Introduction

Bladder cancer is the second most common malignancy of the genitourinary system. Each year, this cancer is diagnosed in approximately 275,000 people worldwide, and about 108,000 die from this disease.

Several types of carcinoma arise on the urothelial surface. The most common type diagnosed in North America, South America, Europe, and Asia is transitional cell carcinoma (TCC), which can arise anywhere in the urinary tract but is usually found in the urinary bladder. In other parts of the world, squamous cell carcinoma is prevalent; its etiology and management differ from those of TCC.

TCC arises from stem cells that are adjacent to the basement membrane of the epithelial surface. Depending on the genetic alterations that occur, these cells may follow different pathways in the expression of their phenotype.

The most common molecular biologic pathway for TCCs involves the development of a papillary tumor that projects into the bladder lumen and, if untreated, eventually penetrates the basement membrane, invades the lamina propria, and then continues into the bladder muscle, where it can metastasize. Nearly 90% of transitional cell bladder tumors exhibit this type of behavior. The remaining 10% follow a different molecular pathway and are called carcinoma in situ (CIS). This is a flat type of tumor that spreads along the surface of the bladder and, over time, may progress to an invasive form of cancer that behaves the same as invasive TCC.

CIS can develop alone or in association with papillary tumors. This type of cancer can be difficult to diagnose because patients may present only with irritative voiding symptoms, which is a common problem in a urology office. Patients usually have microscopic or gross hematuria and are often misdiagnosed with a bladder infection and are treated as such. Cystoscopy may reveal a characteristic red, velvety appearance that resembles an area of inflammation, although, at times, CIS is not visible. Diagnostic tests include a urine cytology test and/or one of several available bladder cancer markers. These tests are highly sensitive in detecting CIS. Bladder biopsies are needed to firmly establish a diagnosis.

Several agents, chemotherapies, and immunotherapies are effective in treating CIS. These are all administered intravesically. Endoscopic surgery, which is the initial treatment for papillary cancers, is not effective for CIS because the disease is often so diffuse and difficult to visualize that surgical removal is not feasible.

The most common intravesical agent used to treat CIS is bacillus Calmette-Guérin (BCG). This is a form of immunotherapy. Serial instillations of this tuberculosis vaccine have been shown to effectively eradicate this disease in 70% of patients and to prevent recurrence and progression. Chemotherapeutic agents such as mitomycin-C (Mutamycin), thiotepa, gemcitabine (Gemzar), and doxorubicin (Adriamycin) can also be instilled into the bladder to treat this disease. Interferon-alfa (IFN-alfa) is another immunotherapeutic agent that is used in conjunction with BCG in some patients.

Zbar et al, while working at the US National Cancer Institute, discovered the principle behind BCG therapy. These investigators conducted a series of experiments that studied the immunomodulating effect of BCG vaccine on various carcinomas in animal models. They found that direct exposure of BCG vaccine to small tumors in immunocompetent hosts could eradicate the tumors. BCG vaccine was tried unsuccessfully in various cancers in humans, but bladder tumors confined to the epithelial layer or lamina propria of the bladder met the postulates that Zbar et al described. These include direct exposure of the cancer cells to BCG, relatively small tumors, repeated exposure, and an immunocompetent host. Small tumors treated repeatedly with intravesical instillations of BCG vaccine eliminated existing tumors and prevented the recurrence of new bladder cancers. This therapeutic strategy is regarded as the most effective form of management for both CIS and papillary bladder tumors.

These intravesical treatments are not effective in the 20% of patients in whom cancer invades the bladder wall; thus, cystectomy or a combination of radiation therapy and chemotherapy is necessary. CIS that invades beyond the lamina propria is considered to be in the same category as a papillary cancer.

Problem

CIS is usually heralded by gross or microscopic hematuria, irritative bladder symptoms, and/or positive cytology or urine tumor marker testing results. More than 30 urinary biomarkers have been reported, but only a few are commercially available; the remainder are still being tested.

Endoscopic biopsies are used to help establish the diagnosis and determine the extent of the cancer.

Multiple biopsy specimens are obtained from suggestive areas and from random sites throughout the bladder. If any evidence indicates invasion into the lamina propria, the CIS is considered to be an invasive TCC and is managed accordingly. A patient with a combination of CIS and TCC is considered to be at high risk for local recurrence and metastatic disease.

Frequency

Each year, bladder cancer is diagnosed in 40,000-50,000 patients in the United States, and most of these patients are men, with a male-to-female ratio of 3:1. CIS represents only 10% of cancers in this population, and, of these 4000-5000 patients with CIS, half have coexisting papillary bladder cancer. Therefore, only about 2500 cases of pure CIS are diagnosed each year. However, many more patients seek the care of urologists because of urinary frequency and urgency that may be accompanied by dysuria. Most of these patients do not have CIS, but the symptoms may be identical. As a result, an evaluation to rule out CIS is warranted in such individuals, and evaluation of these patients can account for a substantial percentage of urologic practice.

Etiology

The development of most bladder cancers, including CIS, is thought to be related to environmental factors. Of patients with bladder cancer, 75% have a history of smoking or exposure to industrial or environmental carcinogens. People who smoke cigarettes are 3 times more likely to develop bladder cancer than those who do not smoke. Secondhand smoke has also been implicated as a risk factor. Even after patients stop smoking, the cancer can still appear 15-20 years later. Patients who continue to smoke after being diagnosed with TCC or CIS and treated have a substantially higher risk of recurrence and development of higher-stage disease.

Patients who are exposed to carcinogenic chemicals because of their occupation are at increased risk of bladder cancer. Petrochemical workers, tire manufacturers, beauticians, leather workers, printers, textile workers, and workers in similar industries are at increased risk. Bladder carcinogens include benzidine, nephelines, aromatic amines, nitrosamines, local radiation therapy, various dyes and solvents, and some chemotherapeutic drugs.

Pathophysiology

CIS is thought to arise because of an early mutation or deletion in the cell cycle regulator TP53. Persons with CIS may also have a mutation or deletion in the 9p arm. If the 9p alteration precedes changes in the TP53 gene, papillary TCC is more likely to develop.

Clinical

CIS has various presentations, including gross hematuria, microscopic hematuria, and irritative bladder symptoms. Diagnosis is often delayed because symptoms are attributed to urinary tract infection. In addition, cystoscopy may not reveal any abnormalities, and no abnormalities are present on imaging studies.

More than 50% of patients with CIS have coexisting papillary cancer. In general, the papillary tumor is diagnosed initially and CIS is discovered during the evaluation and treatment of the papillary tumor.

In cases of pure CIS, urine cytology may lead to the diagnosis. CIS exfoliates cells that have an unusual appearance and are easy to identify via cytologic examination, prompting further evaluation. Unfortunately, even findings from urine cytology may be normal in some patients, in whom the diagnosis is made only when the urologist maintains a high level of suspicion for CIS and obtains random bladder biopsy specimens from patients with worrisome symptoms.

Patients who present with microscopic or gross painless hematuria clearly require urologic evaluation. Urinary frequency, urgency, and dysuria, which are the characteristic symptoms of a urinary tract infection, may also indicate CIS. These symptoms are particularly confusing because they may be intermittent and can resolve with an incidental temporal relationship to the administration of antibiotics, further supporting an erroneous diagnosis of urinary tract infection.

Individuals with persistent bladder irritative symptoms or infections that do not resolve within an appropriate period should undergo urologic evaluation. Investigation includes urine cultures for fungi and tuberculosis and cytology studies.

A physical examination is unlikely to reveal any abnormalities associated with CIS. If a large coexistent bladder cancer is present, a mass may be palpable in the suprapubic area or during a rectal examination.

indications

The initial surgical procedure involved with carcinoma in situ (CIS) is transurethral biopsy of the bladder. Multiple biopsy specimens are obtained from various locations in the bladder. This disease may not be visible, and a map of the areas where biopsy samples were obtained is helpful for subsequent follow-up examinations.

CIS often coexists with papillary TCC. A transurethral resection of these tumors is performed, and biopsy samples are obtained from areas that appear suspicious for CIS and from areas that appear normal. The biopsy samples are usually obtained with a cup biopsy forceps, which fits inside the cystoscope.

Patients who do not respond to intravesical immunotherapy or chemotherapy are candidates for radical cystectomy. Radiation therapy with or without chemotherapy is of limited benefit in patients with CIS but can be useful in those with TCC.

Relevant Anatomy

Most cases of carcinoma in situ (CIS) occur in the bladder; however, CIS can develop in any portion of the urothelial surface. CIS in the urethra, renal pelvis, or ureters is more difficult to diagnose and treat. Imaging studies are usually obtained, but ureteroscopy, cytology, brushings, and biopsy of the prostatic urethra, ureters, and renal pelvis may be necessary.

Contraindications

Immunocompromised patients (eg, those with HIV infection, on steroid therapy), patients with porcine heart valves in whom a systemic infection from the BCG vaccine could occur, and patients receiving anticoagulants are not good candidates for intravesical BCG vaccine. BCG vaccine administration should be immediately stopped in patients who develop severe systemic reactions such as chills and fever, gross hematuria, hepatitis, or acute arthritis. BCG is not contraindicated in those who have previously been vaccinated or who have already tested positive for purified protein derivative (PPD).

Workup

Lab Studies

The laboratory evaluation involves urinalysis to detect hematuria or infection, cytology, urinary tumor marker testing, and bladder biopsies.

  • Urinalysis
    • This routine test is used to evaluate for the presence of RBCs, WBCs, and protein and to assess for urinary tract infection.
    • RBCs in the urine require either a repeat study or an evaluation by a urologist to investigate for any serious disease. Gross hematuria always requires a careful assessment with imaging studies of the entire urinary tract (CT urography) and cystoscopy. Patients with bladder cancer may have gross or microscopic hematuria, and this often resolves spontaneously. This lulls the patient and the clinician into erroneously believing that no significant entity is present.
    • Men do not usually have RBCs in their urine, and any number should lead to further urologic testing. In women, RBCs can frequently be found in a voided specimen, but persistent microhematuria warrants further testing, as does a voided urine sample containing 3 or more RBCs per high-power microscopy field.
  • Urine for culture and sensitivity: Prior to performing an endoscopic examination or initiating any therapy, the urine should be free of evidence of infection.
  • Urine cytology
    • An extremely valuable study, urine cytology is often the test used for diagnosis; suggestive urine cytology findings encourage the urologist to perform a bladder biopsy. With a properly collected urine sample that is promptly placed into fixative, the presence of carcinoma in situ (CIS) is detected in 70-75% of patients.
    • At least 100 mL of a freshly voided specimen, not an overnight sample, is usually sufficient. Cells sitting in the urine overnight tend to become distorted and are difficult to analyze. If the urine is very dilute, the number of cells may be insufficient, necessitating a larger urine volume. Bladder washings can be obtained by placing a catheter into the bladder and vigorously irrigating with saline. The advantage of bladder washing is that larger numbers of cells can be obtained.
    • As with any type of cytologic examination, the experience and skill of the cytopathologist is extremely important. Many hospital laboratories lack the skills and technology necessary to accurately perform this type of study. Good reference laboratories are available if local facilities cannot provide this service.
    • Cytoimmunologic techniques have been developed using cytokeratin 20 as a target molecule. This assay may be more sensitive than conventional cytology, although the ability to detect low-grade tumors tends to be poor in all cytologic examinations, whereas the positive predictive value in patients with CIS tends to be around 75%.
  • Urine tumor markers
    • Numerous molecular tumor markers have been identified in the urine of patients with bladder cancer. The 4 available tests approved by the US Food and Drug Administration (FDA) for bladder cancer evaluation include the BTA stat ([bladder tumor antigen] Polymedco; Redmond, Wash), NMP22 (Matritech; Newton, Mass), DD23, and fluorescence in situ hybridization (FISH). These tests have been studied primarily in patients with papillary cancer, but the results from patients with high-grade tumors correlate with those obtained from persons with CIS. The FISH assay seems to be the most accurate and reliable of this group and is being used more frequently in the clinical setting. However, it remains very expensive.
    • Several cytokeratin markers have been studied. Bladder cancer antigen (BCA) testing measures cytokeratins 8 and 18, while CYFRA 21-1 testing detects cytokeratin 19. Cytokeratin 20 seems to have a higher sensitivity and positive predictive value than standard cytology.
    • In 2001, Sánchez-Carbayo et al compared cytology, BCA, CYFRA 21-1, and NMP22. Voided or bladder-wash specimens from 187 patients with CIS or papillary cancers were collected and analyzed. They noted that BCA had a sensitivity of 69.4%, a specificity of 91.3%, and a positive predictive value of 85%. CYFRA 21-1 had a sensitivity of 67.3%, a specificity of 88.4%, and a positive predictive value of 80.5%. NMP22 had a sensitivity of 61.2%, a specificity of 89.9%, and a positive predictive value of 81.1%. Cytology (positive or negative) had a sensitivity of 35.4%, a specificity of 97.2%, and a positive predictive value of 85.2%.
    • Other markers include telomerase, epithelial growth factor, fibrinogen products, and p53. Currently, these have not gained wide acceptance in clinical practice because they do not have the requisite high level of sensitivity and negative predictive value to substitute for currently accepted methodologies.
    • Van Rhijn and coworkers reviewed the literature for urine markers that would be useful for surveillance and reported on their findings. They found 18 markers that had enough data for evaluation. The highest median sensitivities were reported for CYFRA21-1 (85%), cytokeratin 20 (85%), and microsatellite analysis (89%). The highest specificities were reported for cytology (94%), BTA (92%), and microsatellite analysis (89%). They concluded that microsatellite analysis, ImmunoCyt, NMP22, CYFRA21-1, LewisX and FISH were the most promising, but none can replace cystoscopy with or without biopsy.2 Currently, a reasonable approach would be to use standard cytology or office-based NMP22 routinely with yearly ImmunoCyt or FISH testing.
    • Research to identify urine markers that could help in the diagnosis of TCC and could help determine the effectiveness of intravesical therapy is currently underway.
    • No blood tests are specific for this disease, but a general evaluation is necessary prior to initiating therapy with intravesical BCG vaccine.
    • With regard to the CBC count, the presence of anemia or an elevated WBC count warrants further investigation for an explanation.
  • Chemistry panel
    • Liver function should be evaluated. One of the intravesical agents used to treat CIS is BCG vaccine. Systemic absorption of this agent can produce acute hepatitis. Knowing the findings of liver function tests prior to initiating therapy and repeating these tests during the course of therapy help prevent serious adverse events and determine when therapy should be stopped.
    • Patients with abnormal findings from liver function studies must be observed closely if they are to receive intravesical BCG vaccine. One of the adverse effects of this agent is hepatic toxicity.
  • Renal panel
    • Kidney function should be evaluated prior to the initiation of therapy because patients with marginal or abnormal renal function may have an obstruction or some type of renal disease that may worsen with intravesical therapy. Renal function can be evaluated with serum creatinine measurements or technetium scans of the kidneys.
    • Intravesical therapy can produce significant inflammatory changes in the bladder, with edema of the ureteral orifices. Patients with coexisting papillary tumors growing into the muscle layer of the bladder may have ureteral obstruction.

Imaging Studies

CIS is not apparent on any imaging studies; however, when it coexists with papillary TCC, the entire urinary tract must be evaluated.

  • CT urography
    • This is the most commonly used imaging technique, and it is usually performed with and without contrast. Compared with intravenous urography (IVP), CT urography is becoming the preferred imaging modality for studying the urinary tract. Patients undergoing IVP are often poorly prepared, and obtaining an optimal study is more difficult than with CT urography.
    • CT urography combines a CT scan with intravenous contrast to provide anatomic details of the kidneys, regional lymph nodes, and other abdominal organs that may be affected by this disease. Again, the study is usually performed with and without contrast.
  • Intravenous urography
    • Occasionally, IVP is performed. This study involves the intravenous injection of contrast with a series of radiographic images of the abdomen.
    • IVP has been the study of choice for many years, but it is currently being supplanted by CT urography, which provides much better and more complete information.
  • Ultrasonography
    • Ultrasonography is of limited value in assessing the upper urinary tract but can help identify bladder wall thickening and bladder diverticula.
    • The study is useful to detect obstruction and large tumors, but it does not provide the detail necessary to assess the presence or extent of a neoplasm within the renal pelvis or the ureters. Bladder wall thickening, a finding suggestive of TCC, may be detected.
  • Retrograde pyelography
    • This is necessary only infrequently, but, in some patients, it may be the best study to identify tumors in the ureters, renal pelvis, and infundibula and to evaluate the response to therapy. Injecting dilute contrast into the ureters may be the only way to identify small tumors.
    • Retrograde pyelography can provide excellent detail of the renal pelvis and ureters, but it has largely been supplanted by the other studies.
  • Magnetic resonance imaging
    • MRI can help define small tumors in the renal pelvis and ureter.
    • It also provides good anatomic detail and can help determine if tumor has invaded the wall of the bladder or the serosa.
    • MRI urography with gadolinium is being used more often, especially in patients with allergies to intravenous contrast agents.
  • Positron emission tomography scanning: This has been of limited value in the evaluation of patients with TCC, and results have not been reliable. It is usually used to assess for the presence of metastatic disease.

Diagnostic Procedures

CIS is definitively diagnosed using cystoscopy with bladder biopsies. This is generally performed with the patient under general anesthesia, but obtaining good local anesthesia by instilling anesthetic agents into the bladder is possible.

The urologist generally obtains multiple bladder biopsy specimens from various locations in the bladder to help establish the diagnosis and to determine the extent of the tumor. A process known as bladder mapping is used for this purpose. Biopsy specimens, which are submitted in separate containers, are obtained from different areas using a punch biopsy forceps. The pathologist provides a report for each location from where a specimen was taken.

In order to detect invasion into the lamina propria or muscle, the biopsies should be deep, and the pathologist should record the presence or absence of these areas. At the time of this procedure, the bladder can be lavaged with saline and the specimen can be sent for cytology. The specimen should be labeled as a bladder washing or lavage to assist the pathologist in evaluation, as specimens from washings tend to have larger clumps of cells than simple voided urine.

Histologic Findings

The typical visual appearance of CIS is that of a flat carcinoma extending along the surface of the bladder. This is in contrast to a papillary tumor, which extends on a stalk into the lumen of the bladder. CIS, by definition, does not invade through the basement membrane into the lamina propria. When it does, the cancer is considered to behave as an aggressive TCC and is managed accordingly.

When first diagnosed, as many as 20% of patients with CIS may have unrecognized invasion. Thus, they may not respond to intravesical therapy. This emphasizes the need for repetitive cytology/markers and biopsies.

The histologic pattern of CIS is characterized by bizarre, abnormal cells in the epithelial layer. The cells appear to be high-grade cancers; thus, they are readily detected in cytology specimens.

The pathologist may have difficulty distinguishing between cellular atypia and CIS. A consultant should review the slides if the pathologist is uncertain or diagnoses atypia. Upon further review, these cases usually prove to be CIS. The distinction is important because CIS requires therapy and atypia can be managed with observation. Finally, some pathologists attempt to grade CIS; however, CIS is not graded. An associated papillary tumor would be graded as low or high grade.

Staging

By definition, CIS is confined to the epithelial surface of the urinary tract, which makes this a Ta tumor, although no specific stage designation is assigned.

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. 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. 

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.

Outcome and Prognosis

Currently, BCG vaccine therapy is the only agent approved by the FDA as the primary therapy of carcinoma in situ (CIS), supplanting cystectomy as the treatment of choice in the mid 1980s. Approximately 70% of patients have an initial response to BCG vaccine. Rates of tumor progression vary according to the particular study, but more than 75% of patients who initially have a complete response remain disease-free for more than 5 years. This is equivalent to 45-50% of those who initially respond.

Disease-specific survival rates of 63% at 15 years compare favorably with those of patients treated with cystectomy early in the course of their disease.

Results associated with chemotherapy regimens are not as favorable. Mitomycin-C can eradicate the cancer in 50% or more of patients, particularly if patients are properly dosed (40 mg in 20 mL of saline), are dehydrated, and the urine is alkalinized.

Second-line therapy includes gemcitabine in doses of 1500-2000 mg instilled at weekly intervals. Other chemotherapy agents such as valrubicin and doxorubicin have response rates of 20-30%

Future and Controversies

Patients who do not respond to BCG vaccine or who are unable to receive this agent were at one time limited to cystectomy as the only alternative therapy. Bladder-sparing protocols involving chemotherapy and radiation are available for patients with papillary bladder cancer but not for those with carcinoma in situ (CIS). Neither systemic chemotherapy nor radiation therapy has been shown to be beneficial in patients with this disease.

Currently, intravesical mitomycin-C is an alternative agent that is effective in treating CIS. A combination of INF-alfa with BCG vaccine is also effective. Another alternative is the chemotherapeutic agent gemcitabine, which is instilled into the bladder at doses of 1500 mg or 2000 mg. The availability of these medications has improved the ability of the urologist to eradicate this disease and retain the patient’s bladder. An ongoing debate is related to how long patients should be treated and how to determine if the disease is eradicated.

Improvements in urine cytology and the introduction of various molecular tumor markers enable the clinician to identify the presence of CIS. They also help determine when the disease has recurred, even though it is not visible. These markers are helpful in determining when treatment can be stopped and restarted.

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Urology,

Last Update: 27 March 2024