Cystectomy still best option when bacillus Calmette-Guerin fails

San Francisco-Bacillus Calmette-Guerin (BCG [TheraCys, TICE BCG]) remains the treatment of choice for bladder cancer in the United States, but clinicians and patients face an unpleasant reality: More than one-half of patients with nonmuscle-invasive bladder cancers will eventually fail BCG. Several promising alternative treatments are under development, but radical cystectomy remains the optimal choice for patients who fail BCG.

Observation is not a viable long-term option. Five-year survival rates after cystectomy have changed little over the decades, Dr. O'Donnell told attendees at the 2008 Genitourinary Cancers Symposium here. Five-year survival before 1985 ranged from 60% (PT2 disease) to 21% (PT4 disease); contemporary survival rates range from 67% (PT2 disease) to 27% (PT4 disease).

Older patients in particular have significant comorbidities that can increase the risk of major surgery. Not only can surgery reduce quality of life, but radical cystectomy also carries a morbidity rate of greater than 30% and a mortality rate of 2% to 5%.

Accepting cystectomy is even more difficult because the recommendation is typically made before the disease has progressed clinically. Lack of progression offers the hope of salvage. However, once progression occurs, survival rates plummet. Five-year survival for patients with less than T2 disease ranges between 80% and 90%, Dr. O'Donnell said. Once the disease progresses to T2, survival falls to between 70% and 75%. Fewer than one-half of patients with T3 disease are still alive 5 years after cystectomy.

"Patients do very well if there is no progression," Dr. O'Donnell said. "Once there is muscle invasion, patients die. While there is no absolutely 'safe' window in anticipating progression, the data show that somewhere approaching 2 years after the original index tumor is the point at which you have to intervene with cystectomy to avoid a serious and abrupt dropoff in survival."

Intravesical options

Once BCG treatment fails, there are few conventional treatment options. About 12% of patients respond to interferon (Roferon-A) and about 8% respond to valrubicin (Valstar). But several new intravesical options offer hope for improvement.

Interferon plus BCG is well tolerated and shows an increased salvage rate in phase II trials. Clinicians in Europe are using microwave chemotherapy with mitomycin (Mutamycin) with good results. Published data in patients who have failed BCG show no evidence of disease in 83% of patients after 1 year and 62% after 2 years (Eur Urol 2004; 46:65-71).

"We are looking forward to using it," Dr. O'Donnell said.

Photodynamic therapy with oral porphyrins or intravesical photoactive drugs show promising results, especially in refractory patients with carcinoma in situ, but the therapy remains investigational. There are no formal studies to date with radiation or chemoradiation in patients with nonmuscle-invasive bladder cancer who have failed BCG.

Intravesical gemcitabine (Gemzar) shows exciting phase II results, with low toxicity and good short-term efficacy (Curr Opin Urol 2006; 16:361-6), but responses do not appear to be durable, Dr. O'Donnell said.

Intravesical taxanes also show exciting data with minimal toxicity. Among patients who had failed two courses of BCG or BCG and interferon, 56% showed a complete response and 33% maintained complete response after 14 months of follow-up. Data are from phase I studies, Dr. O'Donnell cautioned.

Combination chemotherapy is also being investigated. Combinations being studied include sequential gemcitabine and mitomycin, sequential doxorubicin hydrochloride (Adriamycin) and gemcitabine, sequential gemcitabine and docetaxel (Taxotere), sequential docetaxel and mitomycin, sequential doxorubicin and docetaxel, and a double sequence of doxorubicin and gemcitabine followed by docetaxel and mitomycin. These combinations can be administered in the office setting, Dr. O'Donnell noted, but no clear winner has emerged.

"BCG failure is a major clinical problem," he said. "Alternate treatments may be applicable, but only in select cases relatively early on. Radical surgery is still very appropriate for anyone who fails BCG. It absolutely must be discussed with these high-risk patients."