Treatment of Carcinoma In Situ 

Treatment of carcinoma in situ (CIS) differs from that of papillary transitional cell carcinoma (TCC). Endoscopic surgery, which is the initial treatment of papillary cancers, is not effective for CIS because the disease is often so diffuse and difficult to visualize that surgical removal is not feasible. When a combination of papillary tumor and CIS is present, the papillary tumor is removed before treatment of the CIS is initiated.

Bacillus Calmette-Guérin (BCG) is the most common intravesical agent used to treat carcinoma in situ (CIS). 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. At 10 years, approximately 30% of patients with CIS who are treated with BCG are disease free.

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 interferon-alfa (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 carcinoma in situ (CIS) include the following:

• Mitomycin-C
• Gemcitabine
• Doxorubicin
• Valrubicin
• Thiotepa
• Cisplatin

No evidence suggests that these adjuvant therapies are as effective as bacillus Calmette-Guérin (BCG). These agents may increase the time to disease recurrence, but no evidence indicates that they prevent disease progression.

Mitomycin-C

Mitomycin-C is the most commonly used chemotherapeutic agent. It is used in both the perioperative and the 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.

Mitomycin-C 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 practice has never been thoroughly studied.

With the use of 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

Gemcitabine is the most recent addition to the list of effective intravesical 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 transitional cell carcinoma (TCC) cell lines and does not affect normal fibroblast cell lines. Serial administration of weekly doses of 1500-2000 mg in 50 mL of saline has shown complete responses in 50% of patients with CIS.

Doxorubicin

Doxorubicin (Adriamycin) is a 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

Valrubicin has been approved as intravesical chemotherapy for CIS that is refractory to BCG. In patients whose conditions do not respond to BCG, the overall response rate to valrubicin is approximately 20%. In some patients, valrubicin chemotherapy can delay time to cystectomy. Valrubicin is currently not commercially available.

Thiotepa and cisplatin

Thiotepa was the original chemotherapeutic agent used for bladder cancer. It is now rarely used because of its limited efficacy. Cisplatin also provides limited benefit and is rarely used to treat CIS.

Morales et al treated 55 patients with 6 weekly instillations of either 4 mg or 8 mg of mycobacterial cell wall-DNA complex following endoscopic tumor resection, and the complete response rate for the 4-mg group at 12 and 18 months was 38%, while the 8-mg group had response rates of 38% and 62% at 12 and 18 months, respectively. Morales et al have been studying the effects of intravesical mycobacterial cell wall–DNA complex as an alternative to standard BCG and as therapy following failure of BCG instillations. The 25 patients in the 4-mg group had received prior therapy and had tumor recurrence.^[1]

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. The laser is introduced through a cystoscope; its light activates the cytotoxic agent, which has preferentially concentrated within the cancer cells. 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.^[2]

Consider patients with recurrent carcinoma in situ (CIS) for an early cystectomy. Recurrent CIS, despite intravesical bacillus Calmette-Guérin (BCG), is associated with a 63% risk of progression to muscle-invasive bladder cancer. Recurrence after BCG treatment may also occur in the upper urinary tract or prostatic urethra. Excellent long-term survival outcomes have been reported in patients with CIS who receive radical cystectomy.^[3]