“For first-time patients for which BCG is indicated there is no advantage to adding either intravesical interferon or oral megadose antioxidant vitamins,” Dr. Michael O’Donnell at the University of Iowa, Iowa City told Reuters Health.
BCG instillation produces a response rate up to 83% in patients with non-muscle invasive bladder cancer (NMIBC), but many patients either do not respond or cannot tolerate treatment and have a rapid recurrence, Dr. O’Donnell and colleagues explain. Since the addition of interferon and vitamins has been seen as promising, they conducted a clinical trial of this strategy.
The study involved 670 NMIBC patients who were randomized to BCG with or without interferon alpha-2b. They were further randomized to receive a recommended daily allowance of vitamins or a megadose vitamin preparation. After a 6-week induction period, responders were given maintenance therapy at regular intervals.
After a median of 2 years’ follow-up, recurrence-free survival was not significantly different in all groups, the researchers report.
Specifically, recurrence-free survival rates were 63% with BCG plus RDA vitamins, 59% with BCG and megadose vitamins, 55% with BCG plus interferon and RDA vitamins, and 61% with BCG plus interferon and megadose vitamins.
Furthermore, those patients treated with BCG plus interferon were more likely to have a fever than those receiving only BCG therapy (11% vs 5%, p=0.0037). Similarly, rates of reported constitutional symptoms in the two groups were 18% vs 11%, respectively (p=0.0183).
Why the negative outcome? “I suspect the reason why the addition of interferon in this group of BCG-naïve patients did NOT show any advantage over BCG alone is two-fold,” Dr. O’Donnell replied.
The reasons have to do with the high response rate to first-time BCG monotherapy. “The mechanism by which Interferon-alpha reinforces BCG is by suppressing the immune antagonizing natural squelcher of excess immunity, namely interleukin-10. This is primarily a problem for patients getting repeat doses of BCG after prior failure, not so much for first time patients getting BCG,” Dr. O’Donnell said.
The second reason has implications for further research. “The set-up design of the study was not optimal for seeing the incremental advantage of interferon. Let’s say 70% of NEW patients would have responded to BCG alone. Obviously interferon is not going to help them since you can’t ‘overcure’ such patients. That leaves 30% that are ‘destined’ to fail. We predicted based on prior studies that the incremental value of interferon to BCG in BCG failure patients was likely about 15% absolute improvement. So, 15% times 30% = 4.5% = the ‘potential’ benefit in this population of BCG-naive patients. This study was not statistically powered to detect such a small difference so we can’t really say anything about it for patients more likely to fail BCG,” Dr. O’Donnell explained.
“However,” he concluded, “if the group to be tested were already all BCG failures (100%) then it is more likely that we would see such a (15%) difference. Such a clinical trial must still be done lest we ‘throw out the baby (interferon) with the wash water’.”
Bacillus Calmette-Guerin With or Without Interferon α-2b and Megadose Versus Recommended Daily Allowance Vitamins During Induction and Maintenance Intravesical Treatment of Nonmuscle Invasive Bladder Cancer
J Urol 2010; 184,1915-1919.