Every year in the U.S. about 17,500 persons develop primary brain cancer. There are about 20,000 brain-cancer surgeries each year. For most, even after surgery, prospects for a normal, healthy life remain grim.
Relapses occur. Conventional post-surgery treatment of radiation and intravenous chemotherapy often prove unsuccessful. Drugs needed to fight the cancerous growth reach the brain in too-low concentrations to be effective. In addition, serious side effects associated with drug delivery, such as anemia and pulmonary fibrosis, have become common problem areas.
Now, thanks to the development of a controlled drug-delivery system that can be implanted at the site of the removed tumor, some brain-cancer patients will have a brighter future. Clinical tests have shown that polymer wafers impreg-nated with a cancer-fighting drug implanted after surgery can help prolong life.
As the biodegradable wafers erode, they release the chemotherapeutic drug to prevent relapses. Moreover, drug delivery takes place over time without the adverse effects common to intravenous delivery.
Researchers report that two highly successful clinical tests, involving patients in North America and Europe, have shown marked improvements in survival rates for those treated by the new method. The treatment system, offered by Guilford Pharmaceuticals, a Baltimore-based biotechnology company, is awaiting regulatory approval from the U.S. Food and Drug Administration.
The novel system, called Gliadel®, consists of a biodegradable polyanhydride polymer matrix that incorporates a generic cancer-fighting drug, carmustine (BCNU). After removing the tumor, the surgeon simply places up to eight wafers into the cavity, then closes it. The wafers slowly degrade, releasing toxins directly to the cancerous tissue.
Dr. Henry Brem, professor of neurosurgery and oncology at Johns Hopkins Medical Institutions, describes the system's development as "very significant for the future treatment of brain cancers." He adds, "Use of biodegradable polymers to deliver prolonged high doses of chemotherapy directly to the tumor spares patients from systemic exposure to the drug. No other form of chemotherapy has shown such a dramatic improvement in survival with so few side effects. It offers physicians a brand new, effective weapon for fighting cancer."
Two double-blind, placebo-controlled clinical tests have shown the viability of the treatment, according Dr. Brem. The tests offered proof, he feels, that chemotherapy can be directed at a target.
The most recent Phase III clinical tests of the Gliadel system took place in Europe. They involved patients undergoing surgery for the first time to remove fatal malignant gliomas, the most common type of primary brain cancer. In the randomized tests, either Gliadel wafers or placebos were implanted in 32 patients.
Three weeks after surgery, all the patients underwent standard radiation therapy. Physicians tracked the patients for two years, or until death. One year after treatment, 63% of the Gliadel-treated patients remained alive, compared to only 19% of the placebo recipients. These results, states Dr. Brem, "confirm and extend the results of our U.S. clinical tests."
With Dr. Brem as lead investigator, the first Phase III test involved 222 gravely ill persons. All in advanced stages of the illness, these patients experienced recurring tumors that required operations for the second or third time.
Twenty-seven medical centers in the U.S. and Canada participated in the tests. An examination of the test results showed that six-month survival rates ranged from 47% for patients with placebo wafers to 60% with the Gliadel treatment.
Patients with glioblastoma multiforme, the most common and severe form of brain tumor, showed even more dramatic results. For these patients, the six-month survival period increased from 36 in the placebo group to 56% for those given the BCNU drug wafer--a 55% improvement.
FUTURE POLYMER DEVELOPMENT AND USES
|1) CURRENT GLIADEL 4%
|- Metastatic Brain Cancer
- SPINAL CANCER
|- Incidence--100,000 NEW CASES/YEAR
- 10,000 SURGERIES
|2) HIGH DOSE BCNU--GLIADEL 20%--BRAIN CANCER
|3) NEW CHEMOTHERAPEUTIC (e.g. CISPLATIN) IN PCPP--FOR BRAIN CANCER
|4) NEW POLYMER--PRAM NEW CHEMOTHERAPEUTIC
- HEAD & NECK
|5) STEROTACTIC PRODUCT/FORM OF USE
- BRAIN CANCER
|- OTHER CANCERS
Polymer makeup. Nick Landekic, a Guilford vice president, reports that the Gliadel polyanhydride polymer system contains 3.85% carmustine (BCNU). The polymer, in turn, consists of polycarboxyphenoxy propane:sebacic acid (PCPP:SA) in a 20:80 copolymer (poly(CPP:SA)20:80).
"The wafer is completely biocompatible and fully biodegradable," says Landekic. The final product is formulated as a 200-mg round wafer, 14 mm in diameter by 1-mm-thick. "That's about the size of a dime," he adds.
Following implant, the wafers slowly erode, releasing BCNU in high concentrations. "Levels of BCNU concentrations are 100 to 1,000 times higher than possible with conventional intravenous administration," Landekic explains. "A level of about 62 mg of BCNU delivered locally achieves substantially higher local brain tissue concentrations than a 3,000-mg dose applied intravenously."
In the current formulation, he points out, drug delivery takes place over a two- to three-week period. However, the ratio of PCPP:SA can be varied to shorten or extend delivery.
Landekic says that while the company is awaiting approval of its New Drug Application from the FDA, Gliadel is available to patients with recurrent malignant gliomas, under a treatment protocol. "Since the FDA cleared a Treatment Investigational New Drug Application last October, over 150 medical institutions have shown interest in the new treatment and want access to the product."
|· Biodegradable polyanhydride polymers
· Polymers derived from hydrolyzable diacid fats
· Sterotatic implantations using needles
Polymer qualities. Guilford says that the biodegradable polyanhydride polymers have several characteristics that make them particularly suitable for this use. First, the polymer matrix is hydrophobic. In other words, this lack of affinity for water protects the drug from degradation by the body. Also, the polymers can be incorporated into the matrix of a broad range of organic and inorganic molecules, including peptides and proteins.
Polyanhydrides also enable a wide range of degradation rates to be produced simply by altering polymer composition. They appear to have no side effects, provide for a constant rate of drug delivery, and can be produced in flexible or rigid forms.
Producing the wafers. The FDA, under its Good Manufacturing Practices (GMP) guidelines, has cleared Guilford's manufacturing facilities for producing the treatment wafers. The company's proprietary process involves polymerization of the two prepolymer components at a melt of 170 to 180C under high vacuum. The resultant copolymer forms a brittle solid at room temperature, says John P. Brennan, Guilford's vice president of operations.
In the manufacturing process, the copolymer is dissolved in a solution of methylene chloride and the BCNU added. After spraying and drying, the solution produces a powder of microspheres that contain BCNU homogeneously dispersed in the polymer matrix. The final step involves compressing the powder into 200-gram, disk-shaped wafers. "Right now," says Brennan, "our operations are hand-labor intensive, but we feel they are conducive to automation."
What's ahead. Clinical test results, along with continuing research, help encourage further development of biodegradable polymer systems to deliver cancer-fighting drugs. Johns Hopkins' Brem is particularly confident about future successes. "New studies will evaluate the effectiveness of higher doses of BCNU than those used in past tests. We even envision the use of polymer implants as the initial therapy for brain tumors."
· Prostate cancer
· Breast cancer
· Esophageal cancer
· Pancreatic cancer
· Hepatic cancer
· Lung cancer
· Colon cancer
Also, Brem points out that such systems can be used to deliver other cancer-fighting drugs that won't pass the natural blood-brain barrier. The "shield" hinders anti-cancer drugs in the blood stream from entering the brain to attack tumor cells. Steroids and immunotoxins also may be more safely delivered with polymers, he feels. "At Johns Hopkins, we've found that a number of drugs can be effectively delivered."
Brem's research involves biological as well as therapeutic agents. One goal: development of tumor vaccines in a polymer matrix that will protect patients against recurrent tumors. The current program in-volves tests with animals.
Guilford's Landekic re-ports the company continues to explore other likely applications for its polyanhydride polymers in tumors of the central nervous system. Among these: the extension of Gliadel's use to fight metastic brain cancer arising from primary tumors in other parts of the body, such as lung or breast cancer. More than 100,000 Americans are diagnosed with brain cancer each year, making such developments particularly welcome.
In addition, the R&D work on polymers connected with Gliadel will make possible the development of other che-motherapeutic agents in the PCPP:SA system. The ratio of PCPP:SA can also be modified to alter drug-delivery profiles. For example, polymers can be formulated using the same two components, with drug delivery durations ranging from a few hours to one to two years.
The company also has new generations of polyanhydride polymers under investigation. Among them: polymers derived from hydrolyzable diacid fats, such as PRAM:SA (ricinoleic acid maleate:sebacic acid), for other oncology applications. Polymer technology, says Landekic, offers the possibility of developing systems to deliver drugs to fight different types of cancer such as prostate, breast, head and neck, esophageal, and others.
Also under development are polymer formulations for use in stereotactic implantation. This procedure involves the use of a needle to implant the polymer matrix with cancer-fighting drugs into the tumor area.