Dr. Grossman's article provides a well-organized review of the literature on the treatment of superficial bladder cancer. At the time of diagnosis, approximately 80% of patients with bladder cancer have superficial tumors (limited to the urothelial lining of the bladder or the underlying lamina propria). In such patients, the risk of distant disease is low, and the natural history of bladder cancer is based on two separate, but related processes: tumor recurrence and progression to a higher stage of disease.
The risk factors for tumor recurrence in patients with newly diagnosed superficial bladder cancer are summarized in Table 1 of the article. These factors must be taken into consideration when deciding which patients to treat with adjunctive therapy after transurethral resection.
Causes of Tumor Recurrence
Bladder tumor recurrence may be due to regrowth of previously resected cancers, growth of new cancers at remote sites in the bladder, or implantation and subsequent proliferation of cells released into the bladder at the time of endoscopic treatment of the original tumor. Evidence exists to support all three mechanisms, and it is likely that all play a role in cancer recurrence to varying degrees.
Various agents and treatment regimens have been evaluated for their ability to decrease tumor recurrence after transurethral resection, and Dr. Grossman concisely summarizes the literature on this subject. Single-dose, perioperative intravesical chemotherapy is an attempt to decrease tumor recurrence caused by tumor cell implantation at the time of transurethral resection. It has previously been demonstrated that bladder mucosa injured by electrocautery is very likely to produce tumor implants, and that the site of urothelial injury represents a preferential site for tumor cell implantation.[1,2] We agree with Dr. Grossman that perioperative intravesical chemotherapy may be a very efficacious, cost-effective way of delivering adjunctive treatment to patients at high risk for bladder tumor recurrence.
Decreasing the Risk of Tumor Progression
A second factor to consider when deciding how to manage a patient with superficial bladder cancer following transurethral resection is the risk of tumor progression. Most Ta tumors (noninvasive papillary) will not progress to muscle-invasive disease. However, as stated in the article, the risk of progression for patients with stage T1 tumors (lamina propria invasion) is 30% at 3 years. This risk may be higher for high-grade lesions and those associated with carcinoma in situ.
Although intravesical chemotherapeutic agents may lower the rate of disease recurrence in patients with superficial bladder cancer, at present there is no evidence to suggest that intravesical chemotherapy has any beneficial influence on the risk of tumor progression. Intravesical bacillus Calmette-Guérin (BCG), however, is effective in treating carcinoma in situ of the bladder and has been shown to lower the rate of disease progression in patients with superficial bladder cancer. A trial of intravesical BCG therapy, therefore, is appropriate for patients with carcinoma in situ or stage T1 disease. While the optimal treatment protocol for BCG is yet to be defined, weekly instillation of BCG for 6 weeks, followed by 3 weekly instillations at 12 weeks (the 6 + 3 regimen) has been recommended by some as the preferred induction regimen.
Recently, a cooperative study demonstrated that bropiramine, an orally administered immunostimulant, is also effective in patients with carcinoma in situ (61% complete response rate). Furthermore, bropirimine produced complete responses in 6 of 12 patients with carcinoma in situ in whom prior BCG therapy failed. Due to its effectiveness and ease of administration, bropiramine may have the potential to eventually replace BCG as front-line therapy for carcinoma in situ of the bladder.
When to Proceed to Aggressive Therapy?
There is currently no consensus regarding when to abandon conservative therapy and proceed with more aggressive treatment for superficial bladder cancer in the face of BCG failure. Although the risk of disease progression in patients with stage T1 bladder cancer is 30% at 3 years, there is no way to reliably predict which of these patients will progress. Lymphatic and vascular invasion, high-grade tumor, multifocality, and tumor adjacent atypia or carcinoma in situ have all been associated with more aggressive behavior by superficial lesions. In the future, markers that predict aggressive behavior in invasive bladder cancer, such as p53 alterations or microvessel count (angiogenesis), may also prove useful in predicting aggressive behavior of high-risk superficial disease.
There is evidence to suggest that patients who do not respond to two courses of intravesical BCG should be considered for more aggressive treatment, such as radical cystectomy. This form of treatment has proven safe and effective in patients with recurrent high-grade T1 lesions and Tis lesions refractory to conservative measures, with 37% of these patients being upstaged to at least muscle-invasive disease (P2) on the cystectomy specimen. Therefore, in the current era of continent and orthotopic urinary diversion, with modern surgical advances that have diminished the morbidity associated with surgery, radical cystectomy should be offered to high-risk patients with superficial bladder cancer in whom previous conservative treatment has proved ineffective.