Efficacy of BCG in bladder cancer may be predicted by cytokine response

San Francisco-Bacillus Calmette-Guérin (BCG [TheraCys, TICE BCG]) has been the standard of care for bladder cancer for nearly 40 years. Little is known about BCG or its mechanism of action, however. A trial currently under way at M.D. Anderson Cancer Center, Houston, may help urologists to separate responders from nonresponders early and tailor therapy for optimal results in those who respond to the drug.

Nearly all of what is known about BCG is empiric, Dr. Kamat reminded the 2010 Genitourinary Cancers Symposium in San Francisco. Even the gold standard 6-week induction was developed because the product was most commonly available as a six-vial pack.

There is no recognized marker for BCG response, although researchers have come to agree on a few key assumptions: BCG is a nonspecific immune system stimulator that evokes an inflammatory response involving a wide range of cell types; successful BCG therapy requires an immunocompetent host response; BCG instillation produces an early granulocytic influx into the bladder wall followed by mononuclear cells; and BCG instillation activates macrophages, T-lymphocytes (CD4 and CD8 cells), B-lymphocytes, natural killer cells, and BCG-activated killer cells.

Role of cytokines, gene expression

Dr. Kamat explained that BCG stimulates cytokine production, which enhances natural killer cell activity, eventually shifting the host from T helper cell 2 (Th2) to T helper cell 1 (Th1) immune response. This Th1 cytokine response is proinflammatory and is usually accompanied by increased production of interferon (IFN)-gamma, interleukins 2 and 12 (IL-2, IL-12), tumor necrosis factor (TNF), and TNF-related apoptosis-inducing ligand (TRAIL) and decreased production of IL-6 and IL-10.

This proinflammatory response seems to be associated with favorable response to BCG, Dr. Kamat added. Several small retrospective trials have suggested that urinary cytokines may be useful as markers of BCG response, including IL-2, IL-8, IL-18, and TRAIL.

Gene expression also appears to play a role. A small study indicated that IL-6 genotype is associated with an increased odds ratio for bladder cancer in smokers (9.83), former smokers (3.91), and never-smokers (1.16). IL-6 genotype also correlates with recurrence of bladder cancer and decreasing probability of survival following BCG therapy.

"The reaction to BCG in bladder cancer is complex," Dr. Kamat said. "What we may need is a panel of cytokine markers that correlate to predicted response. We may also find that the genetic profile of individual patients can separate responders from nonresponders."

Dr. Kamat is running a prospective trial studying cytokine response to BCG as a predictor of efficacy. The trial at M.D. Anderson is also looking at specific genes and genotypes as predictors of response as well as cytogenetic abnormalities in urine sediment that predict tumor recurrence.

The trial is still accruing patients, Dr. Kamat said, and early results are promising but complex. A nomogram based on early results has an area under the curve of 85.5%.

"This is pretty good," Dr. Kamat said. "Anyone who has worked with BCG knows that we don't have anything at all that approximates this result."

The goal, he continued, is to develop prognostic factors to accurately separate responders from nonresponders and to use cytokine response to monitor, tailor, and optimize BCG therapy to the individual patient.

Dr. Kamat has a consultant/advisory role for Biosite, receives honoraria from Endo Pharmaceuticals and Precision Therapeutics, and receives research funding from Bioniche Life Sciences and Biosite.