urinary frequency or painful urination for 24 hours after treatment.

Gemcitabine

This medication works by inhibiting processes required for DNA synthesis and is administered according to the same protocol as BCG.

Valrubicin

Valrubicin is classified is an anti-tumor antibiotic derived from the soil fungus Streptomyces. It acts during multiple phases of the cell cycle and is considered cell-cycle specific. It is administered according to the same protocol as BCG.

Docetaxel

Docetaxal (Taxotere) is a promising “salvage” chemotherapeutic medication that is now being trialed for high-risk, non-muscle invasive bladder cancer after BCG failure. Like BCG it is instilled within the bladder once weekly for 6 weeks.

Side Effects of Bladder Instillations

Side effects of the intravesical administration of the aforementioned medications include bladder irritation, urinary urgency and frequency, painful urination, bladder spasms, blood in the urine, bladder pain, urinary incontinence, and urinary infection. These side effects are generally short-lived and temporary.

Advice Before and After BCG Intravesical Therapy

1. Restrict fluid intake, consumption of caffeinated beverages, and use of water pills for several hours prior to the procedure.
2. Retain the BCG in the bladder for 2 hours if possible.
3. Rotate so that medication bathes all surface areas of the bladder (supine, left side, right side, prone).
4. Care should be used when urinating after the BCG is instilled to avoid contaminating one’s hands or genitals with the BCG. Men should sit to urinate to reduce the likelihood of self-contamination. Hands and genitals should be thoroughly washed afterwards.
5. Add household bleach to the toilet after every void for the first 6 hours; allow the bleach to stand for 15 minutes before flushing to deactivate the BCG.
6. Increase fluid intake after the first void.
7. If sexually active, wear a condom when you have sexual intercourse throughout the entire treatment course.

Advice Before and After Mitomycin, Gemcitabine, and Valrubicin Intravesical Therapy

1. Restrict fluid intake, consumption of caffeinated beverages, and use of water pills for several hours prior to the procedure.
2. Retain the medication for 2 hours if possible.
3. Rotate body so that medication bathes all surface areas of the bladder (supine, left side, right side, prone).
4. Sit to void after to avoid urine splashing.
5. Increase fluid intake after the first void.
6. Wash perineum or head of penis after voiding to decrease chemical irritation.

Andrew Siegel MD