BLADDER CANCER - INTRAVESICAL CHEMOTHERAPY

Introduction
Cancer of the bladder is the fourth most common cancer among men and the eighth most common cancer among women. About 40,00 men and 15,000 women will develop bladder cancer this year in the United States. There will be 250,000 new cases of bladder cancer worldwide. Bladder cancer is the fourth leading cause of cancer and the seventh leading cause of cancer death. Cancer of the bladder may occur at any age, but it usually strikes those over 50 years old.

If detected and treated early, bladder cancer is almost always cured (the 5-year survival rate of early bladder cancer is 90%). Unfortunately, less than one in ten patients with metastatic bladder cancer survive five or more years (metastatic means the cancer has spread to other areas such as lymph nodes, bones, lung, etc). Each year about 8,500 men and 4,000 women will die of the disease. During the past 30 years, the death rate for bladder cancer has declined slightly for men, more so for women. This success is attributed to earlier detection and better treatment options.

Bladder cancers are classified into two main categories, superficial (basically involving only the bladder lining) and invasive (spreading into layers of bladder wall underneath the lining or the muscular layer of the bladder or beyond). The deeper a cancer grows into the bladder wall, the more difficult it is to treat effectively. About 70 percent of newly diagnosed cases are classified as superficial tumors. The remaining 30 percent of bladder cancers have penetrated further into the bladder wall and may involve other organs. Bladder cancer is sometimes referred to as TCC or transitional cell cancer, a name that derives from the normal 'transitional cell' lining of the bladder

Patients with early bladder cancer are usually treated by removing the cancer or cancers with a telescopic electric knife. This procedure is called transurethral resection of bladder tumor or TURBT.

Even if the cancer is removed completely with this technique, a significant chance of recurrence of the cancer exists. This occurrence usually happens within two years, but may occur 5 or even 10 years later. Many times the recurrence of the cancer may be more aggressive and more invasive. About 70% of patients with an initial bladder cancer will have a recurrence.

Who is at risk for recurrence of bladder cancer?
Patients at most risk are those who have:
    multiple tumors simultaneously in different parts of the bladder
    tumors which microscopically demonstrate aggressive behavior
         or chromosome abnormalities
    a history of previous bladder tumors
    exposure to cancer causing substances (particularly smoking)
    a condition called carcinoma in situ (CIS).

What is CIS?
Carcinoma in situ or CIS is a form of superficial bladder cancer in which the malignant, or cancerous, cells are limited to the bladder lining. CIS is present in 20 to 30 percent of bladder cancer cases and may be diffuse - occurring in several areas along the bladder lining. Telescopically, the bladder may appear normal or perhaps slightly reddened. However, biopsies of these areas show malignant cells. Malignant cells may even be seen in urine specimens that are viewed with special stains (cytology). The significance of CIS is that recurrence of cancer almost always occurs within 24 months and often returns as a more aggressive and invasive cancer that is not easily treated. In such cases, surgery may be required, and occasionally the entire bladder must be removed.

How do we treat patients at high risk for recurrence?
The reason for 'Intravesical Chemotherapy'
Patients who are at high risk for reccurence are often recommended to have special medications instilled into the bladder, a treatment called 'intravesical chemotherapy' (intravesical means 'in the bladder' and chemotherapy simply means 'treatment with chemicals').

Who should not receive Intravesical Chemotherapy?
Patients whose cancers have invaded into the muscle of bladder are not likely to be helped by intravesical chemotherapy. The treatments are only for those patients whose cancers are limited to the lining layer of the bladder.

Patients with active urinary tract infections should not receive intravesical chemotherapy until the infections has been treated and the symptoms of the infection resolved.

Patients whose bladder capacity is too small to hold the medications for at least an hour are not good candidates.

Cautionary situations include: heart valve patients, or blood thinning medications.

What types of medications are used for intravesical chemotherapy?
There are many different types of medication used for intravesical chemotherapy and some of the treatment regimens date back 50 years. Some of the current medications are identical to those used for other types of cancer, but when given 'intravesically', the side effects are usually mild and relate only to the bladder. Some of the currently used drugs include Thiotepa, Mitomycin-C, Adriamycin, interferon and Valstar.

More recently, medications have been used which are unlike other types of chemotherapy. These newer drugs act by stimulating the body's immune system. These drugs do not directly kill cancer cells but act to stimulate the body's own defense mechanism by creating inflammation in the bladder wall. The inflammation causes white blood cells to attack the diseased bladder lining and this may reduce the risk that cancer will return to the areas treated.

The most common side effect of 'intravesical chemotherapy' is bladder irritation, which results from inflammation of the entire bladder lining at the same time, healthy and unhealthy. The most successful of these drugs is BCG.

Other drugs, still experimental, include interferon and interleukin.

Intravesical Treatments - General overview of method of treatment
A catheter or small rubber tube is passed through the urethra into the bladder and all of the urine in the bladder is allowed to drain out. The treatment medication is then instilled into the bladder slowly and the catheter is removed. The medication is usually retained in the bladder for a period of time, usually about two hours.

What are the side effects of Intravesical Chemotherapy?
Each medicine is unique, but all share the possibility of similar complications.

These include:
Continuous pain or burning on urination (chemical cystitis)
Tendency to have bladder infections (bacterial cystitis)
Bright red blood or blood clots in the urine.
Fever or chills or malaise (generalized feeling of discomfort or illness).
Flu-like symptoms, joint pain, prolonged coughing, skin rash. (particularly BCG)
Allergic reactions.
Low white blood counts or anemia (particularly Thiotepa, but with all anti-cancer chemotherapy drugs)

Patients should expect some urgency, increased frequency of urination, and possible burning with urination. The symptoms usually become worse with consecutive treatments but may be tolerable throughout. To some the symptoms are intolerable and we will try to treat the side effects. Treatments may have to be stopped, temporarily or permanently, if complications or severe side effects persist.

How often is the chemotherapy given?
Each drug has many different treatment plans. In the beginning, most are given once a week for four to eight weeks. Some drugs like BCG are also given intermittently over one to two years to promote the 'inflammatory' response and most studies suggest that this maintenance regiment to reduce cancer recurrence. Only BCG has been clearly shown to be effective in maintenance usage

How will I know if the therapy is successful?
Telescopic examinations of the bladder (cystoscopy) will be performed in the office at regular intervals, usually every three months for the first one to two years. If no cancers are found, the examinations will become less frequent, but usually no less than once a year. Follow-up cystoscopy will be required at intervals for at least ten years after the occurence of a bladder tumor. Washings of the bladder (cytology) may be sent to the laboratory to see if cancer cells can be found microscopically. Patients with positive or suspicious cytology reports are followed more closely with repeat cystoscopy.

The different types of 'intravesical chemotherapy

BCG?
BCG is a strain of Bacillus Calmette Guerin vaccine, a live but weakened bacterial preparation (Mycobacterium bovis is its official name). This medication was originally developed as a vaccine for tuberculosis at the beginning of the 20th century. Subsequently, BCG was found to be successful in treating certain bladder cancers when the BCG was instilled into the bladder. As mentioned above, BCG acts by stimulating an inflammation in the bladder.

Because BCG is a live bacteria, some patients are not good candidates to use the drug. Concerns about BCG infections of the bladder wall or spreading into the body in patients who have difficulty handling infections (HIV, AIDS, Steroid use) make the use of BCG too risky. Patients with active tuberculosis should not receive BCG. Severe side effects of BCG treatments are uncommon but include life threatening infections throughout the body with BCG bacteria. These are treated as if the patients had severe tuberculosis.

Many physicians have different protocols for BCG. Some give more, some give less. A commonly used course of BCG treatment is once a week for six (6) weeks followed by a six week rest period. At 12 weeks, a telescopic examination of the bladder (or cystoscopy) will be done to see if the cancer has returned. If not, an additional three weeks of treatments will be started. Patients will be seen every three months for a cystoscopy and every six months, an additional three weeks of treatments will be given. The treatments will continue for two years.

Reviewing studies on BCG installation compared to no prevention treatment, we find a 40-50% reduction in recurrence of bladder cancers in patients treated. Almost every study comparing BCG to other drugs shows clear superiority of BCG.

In patients with CIS (carcinoma in situ), a dangerous pre-cancerous situation, BCG is the only agent which has shown to be effective. Up to 70 patients with CIS will have a complete response after an appropriate course of BCG.

Because BCG works by stimulating the immune system, a recurrence of cancer at the first follow up may mean that the immune system had not yet been stimulated enough. Also, BCG may not be as effective in treating a small cancer that could not be seen at the first telescopic examination. Recurrences of bladder cancer early in a BCG treatment should be treated with removal of the tumor and continuation of the BCG. Patients who have responded to BCG but have recurrence of cancer years later may respond to another course after the tumor is removed. One investigator suggested that patients respond better if the begin megavitamins with vitamin A, B6, C and E while using BCG. This has not been confirmed by other studies. (note: These investigators are marketing their vitamins!)

Mild to moderate side effects from BCG are expected with up to 90% of patients having some symptoms of cystitis. Burning with urination, frequency and urgency of urination, low-grade fevers, lack of energy, and/or blood in the urine will often be seen after the second to fourth installation. These side effects are anticipated and are due to the stimulation of the immune system. Treatment of symptoms with bladder sedating medications and anti-inflammatories are usually successful in making symptoms tolerable.

More significant side effects are seen in one in twenty patients and are listed below:

• 
  Uncommon allergic reaction ranging from skin rashes of several types; wheezing with shortness of breath; drop in blood pressure and possible loss of consciousness, shock
  Significant bleeding in the urine
  Widespread BCG infection with fever, night sweats, cough and liver involvement
  Possible infections throughout the body which may involve the liver (hepatitis), lungs (pneumonitis), prostate (prostatitis), testes and epididymis(epididymo-orchitis), and kidneys (pyelonephritis).
  BCG infection of the prostate
  Inability to urinate
  Severe scarring of the bladder with subsequent small capacity
  Severe scarring of the ureter with obstruction to flow of urine into the bladder
  

All of these complications of are treated with drugs that are used for tuberculosis. These include isoniazid, rifampicin, cycloserine, and prednisone.

Thiotepa
Thiotepa has been used for more than four decades to prevent bladder cancer recurrences. Thiotepa can also treat residual cancers that could not be removed with about one in three responding completely (one in three don't respond at all). It has been shown in most studies to delay the return of lower grade or unaggressive cancers. Its use in carcinoma in situ (CIS) is less impressive.

Thiotepa is an active chemotherapy agent and is absorbed into the body. The major concern is its effects on the bone marrow with a lowering of the white blood cell and platelet counts. Patients must have their blood counts checked if Thiotepa is used. The effect on the bone marrow is more severe if the patient has a very large tumor, has just had surgery on the bladder or in the presence of a urinary tract infection. About one in four patients will have symptoms similar to a bladder infection caused by irritation of the bladder lining. This is also called 'chemical cystitis'. The symptoms are usually mild and often respond to medications.

The standard Thiotepa protocol is 4 - 6 weekly installations with 15 - 30 milligrams of drug. Some physicians use it on a monthly basis for up to one year. Thiotepa seems to work better if used just after the tumor is removed. However more drug is absorbed if used within the first few days after surgery which could lead to complications from effects on white blood cells and other blood products.


Mitomycin C
Mitomycin C is technically in the antibiotic class of drugs, but is not used as an antibiotic. Mitomycin C has a wide range of chemotherapy applications. Complete response of low grade bladder tumors are seen in almost one-half of patients. It is used widely as a preventative for bladder cancer recurrence and also for CIS. It can be used in patients who do not respond to BCG. Current protocols for Mitomycin C vary widely and doses of 20-60 mgs used weekly for 6-8 weeks. Each installation is held for two hours.

Some patients will have chemical cystitis by the end of the treatment protocol, but Mitomycin C is probably the most easily tolerated of the drugs used to prevent bladder tumors. Some patients will develop marked shrinkage of bladder capacity. Some patients will develop a unique rash of the face and palms.

Adriamycin
Adriamycin (or doxorubicin) is also technically in the antibiotic class of drugs. It also has a wide range of chemotherapy applications. It can be used as a preventative for bladder cancer recurrence. About one in six patients will be tumor free at five years. Between 30 to 90 mg are used weekly for 4 to 6 weeks. Each installation is held for two hours.

One half of patients will have chemical cystitis by the end of the treatment protocol. A rare patient will develop marked shrinkage of bladder capacity.

Interferon
Interferons are anti-viral agents that have been used in research against bladder cancer. Success has been reasonably good with only mild chemical cystitis symptoms and a flu-like syndrome in about one-fourth of patients. Usually Interferon (alpha interferon 2b or Intron) is given as 100 million units, once a week for twelve weeks followed by a monthly installation for the next 9 months (one year of treatments in total). In patients who cannot tolerate full doses of BCG, a mixture of week BCG (one-tenth strength) with 50 million units of Interferon may be more tolerable.

Valstar
Valstar is a new drug used only in patients with CIS who do not respond to BCG. Only 1 in 5 patients will respond to Valstar and if the CIS is still present three months after treatment, removal of the bladder is recommended. The usual dose is 800 mgs weekly for six weeks. Chemical cystitis is to be expected but bone marrow effects are not seen. Many patients have blood in their urine after the installation which is to be kept in the bladder for two hours if possible.

Other drugs...
Epodyl: A drug similar to Thiotepa. 35% of patients will have a complete response to tumor if it is still present. Recurrences are reduced by 35% as well. Over half of the patients will develop a chemical cystitis, 20% will have reduced bladder capacity and a small percentage will have bone marrow effects noted.

Epirubicin: A drug similar to doxorubicin with similar side effects and effectiveness. One dose of Epirubicin reduced recurrences in more than 10% compared to surgery alone.

Mitoxantrone: A prostate cancer drug that is being studied for use in the bladder. Some investigational studies showed a reduced recurrence rate with acceptable levels of bladder irritation in about 1 of 4 patients.

Newer Immune drugs being researched
KLH
KLH or Keyhole limpet hemocyanin, is a non specific immune stimulator that was shown in one study to be more effective than Mitomycin C in preventing recurrent bladder cancer. It has also shown some effectiveness in CIS and is still being studied.

Bropirimine
Another new immune stimulating drug that is given into the bladder and can be take by mouth. The best responders were in those patients who had not received other treatments.

Photodynamic Therapy
Photodynamic therapy or PDT uses intravenous medicine that are activated by certain types of laser light. A drug, Photofrin, is given intravenously and this is followed by the placement of a special laser light into the bladder. PDT has been shown to be effective against CIS as well as preventing recurrence of bladder cancer. PDT did not work on tumors bigger than 1 inch in diameter. A fairly severe chemical cystitis occurs with PDT therapy. Up to 10% of patients develop severe bladder scarring. A major drawback is that patients must stay out of sunlight for up to six weeks!

How do we select the drugs or treatment to use?
All drugs mentioned in this pamphlet have activity in reducing recurrences and many will make current tumors, if not removable, shrink or go away. Some of the drugs have activity against CIS or carcinoma in situ. BCG has clearly the best results in long term studies when used for prevention of tumor recurrence and for the treatment of CIS. Chronic use of BCG significantly reduces recurrences. The other drugs which are chemotherapy agents are more difficult to distinguish between each other in terms of effectiveness. Final drug selection may have more to do with physician preference and prior experiences. The role of megavitamins is still to be determined.