The combination of Bacillus Calmette Guérin (BCG) and mitomycin given via electromotive delivery resulted in significantly lower rates of recurrence and disease progression, as well as increased survival, compared with BCG alone in patients with high—risk superficial bladder cancer, according to a study by Italian researchers (Lancet Oncology 2006;7:43—51).
The results appear to contradict earlier studies where mitomycin added to BCG failed to increase survival compared with BCG alone. The electromotive delivery used in the new study, however, is not approved or widely available in the United States, so it is unlikely that it will be adopted anytime soon by US oncologists.
“To the best of our knowledge, this is the first time simultaneous reduction of all these endpoints [i.e., recurrence, disease progression, mortality, and disease—specific mortality] has been reported in superficial bladder cancer,” said the lead author of the study, Professor Savino M. Di Stasi, MD, PhD, of the Department of Surgery/Urology at Tor Vergata University in Rome.
“In patients with high—risk superficial bladder cancer, intravesical sequential BCG/electromotive mitomycin significantly reduces recurrence, facilitates bladder preservation, and impacts favorably on overall and disease—specific survival. Overall toxic effects were similar in the group that received sequential BCG and electromotive mitomycin compared with BCG alone. Close follow—up and regular communication can optimize safety.”
The rationale for the study was based on the idea that BCG induces inflammation, which increases the permeability of the bladder mucosa, allowing more extensive penetration of mitomycin to the target tissue.
Previous studies had suggested that electromotive delivery achieved superior outcomes compared with passive diffusion.
The technique for electromotive delivery in this study, Professor Di Stasi explained, involved intravesical delivery of mitomycin via a catheter electrode retained in the bladder for 30 minutes while a pulsed electric current was given externally on the lower abdomen through two cathode electrodes. The bladder was then emptied and the catheter removed.
Superior Efficacy for Sequential Treatment
The study enrolled 212 patients with high—risk (Stage pT1) bladder cancer and randomized them to receive either BCG infusion once a week for six weeks or BCG infusion once a week for two weeks followed by electromotive mitomycin once a week (one cycle) for three cycles.
Patients who had a complete response then underwent maintenance therapy with their assigned treatment—those in the BCG group received one infusion of BCG a month for 10 months, and the other group had electromotive mitomycin once a month for two months followed by BCG infusion once a month (one cycle) for three cycles.
At a median follow—up of 88 months, those assigned to sequential BCG and electromotive mitomycin had a disease—free interval of 69 months compared with 21 months for BCG alone.
Recurrence rates were 41.9% versus 57.9%, respectively. Overall mortality was 21.5% versus 32.4%, respectively; and disease—specific mortality was 5.6% versus 16.2%, respectively.
“Oncologists and urologists may wish to inform their patients with superficial bladder cancer about the individual risks and benefits of standard treatment regimens and this novel therapeutic approach, or suggest participation in a clinical trial evaluating this regimen,” Professor Di Stasi said.
Previous Studies Disappointing
He noted that although previous studies of intravesical electromotive delivery of mitomycin versus intravesical passive diffusion of mitomycin and intravesical BCG as the control arm were disappointing, those studies had used the sequence in reverse of the approach used by his team. Also, mitomycin was given by passive diffusion in previous studies.
“The timing and scheduling of both drugs in our study were selected to keep the benefits of both drugs at an optimum,” Professor Di Stasi said, noting, though, that the optimum maintenance regimen of BCG remains to be defined, because commonly used induction and maintenance regimens are arbitrary.
He suggested that restaging transurethral resection should be done on all patients with Stage T1 bladder cancer, since 29 patients in his study were found to be understaged after meticulous initial transurethral resection—“this was surprising,” he said.
‘Thrown Down the Gauntlet’
In an accompanying editorial, Stephen J. Harland, MD, of the Department of Oncology and Institute of Urology at University College in London, commended Dr. Di Stasi and his colleagues for their vision in developing this treatment—“They have thrown down the gauntlet to a hitherto skeptical urological community,” Dr. Harland said.
The study is only the second to show a significant improvement in disease progression for this group of patients, and therefore should be regarded as important, Dr. Harland added.
Adjuvant intravesical BCG with maintenance treatment has been shown to reduce the risk of recurrence and is now considered the standard of care after transurethral resection for many patients with superficial bladder cancer, Dr. Harland continued.
Electromotive delivery of mitomycin by the use of an apparatus powered by 10 1.5 volt batteries achieved 5.5 times higher peak plasma concentrations compared with passive diffusion, suggesting that the bladder wall cells were exposed to incremental concentrations of a similar magnitude.
The new data from Di Stasi and colleagues suggest that the additional efficacy produced by electromotive delivery can reduce progression rates, Dr. Harland said
Despite the good results achieved with BCG followed by electromotive delivery of mitomycin, however, many patients with pathological T1 Grade 3 disease remain at risk of progression, he said. One way to address this would be early repeat biopsy after diagnosis of high—risk bladder cancer to help identify patients likely to have disease progression in the future.
View from US
Harry Herr, MD, a bladder cancer expert at Memorial Sloan—Kettering Cancer Center, where he is an Attending Surgeon in the Department of Urology and a lecturer on the topic, said he was unfamiliar with the technique of electromotive delivery, and after questioning his colleagues for comments for this article, he found that they too did not know much about the method.
Previous studies comparing mitomycin with BCG have shown a clear superiority for BCG, Dr. Herr noted, adding that in a study by a Finnish group, sequencing mitomycin with BCG failed to enhance BCG in superficial bladder cancer.
“These results were disappointing, because we would all like to find ways to enhance the effectiveness of BCG, and sequencing is a reasonable option,” Dr. Herr said.
He complimented the authors for a well—designed study with appropriate patient selection. “The results were excellent—perhaps too impressive, and that was surprising. Not being familiar with the electrode technique makes me skeptical. However, we cannot discount results from this well—done study. I'm skeptical but I will keep an open mind,” Dr. Herr stated.
When asked what would change his mind, he said that more studies are needed to prove the utility and effectiveness of the sequencing schedule and the electromotive delivery technique. Also, the device would have to be approved by the FDA.
“The requirements for this technique are not attractive for a center with a huge patient volume, such as MSKCC. There are several challenges to be overcome before this technique is adopted in the US,” he said.