Treatment of High-Risk Non-Muscle-Invasive Bladder Cancer

Seth P. Lerner


Nat Clin Pract Urol. 2006;3(8):398-399. 

High-risk, non-muscle-invasive bladder cancer is defined as any transitional cell carcinoma (TCC) of the bladder that is high-grade, whether it is primary or recurrent. This high-risk group includes patients with high-grade papillary stage Ta or T1 tumors and any patient with carcinoma in situ (CIS), and makes up 15–44% of patients with non-muscle-invasive cancer in some series.[1,2] The probability of progression to muscle-invasive cancer within 5 years of diagnosis is highest for this group of patients, and ranges from 25% to 50%, depending on case mix and treatment; the risk of progression for low-risk and intermediate-risk patients is 5–15%. Progression is invariably associated with a decreased probability of survival. Thus, accurate identification of grade and stage and a carefully thought out and managed treatment plan are paramount to achieving durable disease control and ensuring long-term survival.

Accurate staging, which is imperative for proper treatment planning, is particularly important in patients with a primary stage T1, grade 3 (T1G3) tumor. Consideration should be given to asking a referee pathologist to review the specimen, as there is significant variability in the accuracy of assigning clinical stage and grade. Up to 40% of patients who undergo radical cystectomy are understaged; this would lead to inappropriate therapy if a T2 tumor were misidentified as a T1 tumor. Therefore, re-resection of the bed of a T1G3 tumor within 4–6 weeks of the initial transurethral resection of bladder tumor is essential for accurate staging. Detrusor-muscle tissue should be included in the specimen to ensure accurate stage determination. Muscle bundles in the lamina propria, the muscularis mucosae, can be misinterpreted as muscle invasion. If persistent T1G3 tumor is found, serious consideration should be given to radical cystectomy. The presence of lymphatic or vascular invasion, if confirmed by a referee genitourinary pathologist, should also prompt consideration of radical cystectomy. Other indications for radical cystectomy are micropapillary disease (a particularly aggressive variant of TCC), primary adenocarcinoma, and squamous cell carcinoma—none of which are considered responsive to intravesical therapy.

Understanding the status of the normal-appearing mucosa is important in identifying patients with associated CIS. The combination of CIS with T1G3 cancer is associated with a higher risk of progression. While much has been written about the potential utility of aberrant expression of cell-cycle regulatory genes, including p53 and the retinoblastoma tumor suppressor genes, such biomarkers have not been validated prospectively and should not be used to drive decision-making in the management of high-risk, non-muscle-invasive bladder cancer at this time. Upper-tract evaluation is also important in the initial staging work-up. Hydronephrosis on the same side as the tumor is highly significant, in that it implies a muscle-invasive cancer. Upper-tract evaluation should be continued annually for the life of the patient, as there is a ≤20–25% incidence of upper-tract tumors 10 years after diagnosis of high-risk disease.[3]

The treatment of choice for CIS and the prophylaxis of completely resected, high-risk papillary disease is a 6-week induction course of bacille Calmette–Guérin (BCG). Peak induction of cytokines occurs around the fourth treatment, and is sustained through to the sixth treatment. I recommend that all patients with high-risk disease undergo pathologic confirmation of response, with cystoscopy, barbotage cytology, and biopsies of the previous tumor sites and areas of CIS performed within 6 weeks of the completion of induction BCG. If cytology and biopsy results are negative, the patient has had an initial complete response, and subsequent follow-up evaluations can be performed with cystoscopy and barbotage cytology in the office. In a secondary analysis of the randomized, controlled Southwest Oncology Group (SWOG) trial comparing induction BCG with and without maintenance BCG, failure to achieve an initial complete response after induction BCG was an independent predictor of decreased survival. Without additional therapy, patients who are cytologically positive, but biopsy negative, at the initial evaluation can convert to a negative cytology at the next, 3-month, evaluation.[4] This indicates that some patients take more time to respond to the induction course of BCG.

Data from the SWOG trial support the use of maintenance BCG in patients with an initial complete response.[4] Maintenance therapy consists of three weekly instillations administered at 3 and 6 months, then at 6-month intervals up to the 3-year mark. Peak cytokine induction is reached earlier with maintenance therapy, usually by the second or third dose. While monthly maintenance BCG has been shown to be superior to monthly maintenance with mitomycin C, the induction of cytokines with a single dose of BCG might not be adequate; therefore, I prefer the three weekly maintenance regimen.

In the SWOG trial, only 16% of patients completed the 3 years of maintenance therapy. As no dose reduction was allowed, many patients dropped out because of toxicity. There is ample evidence that the BCG dose can be reduced to as little as a hundredth of a dose and still maintain an adequate cytokine response. This could enable continued administration of BCG in patients with a durable complete response and negative cystoscopy and cytology. Dose-reduction and alternative maintenance schedules are currently being tested in randomized, clinical trials.[5]

The use of salvage therapy in patients with recurrence of high-risk disease is one of the most important clinical issues for the urologist. The safest approach is to proceed with radical cystectomy, to avoid the risk of subsequent progression to muscle-invasive cancer, which is associated with a lower probability of survival.[6] When this is not feasible, or when the patient recurs with low-risk or intermediate-risk disease (TaG1, TaG2, or multifocal papillary disease that is not high grade), an alternative approach is to use BCG in combination with interferon α. Two phase II studies and a large, three-arm, comparative trial led by O'Donnell clearly demonstrate that some patients can achieve a durable complete response with this regimen.[7] The response rates to salvage combination immunotherapy of patients who have failed two prior BCG regimens or never achieved a complete response with BCG are low, and these patients should be advised to undergo cystectomy. There are no data at this time from randomized, clinical trials to support the use of combination immunotherapy as the initial treatment for high-risk disease.

Other salvage intravesical treatment options are being evaluated in clinical trials. Gemcitabine, an active agent for the treatment of metastatic TCC, has shown activity in several phase II trials of intravesical therapy, and will be evaluated in patients who have failed at least one course of BCG in a SWOG trial.[8,9]Mitomycin, combined with hyperthermia, has shown significant activity in intermediate-risk and high-risk patients, including those who have failed BCG.[10]

Finally, radical cystectomy can be the first treatment of choice for young, otherwise healthy patients with high-grade T1 disease, or for patients with multifocal CIS who cannot tolerate BCG. Possible indications for cystectomy include multifocal disease, deep involvement of the lamina propria, and associated CIS. The 5-year disease-free survival rate with radical cystectomy is approximately 85% for patients with pathologic node-negative T1 tumors, and 95% for pathologic stage pT0, pTa or pTis tumors, making radical cystectomy an excellent initial treatment for selected high-risk patients (E Skinner, personal communication).

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