CAMBRIDGE, Mass.--The US Food and Drug Administration last week approved the first new major brain cancer treatment in more than two decades and the first treatment ever to deliver chemotherapy directly to the tumor site. The product, a dime-sized polymer wafer that dissolves slowly when placed in the brain, is based on novel polymers developed by Massachusetts Institute of Technology Professor Robert S. Langer and colleagues.
"The goal is to put the wafers in the brain and prevent tumors from recurring," said Dr. Langer, the Germeshausen Professor of Chemical and Biomedical Engineering in the MIT Department of Chemical Engineering. "Our hope is to use these on other types of cancer and diseases in the future."
The wafer, called Gliadel, will be made by Guilford Pharmaceuticals Inc., a Baltimore biotechnology company, under license from MIT. Rhone-Poulenc Rorer Inc. of Collegeville, PA, owns most of the worldwide marketing rights to the product.
Gliadel was approved to treat glioblastoma multiforme (GBM), one of the most deadly of all cancers. When GBM strikes, it progresses rapidly and often can kill a patient within one year. GBM also is the most common among the 20,000 primary brain tumors diagnosed in the United States each year.
Pivotal Phase III clinical trials showed that Gliadel improves the survival rate of patients. The wafer was tested on 222 patients undergoing surgery for recurrent brain tumors. After six months, the survival rate was 56 percent for patients with the Gliadel implant versus 36 percent for the group which did not receive the wafer.
A second Phase III trial conducted in Europe for primary brain tumors recently showed that after one year, the survival rate was 63 percent for patients with Gliadel versus 19 percent for the group which did not receive the wafer. Even more significantly, the trial showed that after two years, the survival rate for patients with Gliadel was 31 percent versus 6 percent for the group without the wafer.
The wafer overcomes the traditional problem of getting drugs across the blood-brain barrier. It sits right on the affected site, so more medicine gets where it is needed. Also, it is safer; it does not cause the debilitating side effects of conventional chemotherapy.
As many as eight wafers can be implanted into a GBM tumor cavity after surgery to prevent the rapid recurrence of a new tumor. The Gliadel wafer is made of a biodegradable polymer impregnated with carmustine, a potent anticancer drug. Unlike other existing degradable polymers which become spongy and can fall apart unevenly over time, the wafer dissolves evenly like a bar of soap. This ensures the release of a steady flow of the drug without any possibility of a sudden chunk of the drug being released and potentially causing an overdose.
The Gliadel wafer dissolves within two or three weeks. However, by changing its chemistry, the polymer can be made to last from one day to six years for other medical applications.
The wafer is the result of a 17-year effort by Professor Langer and colleagues that began in 1979, when he launched a program at MIT specifically to design polymers for medical use. Principal funding sources for the work were the National Institutes of Health and Nova Pharmaceuticals Inc. (which subsequently spawned Guilford Pharmaceuticals).
Professor Langer's research at MIT has focused on developing revolutionary methods for the controlled release of drugs using synthetic polymers. To do this, one of his objectives was to synthesize a new family of polymers called polyanhydrides.
In 1985 Professor Langer teamed with Dr. Henry Brem, a neurosurgeon at Johns Hopkins Medical School, to adapt these polymers so that they could deliver a chemotherapeutic drug directly at the site of the brain tumor using a small wafer.
Professor Abraham Domb of Hebrew University of Jerusalem, and Professor Kam Leong of Johns Hopkins University, both of whom were postdoctoral fellows in Professor Langer's laboratory during the 1980s, played a major role in the synthesis of these polymers, as did Howie Rosen, a former graduate student of Professor Langer who is now at the biotechnology company Alza Corp. in Palo Alto, CA. Former MIT graduate student Cato Laurencin, now a professor at Allegheny University and Drexel University, played a significant role in the 1980s in safety studies of these polymers.
Their aim was to make the wafers easy to use and effective. It takes about three extra minutes during surgery to line the tumor cavity with as many as eight polymer wafers.
Professor Langer said the wafer also is the first synthetic degradable polymer other than a polyester (such as those that have been used in sutures for many years) that has been approved by the FDA for medical purposes. He hopes to expand its use beyond GBM in the future.
The FDA already has approved a Phase I trial of this family of polymers for locally releasing the antibiotic gentamicin to treat the bone disease osteomyelitis.
"This shows us how a localized controlled-release system can possibly be used to treat cancers and other diseases," Professor Langer said. "It also provides a new approach as to how materials can be specifically designed for medical purposes. We hope these studies will encourage others to synthesize and develop novel materials that have the precise chemical, biological and engineering characteristics to address specific medical problems."