The American Urological Association (AUA) has issued guidelines for the management of nonmuscle invasive bladder cancer (Stages Ta, T1 and TIS). Developed by the AUA Bladder Cancer Clinical Guidelines Panel, the recommendations are based on outcomes data from randomized controlled trials and on expert opinion. The summary of the AUA report is published in the November 1999 issue of the Journal of Urology. The complete report can be obtained from the Guideline Division, American Urological Association, 1120 N. Charles St., Baltimore, MD 21201; telephone requests: 410-223-4367; fax requests: 410-223-4375.

The AUA Bladder Cancer Clinical Guidelines Panel analyzed 181 articles, published from 1966 to 1998, to collect data on the benefits and adverse effects of treatment and to derive estimates of the probability of tumor recurrence, tumor progression and complications of treatment. The results of transurethral resection of the bladder tumor alone were compared with those of resection plus adjuvant intravesical therapy with thiopeta, bacillus Calmette-Guérin (BCG), mitomycin C or doxorubicin.

According to the guidelines panel, the most important finding of the meta-analysis is that the use of intravesical agents after surgery lowers the probability of tumor recurrence but not the probability of tumor progression. This finding underscores the need for careful follow-up for the development of muscle invasive cancer.

With respect to the adverse effects of treatment, data revealed that the most common adverse outcomes of treatment are bladder symptoms. The most frequent immediate symptoms are dysuria, frequency and nocturia, urgency, pain and cramping, and passing of debris in the urine. Long-term adverse outcomes include bladder contracture.

Categories for the Recommendations

The AUA bladder cancer guidelines panel graded the treatment recommendations according to levels of flexibility as determined by the strength of evidence and the expected amount of variation in patient preferences. The recommendations are classified in three categories: a “standard,” a “guideline” and an “option.” A standard has the least flexibility, a guideline has significantly more flexibility, and an option is the most flexible of the recommendations. In the AUA guidelines, a policy is considered a standard if the outcomes of the alternative interventions are sufficiently well known to permit decisions and if there is unanimity about the preferred intervention. A policy is considered a guideline if the outcomes of the interventions are sufficiently well known to permit decisions and if there is appreciable but not unanimous agreement about the preferred intervention. A policy is considered an option if the outcomes of the interventions are not sufficiently well known to permit decisions, if preferences among the outcomes are not known and if patients' preferences are divided among the alternative interventions or patients are indifferent about alternative interventions.

Recognizing the differences in decisions that would be made according to the clinical setting, the guidelines panel developed recommendations for three clinical settings: (1) patients with an abnormal growth on the urothelium that has not yet been diagnosed as bladder cancer; (2) patients with bladder cancer of any grade, of stage Ta or T1, with or without carcinoma in situ, who have not received intravesical therapy; and (3) patients with carcinoma in situ or high-grade T1 cancer who have received at least one course of intravesical therapy.

Recommendations for All Patients

A discussion of the benefits and side effects of intravesical therapy is defined as a standard policy for all patients. The panel found that there is little information to define the optimal dose of adjuvant therapy, the number and timing of instillations and the influence of long-term maintenance therapy. Randomized studies that support the use of maintenance BCG therapy have been performed but they were excluded from analysis because the results are reported only in abstract form. Other trials also appear to support the role of maintenance therapy.

Undiagnosed Bladder Tumor

The recommendations state that the standard policy in patients presenting with a bladder tumor is the need to obtain a histologic diagnosis of the tumor. The report notes that intravesical therapy should not be used in the absence of a histologic diagnosis.

Stage Ta or T1 Cancer and No Prior Intravesical Therapy

Surgical Eradication. Complete surgical eradication of all visible tumors, if this is feasible, is the standard policy in patients with stage Ta or T1 bladder cancer of any grade not previously treated with intravesical therapy.

The method used to surgically eradicate the tumor is classified as an optional policy, with electrocautery resection, fulguration or laser ablation cited as optional methods. This recommendation is based on the panel's expert opinion.

Adjuvant Intravesical Therapy. An option in patients with low-grade Ta bladder cancer is the use of adjuvant intravesical chemotherapy or immunotherapy after endoscopic removal of the lesion. The panel states that a recommendation for adjuvant therapy stronger than an option for patients with bladder cancer of any grade, stage Ta or T1, with or without carcinoma in situ, cannot be supported on the basis of outcomes data. The panel found that outcomes data for patients with low-grade Ta cancer are difficult to obtain because most studies have combined patients with low-grade stage Ta tumors and patients with stage T1 bladder cancer and higher grade cancers.

The panel's expert opinion is that many patients with low-grade Ta tumors do not require adjuvant intravesical therapy. According to the recommendations, the risk of disease progression is low (less than 10 percent) in this group, and there is little evidence that adjuvant therapy affects disease progression.

In patients with carcinoma in situ or T1 or high-grade Ta tumors, the panel recommends as a guideline the use of intravesical instillation of BCG or mitomycin C. On the basis of the medical literature and the panel's opinion, BCG and mitomycin C are superior to doxorubicin or thiotepa for reducing recurrence of these tumors.

Cystectomy. Categorized as an optional policy, based on the panel's expert opinion, is the use of cystectomy as initial therapy in some patients with carcinoma in situ or T1 tumors. The recommendations explain that cystectomy is deemed to be an option because of the risk of progression to muscle invasive disease even after intravesical therapy. An increased risk of disease progression is associated with large tumor, high-grade tumor, location of the tumor at a site that is poorly accessible to complete resection, diffuse disease, infiltration of lymphatic or vascular spaces and prostatic urethral involvement.

Carcinoma in Situ or High-Grade T1 Cancer and Prior Intravesical Therapy

Cystectomy. Cystectomy is classified as an optional policy in patients with carcinoma in situ or high-grade T1 bladder cancer that has persisted or recurred after initial intravesical treatment. This recommendation is based on the panel's expert opinion rather than evidence from outcomes data. The recommendations note that data show a substantial risk of progression to muscle invasive cancer in patients with diffuse carcinoma in situ and high-grade T1 tumors. It is not known whether intravesical therapy alters this risk. As a result, the recommendations state, some patients with symptomatic disease or high-grade tumors may prefer to undergo cystectomy.

Intravesical Therapy. The recommendations state that additional intravesical therapy may be considered an option for patients with carcinoma in situ or high-grade T1 cancers that have persisted or recurred after initial intravesical therapy. This recommendation is based on the panel's expert opinion. While optimal dosing regimens have not been established, the recommendations state that six weekly instillations are used most often.

Recommendations for Future Research

The AUA guidelines panel notes that substratification of stage T1 bladder cancer based on depth of infiltration needs further clarification. Also, the risk and significance of urothelial carcinoma outside the bladder must be further determined. The report notes that the risk of urothelial cancer in the ureter or intrarenal collecting system in patients with carcinoma in situ may exceed the generally accepted rate of 5 percent. Another area that needs further elucidation is the role of treatment regimens using alternating or combined medications. In addition, the report states that randomized studies are needed to investigate the effects of early instillation of medications, sometimes immediately after transurethral resection of the bladder tumor.