BALTIMORE, MD -- October 21, 1999 -- Physicians should consider using intravesical chemotherapy or immunotherapy as adjuvant therapy following surgery for non-muscle-invasive bladder cancer, according to new treatment guidelines released today by the American Urological Association (AUA). Currently, there is wide variation in the use of adjuvant therapy after transurethral resection of the bladder.
"For patients who have not had prior intravesical therapy, adjuvant intravesical chemotherapy or immunotherapy is an option for treatment after endoscopic removal of low-grade bladder cancers," the AUA guidelines report states. "All the intravesical agents studied, when used after transurethral resection, result in lower probability of recurrence than surgery alone."
Although the data examined by the AUA panel shows that the intravesical agents decrease bladder cancer recurrence rates, there is no evidence that they affect long-term progression and they may not be appropriate in all cases. "The fact that the peer reviewed published data show that the use of intravesical agents used after surgery lowers the probability of recurrence but not progression is the most important finding that we made," says panel Chair Dr. Joseph A. Smith, Jr., of the Vanderbilt University Medical Center.
"It certainly is something that needs to be examined through further research.
"It also underscores the fact that careful followup is required because bladder cancer patients are at risk for progression to muscle invasive cancer which may require bladder removal."
According to Dr. Smith, the guidelines are especially important because "they establish an objective basis for physicians to use in determining treatment options to decrease bladder cancer recurrence."
Chemotherapy and immunotherapy agents reviewed by the panel include thiotepa, BCG, mitomycin C, and doxorubicin.
Two of the agents-BCG or mitomycin C-are recommended for treatment after endoscopic removal of high-grade tumors that have begun to penetrate the superficial bladder wall but not the muscle because they are superior for reducing recurrence of tumors, according to the guidelines.
The guidelines report was produced by the AUA Bladder Cancer Clinical Guidelines Panel, a group of bladder cancer experts that analyzed published outcomes data to assess potential benefits and possible adverse effects of treatment interventions and developed practice policy recommendations. The guidelines were released in the form of a summary article in the November Journal of Urology, the monthly peer-reviewed journal of the American Urological Association.
According to the American Urological Association, more than 50,000 new bladder cancer cases are diagnosed each year in the United States and the incidence rate is slowly rising. Primarily a disease of middle and old age (more than 70 percent of new cases are diagnosed in persons 65 and older), the incidence is expected to increase as the U.S. population ages.
Smoking was cited by the panel as a significant cause of bladder cancer.
"One half of all bladder cancer cases in the United States are associated with cigarette smoking," says Salt Lake City urologist Dr. Richard Labasky, a member of the AUA guidelines panel.
"While not directly related to the treatment guidelines recommendations for physicians, that fact should be a key message for the general public about preventing bladder cancer."
The three types of outcomes the panel determined to be most important in their analysis are: 1) probability for tumor recurrence; 2) risk for tumor progression; and 3) complications of treatment.
Once relevant peer-reviewed published articles were reviewed and data from these articles analyzed, recommendations were made for three types of patients:
- A patient who presents with an abnormal growth on the urothelium but has not yet been diagnosed with bladder cancer.
- A patient with established bladder cancer of any grade, stages Ta or T1, with or without carcinoma in situ, who has not had prior intravesical therapy.
- A patient with carcinoma in situ or an aggressive cancer that has begun to penetrate the bladder wall, who has had at least one course of intravesical therapy.
Panel policy recommendations were categorized into three grades of flexibility as determined by the strength of the available evidence and the expected amount of variation in patient preferences. The three levels are standards, which have the least flexibility; guidelines, which have significantly more flexibility; and options, which have the most flexibility.
The guidelines panel recommended as a standard that physicians should discuss with all three types of index patients treatment alternatives and the benefits and risks of each alternative, including side effects. While the panel’s report states that the incidence of serious or life threatening side effects of any agent are low, all the agents have side effects, some in common and some unique to a particular agent.
For the index patient who presents to a physician with an abnormal growth on the urothelium but has not yet been diagnosed with bladder cancer, the panel recommends as a standard that a biopsy should be obtained for pathological analysis. Once a diagnosis of bladder cancer has been established, the panel recommends as a standard that complete eradication of all tumors should be performed if surgically feasible and if the patient’s medical condition permits.
The panel recommends adjuvant intravesical chemotherapy or immunotherapy as an option for treating this patient after endoscopic removal of low-grade bladder cancers because the outcomes data "show a decreased recurrence probability for all the intravesical therapies studied, compared to transurethral resection alone." However, based upon panel opinion, many patients with low- grade tumors do not require adjuvant intravesical therapy.
There is a low risk of disease progression in this group and little evidence that adjunct therapy affects the progression rate, according to the report.
Panel members did recommend, as a guideline, intravesical use of either BCG or mitomycin C for treatment of carcinoma in situ and for treatment after removal of tumors that have begun to penetrate the bladder wall and high-grade Ta tumors. This recommendation is "based on evidence from the literature and panel opinion that both BCG and mitomycin C are superior to doxorubicin or thiotepa for reducing recurrence of these tumors."
Because there is some risk of progression to muscle-invasive disease even after intravesical therapy, the report stated that, as an option, bladder removal may be considered as an initial treatment option in certain patients, based on several factors including large tumor size, high grade of tumor, and tumor location.
In patients with carcinoma in situ or high-grade tumors who have had at least one course of intravesical therapy, the panel report states that cystectomy (a surgical procedure to remove the bladder) and further intravesical therapy may be considered as options for cancers that have persisted or recurred.
In concluding its report, the AUA panel recommended several areas where further research is needed, including dose and frequency of agents used in adjuvant therapy; the probability of progression; the risk and significance of urothelial carcinoma outside the bladder, and the role of treatment regimens using alternative or combined drugs.