Attacking Brain Cancer at Tumor Site Extends Survival
DURHAM, N.C. -- John Sampson, M.D., inserts four catheters into Meredith Hanson's skull and prepares to infuse an experimental drug into the cavity where her deadly brain tumor once sat. Just a few errant cancer cells lurking amidst her healthy brain tissue could quickly re-grow the tumor which he recently removed.
Over the next four days, Hansen chats with family and walks the hospital halls as a small pump slowly pushes the drug concoction directly into her brain. The new drug and its targeted attack provide the best possible chance of subduing Hansen's glioblastoma multiforme, a deadly brain cancer that claims its patients within a year of diagnosis.
Already, the experimental therapy has nearly doubled the expected median survival time for 24 patients enrolled in phase I and III clinical trials at the Duke Comprehensive Cancer Center's Brain Tumor Center.
Reaching the tumor is no small feat, given how glioblastoma wraps itself around normal cells just beyond the primary tumor mass. The catheters bypass healthy brain tissue and deliver the drug precisely to the sites of any remaining cancer cells that have been illuminated by magnetic resonance imaging. A forceful current sweeps the drug into the tumor space using computer generated imagery that directs the surgeon's placement of each catheter.
Once in place, the drugs target only those brain cells that express the IL13 receptor, a docking site on the surface of glioblastoma cells. Normal cells have no IL13 receptor so the drug is not allowed inside, sparing healthy tissue the toxic side effects of the drug.
Such extraordinary measures ensure that the drugs reach their intended target and bypass healthy brain cells. Traditional chemotherapy, delivered intravenously, must cross several barriers that limit its entry into the brain.
"Drugs that shrink tumors in other parts of the body often fail when we apply them to brain cancer, in part because so little of the drug permeates the blood-brain barrier and in part because the drugs indiscriminately attack healthy and cancerous cells, so we're limited to lower doses," said Sampson, a neurosurgeon at the Duke Brain Tumor Center. "Directly infusing drugs into the tumor cavity allows us to blanket the area with much higher concentrations of the drug –without causing toxicity -- than we would be able to with intravenous chemotherapy."
Duke is among 50 centers nationwide testing IL13-PE38QQR or other novel drugs as targeted treatments against glioblastoma, the most common and aggressive form of primary brain tumors. Such tumors usually occur in adults between the ages of 40 and 60.
Hansen was diagnosed at the young age of 30, just a month after giving birth to her first child. Hansen said the Duke treatment presents the best odds of allowing her to see her child grow up.
"The Duke doctors said, 'we're going to try to cure you until we're proven otherwise, and that's the exact moment that hope began for us, because we'd had nothing but bad news for weeks,'" said Keith Hansen, Meredith's husband.
Aggressive treatment is critical to prolonging her survival, but current therapies have done little to stem this tumor's ferocity. Sampson is hoping this novel delivery technique, called convection-enhanced delivery, and the targeted drug it delivers will improve the odds for his patients. More than simply an influx of drug, the technique employs a forceful current that carries the drug farther and wider than would occur with drug alone.
Precision catheter placement is key to the technique's success, said Sampson. Specially-designed computer software translates data from images of the patient's brain and instructs surgeons where to place the catheters for the optimal rate and depth of infusion, fluid distribution in the affected area, and proximity to critical blood vessels. Catheters placed too close to the surface can leak, while those placed too deep or remote from the tumor cavity can fail to reach their target.
We take MRI images of the patient's brain, and a novel software program extracts data from these images that specifies the placement of each catheter," said Sampson, who helped develop and test the software at Duke. "The most difficult aspect of the treatment is placing catheters in precise locations throughout the brain to achieve complete coverage, similar to placing sprinklers across a lawn to ensure there are no dry spots."
Sampson said previous attempts to directly infuse drugs in the brain have failed because the drugs simply leaked out of the brain. The new software was developed specifically to treat brain tumors, and it has dramatically improved surgeons' ability to ensure that the drug being delivered is actually reaching the tumor tissue, he said.
The drugs themselves are highly selective in that they target only the cancer cells. IL13-PE38QQR contains a tumor-targeting molecule called IL-13 that docks on the surface of cancer cells. Then the drug releases a toxin (Pseudomonas Exotoxin or PE) inside the cell. The toxin interferes with the cancer cell's protein production and immediately causes its demise.
Both drugs have shown promise in extending survival far beyond the usual eight to twelve months, said Sampson. The Duke patients who received IL13-PE38QQR have survived 44 weeks compared to just 26 weeks for patients who did not receive the drug, Sampson reported in November, 2004, at The Society for Neuro-Oncology meeting in Toronto.
"There are a number of remarkable success stories with the experimental compounds," said Sampson. "Some patients have lived up to five times longer than expected."
If the experimental therapy continues to show benefit, additional clinical trials will be conducted in larger populations of patients at Duke and nationwide. The study is being funded by Neopharm, Inc., maker of IL13-PE38QQR. BrainLAB developed the software for the image-guided surgical placement of catheters. Sampson has served as a paid consultant for Neopharm, Inc., and BrainLAB.