eMedicine Specialties > Urology > Cancer, Bladder, Penis, and Urethra
Carcinoma In Situ of the Urinary Bladder: Treatment
Updated: Oct 9, 2007
Treatment
Medical Therapy
Two categories of medications are used to treat carcinoma in situ (CIS)—chemotherapy drugs and immunotherapy drugs. BCG vaccine is the principal immunotherapeutic agent used for the eradication of CIS. IFN-alfa, an immune modulator, may be used in conjunction with BCG vaccine, but it has not been effective as monotherapy. Bropirimine is an oral immunostimulant thought to have properties similar to IFN-alfa. This agent was found to have limited effectiveness and was never approved for commercial use. Keyhole limpet hemocyanin is another immune adjuvant that never progressed past phase 2 testing.
The original BCG vaccine was developed at the Pasteur Institute from an attenuated strain of Mycobacterium bovis. Subcultures were made and sent to other parts of the world. Two BCG products are commercially available in the United States. The Tice strain, which is a substrain of the original Pasteur product, is manufactured by Organon Pharmaceuticals. The TheraCys strain is made by Aventis/Pasteur. These products, in addition to the Tokyo 172 substrain and the Danish substrain, are available in countries other than the United States.
No one product has been shown to have consistent clinical superiority. BCG viability is an important consideration for the vaccine to be effective. This viability is measured in colony-forming units (CFUs). A vaccine that contains no or very few live organisms would be clinically ineffective. One dose, either an ampule or vial, may vary in weight from one product to another, but the CFU should be similar. Tice BCG has 1-8X10-8 CFUs. TheraCys has 10.5 +/-8.7X10-8 CFUs.
In a study that compared Tokyo172 with the Connaught vaccines, Ikeda et al found that the Tokyo172 vaccine had 48.77 +/-5.43 CFUs per dose, while the Connaught strain had 3.77 +/-1.45 CFUs.3 This implies that a smaller dose of Tokyo172 is likely to be as effective as a much larger dose of the Connaught strain.
Both the Tice and the TheraCys BCG vaccines are available in vials that contain a freeze-dried preparation of both live and dead organisms. The preparation is activated by dissolving the powder in 1 mL of sterile water and diluting the mixture with 30-50 mL of saline. The solution is instilled into the bladder through a catheter. The patient voids the solution after 1-2 hours.
Once in the bladder, the live organisms enter macrophages, where they induce the same type of histologic and immunologic reaction as found in patients with tuberculosis. BCG vaccine also has a predilection for entering bladder cancer cells, where the proteins are broken down and fragments are combined with histocompatibility antigens and displayed on the cell surface. This induces a cytokine and direct cell-to-cell cytotoxicity response, which targets these cells for destruction.
For BCG vaccine to be effective, the host should be immunocompetent, the tumor burden should be small, direct contact with the tumor should occur, and the dose should be adequate to incite a reaction. Studies have consistently shown that BCG treatment can eradicate this cancer in 70% of patients with CIS who meet these criteria. To prevent cancer recurrence, long-term maintenance therapy following the induction phase is necessary.
To induce a BCG reaction, multiple instillations of BCG vaccine are required. Typically, 6 weekly instillations comprise the induction phase, although some patients respond with fewer instillations and some require more. Each patient's response should be assessed each time they come for an instillation. The induction phase is considered complete when the immunologic reaction has occurred. This is evident when the patient has irritative bladder symptoms, WBCs are in the urine without evidence of infection, and microscopic hematuria is present. Once the patient has been induced or vaccinated, this phase of therapy has been completed.
The BCG solution is prepared by initially dissolving the freeze-dried powder with the diluent that comes with the preparation. This solution is diluted further with saline so that the total volume is approximately 30 mL. The BCG solution should be used within 2-3 hours. It is instilled into the bladder via a small catheter by gravity or a slow drip (not forced into the bladder). The solution should be retained for 1.5-2 hours.
Patients do not have to remain in the office during the retention time. Patients should not be given antibiotics at the time of the instillation. These medications can kill the live organisms and negate the effect of the treatment. The individuals who prepare and administer BCG should wear gloves and avoid spilling or touching the vaccine. BCG may cause a strong local reaction in a sore or a cut. If the vaccine is splashed into an eye, it should immediately be washed. This is a preparation that contains live organisms; care should be taken during preparation and administration and disposal of the supplies.
The patient should wash out the toilet with bleach following the next 3 urinations to avoid exposure of the vaccine to other family members. If the patient ordinarily retains more than 60 mL of urine, the bladder may need to be drained after the BCG solution is retained for 2 hours.
When induction is completed, a course of immunoprophylaxis or maintenance therapy is begun. Prolonging the course of therapy has been shown to reduce the frequency of recurrence and progression. These intervals have varied from instillations administered monthly to every 3 months or every 6 months. The optimum frequency and duration of this therapy seems to vary, but a Southwest Oncology study found that 2-3 instillations every 3 months is effective.4 Most agree that a maintenance program of at least one year is necessary. From the immunologic point of view, establishing this interval is difficult because patient variability is great and this is a biologic product whose dose may differ slightly with each instillation. The products also vary. Antigenic stimulation becomes greater with consecutive instillations but decreases dramatically when the stimulation is excessive.
Data from a small study conducted by Palou et al indicated that patients who are tumor-free after 6 months of therapy are likely to remain so indefinitely and do not need additional maintenance.5 Most studies have shown the benefit of using maintenance therapy for at least one year.
Patients often have difficulty completing long-term therapy because of irritative adverse effects in the bladder. The intervals between instillations should be lengthened; in addition, dose modification may also be necessary. Generally, a full ampule is administered, but some patients respond just as well to half or even one third of a dose and seem to have fewer adverse effects. The dose selection depends on the degree of reaction in the patient. Patients treated with the Tokyo172 substrain need only a 25% dose because of the potency of this product. The intent of the treatment is to elicit an immune response without overwhelming the immune system.
A failure to respond to BCG vaccine may be defined as persistent or recurrent tumor when a BCG vaccine reaction is evident. If this occurs within the course of a year, an alternative strategy is to combine BCG with IFN-alfa. In this situation, 50 million units of IFN-alfa can be instilled into the bladder, with the BCG vaccine administered 1 hour later. The IFN-alfa up-regulates the major histocompatibility complex/BCG vaccine antigen complex, which enhances the immunologic response. With this combination, doses of BCG vaccine as small as one tenth of a vial have been shown to be effective. IFN-alfa is well-tolerated, and the lower doses of BCG vaccine are usually associated with decreased adverse effects.
Chemotherapeutic agents that can be administered intravesically to treat CIS include mitomycin-C, gemcitabine, thiotepa, doxorubicin, cisplatin, and valrubicin. In randomized studies comparing these agents to BCG vaccine, results have been mixed. Several studies from Europe have reported similar responses comparing mitomycin-C to BCG vaccine, while an American study found BCG vaccine to be superior.
Mitomycin-C is the most commonly used chemotherapeutic agent. It is used in both the perioperative and treatment periods. Immediately following a transurethral resection of a papillary tumor, mitomycin-C, 40 mg in 20 mL of saline, is instilled into the bladder and held there for an hour. In the treatment phase, the same dosing is used, but the patient's urine should be alkalinized for maximum effect. The treatments are administered weekly for at least 6 weeks before a maintenance program is started, consisting of monthly instillations for one year.
This agent is usually well-tolerated, but excess use can cause symptoms of cystitis; if this occurs, the instillation frequency should be reduced. A bladder retention time of 2 hours is usually advised, although this issue has never been thoroughly studied. Following this protocol, a recurrence-free incidence rate of 41% has been reported. These data demonstrate that, although intravesical chemotherapy does not match the results obtained with BCG vaccine, this is an effective agent, and its benefits can be maximized by following these recommendations.
Gemcitabine is the most recent addition to the list of effective agents. This chemotherapy drug is administered according to the same protocol as BCG (ie, 6 weekly treatments followed by maintenance for 1 y). This agent has caused very few side effects. Gemcitabine is a prodrug that requires activation by intracellular phosphorylation. It has shown selective killing in human TCC cell lines and does not affect normal fibroblast cell lines. Serial administration of doses ranging from 1500-2000 mg in 50 mL of saline have shown complete responses in 50% of patients with CIS.
Doxorubicin (Adriamycin) is chemotherapy agent that can be effective, although comparison studies indicate that it is not as effective as mitomycin-C or BCG. It is administered in a dose of 50 mg in 50 mL of saline.
Valrubicin is used in patients in whom BCG vaccine therapy has failed, and valrubicin induces a response in 20% of these patients. Thiotepa and cisplatin have limited benefit and are rarely used to treat CIS.
The intravesical instillation of either BCG vaccine or chemotherapy is initiated approximately 2-4 weeks following endoscopic resection of any visible papillary tumors or bladder biopsies. The bladder is usually healed enough to avoid systemic distribution of the organism.
Contraindications to BCG vaccine therapy include immunosuppression, cancer invading into the bladder muscle, large tumor volume, and concomitant anticoagulation therapy. Reports have described BCG vaccine organisms identified on vascular grafts in patients who have died following BCG vaccine sepsis.
Photodynamic therapy has been shown to be effective, but it has limited usefulness because of adverse effects. This treatment involves the intravenous injection of a porphyrin derivative followed 24 hours later with exposure of the bladder surface to laser light, activating the cytotoxic agent, which has preferentially concentrated within the cancer cells. The laser is introduced through a cystoscope. The major adverse effect is severe photosensitivity, which can last for several months.
Colombo et al have reported beneficial results using a combination of intravesical mitomycin-C and local microwave-induced hyperthermia. They compared a group of these patients with patients receiving only mitomycin-C and found a significant improvement in survival in the patients receiving combined therapy.6
Surgical Therapy
The only surgical treatment for CIS is radical cystectomy. For a more in-depth description of this procedure, see Cystectomy, Radical. The 10-year survival rate after cystectomy in patients in whom BCG vaccine therapy failed approaches 90% if the tumor is confined to the bladder surface.
Eliminating some visible lesions with fulguration or laser therapy is possible, but many of the CIS lesions are not visible.
Bladder biopsies may be performed as a part of the patient's follow-up. These are necessary to determine if the cancer has been eradicated.
Preoperative Details
Minimal preoperative care is necessary for cystoscopy and bladder biopsies. Any papillary tumors are resected at the same time. These are usually outpatient procedures and, on occasion, can be performed in the urologist's office.
In contrast, preoperative assessment prior to cystectomy can be extensive. See Cystectomy, Radical for details.
Intraoperative Details
Careful bladder mapping of biopsy sites is helpful in determining the extent of the cancer and allowing better follow-up examinations. Adequate tissue should be obtained to allow the pathologist to determine the depth of penetration of the tumor. Usually, a cold-cup biopsy forceps is used to avoid cautery artifact to the specimen. In general, biopsy specimens are taken from the left lateral wall, right lateral wall, base, dome, and trigone of the bladder, as well as from the prostatic urethra. Obtain biopsy specimens from any areas of suspicious erythema that are not included in these biopsies and label them as an additional site. Following tissue acquisition, the biopsy sites can be cauterized for hemostasis. Avoid damaging the ureteral orifice or intramural tunnel of the ureter. If potential damage to the ureteral orifice is unavoidable because of the location of suspicious lesions, a ureteral stent may be placed.
Retrograde pyelography is generally discouraged during bladder biopsies to avoid reflux of malignant cells, but the study may be performed if the patient has contrast allergies or other issues that prevent other imaging modalities for evaluation of the upper urinary tract. Ureteral washes for cytologic analysis may also be performed. These should be obtained with saline (not water) and should be collected prior to the instillation of any contrast material, which has been shown to negatively affect cytology results.
See Cystectomy, Radical for intraoperative details of this procedure.
Postoperative Details
Occasionally, a catheter may need to be left in place for 1-3 days after bladder biopsies. It is usually removed in the urology office.
Within the first 24 hours, a single intravesical instillation of mitomycin-C (40 mg in 20 mL of saline) has been shown to reduce the frequency of tumor recurrence and should be considered the standard of care after transurethral resection of the bladder tumor (TURBT) or positive bladder biopsy findings.
Follow-up
Following successful treatment of initial or recurrent CIS with intravesical BCG vaccine, chemotherapy, or both, patients are monitored at regular intervals with cystoscopy and urine cytology, usually every 3 months for the first 1-2 years and every 6 months thereafter. IVP is also usually performed every 6-12 months. This follow-up continues for a minimum of 5 years.
Following cystectomy and urinary diversion, cytology is performed every 3 months for the first 1-2 years and every 6 months thereafter. In patients with a urostomy or continent diversion, a catheterized specimen is obtained from the stoma, not the urostomy bag, because contact with the bag and the stagnant nature of urine in the bag confounds the cytologic findings. If the patient did not undergo a urethrectomy, a urethral wash for cytology should also be performed on this schedule. Patients with an intestinal neobladder should provide a voided specimen. IVP or loopography should be performed every 6-12 months to evaluate the upper urinary tract, as should CT scanning, chest radiography, and serum chemistry studies to rule out metastatic disease. After 2-3 years, a vitamin B-12 level should be checked because many of these patients develop deficiency of this vitamin.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Bladder Cancer and Blood in the Urine.
Complications
Usually, the first 1-3 instillations of BCG vaccine cause very few adverse effects, unless the patient has been previously vaccinated with BCG vaccine or has a history of tuberculosis. After the third instillation, patients usually begin experiencing irritative bladder symptoms and/or flulike symptoms that last 24-72 hours. These symptoms are usually mild and can be controlled with bladder sedatives and antihistamines, and they are often perceived as favorable immunological responses to the therapy. Nearly 80% of patients can expect to experience this type of reaction.
Patients who develop a fever of higher than 39°C (102.2°F) and those who have gross hematuria, severe irritative symptoms lasting more than 72 hours, a urinary tract infection, elevated liver enzyme levels, arthritis, epididymoorchitis, or acute prostatitis should not receive additional BCG vaccine therapy until these findings have resolved. If BCG vaccine must be resumed, a half or a quarter dose can be administered. These are symptoms of a systemic BCG vaccine reaction, and further administration is unnecessary, immunosuppressive, and potentially lethal.
Severe reactions to BCG vaccine, including high-grade fevers (ie, temperature >40°C [104°F]), hepatotoxicity, respiratory distress, chills, hemodynamic instability, and mental status changes, suggest life-threatening septicemia. These are emergencies, and patients should be hospitalized. A urine culture should be obtained because many cases of septicemia following BCG vaccine instillation are caused by more common uropathogens rather than the organisms in the BCG vaccine. Tuberculosis organisms from the urine or tissues are usually difficult to culture. Treatment should be initiated without waiting for culture results. Broad-spectrum antibiotics should be administered intravenously, and the patient should be started on antituberculosis therapy, including rifampin, isoniazid, and cycloserine, which is the only antituberculosis drug to reach bacteriocidal levels within 24 hours of administration. Corticosteroids are also recommended in some patients.
When BCG vaccine therapy was introduced, several deaths were reported, all of which could be attributed to improper use of this agent. Today, a death is extraordinary because clinicians have learned how to administer this agent and to stop therapy before a patient becomes ill.
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 Treatment: Carcinoma In Situ of the Urinary Bladder |
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Further Reading
Keywords
carcinoma in situ of the urinary bladder, CIS of the urinary bladder, bladder cancer, flat carcinoma of the urothelium, transitional cell carcinoma, TCC, papillary tumors, cystectomy, bacillus Calmette-Guérin, BCG, gross hematuria, microscopic hematuria, irritative bladder symptoms, bacillus Calmette-Guérin vaccine, BCG vaccine, bladder CIS, CIS of the bladder, urinary CIS, urothelial CIS, transurethral biopsy of the bladder
