Long Island Neurosurgical & Spinal Associates (LINSA)

Brain Surgery

Malignant Glioma Background

Malignant glioma is the most common form of brain cancer. It is one of the most rapidly progressive and universally fatal of all cancer types. The American Cancer Society estimates that each year approximately 17,500 people develop new cases of primary brain cancer. Including metastatic brain cancer, more than 100,000 Americans are diagnosed with brain tumors each year. Brain tumors may occur at any age, but are most common in early adult or middle life, often striking people in the prime of their lives. Brain tumors are found in about 2% of routine autopsies. The cause of brain tumors is unknown.

There have been no significant new developments in the treatment of brain cancer for over 20 years, and the prognosis with current treatments is generally grim. Current standard practice consists of surgery (craniotomy) to remove the tumor, followed by radiation therapy. Systemic chemotherapy with carmustine (BCNU) is also often used. Brain cancer has a very high recurrence rate, however, and invariably results in death within a short time.

GLIADELŪ - General Description

GLIADELŪ is a new drug product for the treatment of brain cancer. It is a biodegradable polymer implant, and is the first fundamentally new approach to the treatment of brain cancer in over 20 years. GLIADELŪ polymer implants are small, white wafers which are left in the surgical cavities created when a brain tumor is removed. As the wafer slowly erodes in the brain, it releases the cancer chemotherapeutic drug carmustine (BCNU) directly to the tumor site in high concentrations over an extended period of time.

GLIADELŪ is a polyanhydride implantable polymer drug delivery system, containing 3.85% carmustine (BCNU). The polymer is composed of polycarboxyphenoxy propane:sebacic acid in a 20:80 copolymer [poly(CPP:SA)20:80]. The final product is formulated as a 200 mg, round disk wafer, 14 mm in diameter by 1 mm thick, which is approximately the same size as a dime.

The wafers are placed directly into the brain at the time of surgical removal of a brain tumor, permitting BCNU to be delivered directly to the site of the tumor for an extended period of time. Up to 8 wafers can be placed at one time. This results in much higher local concentrations of BCNU than can be achieved with systemic administration. As a result, antineoplastic activity is significantly increased, and side effects decreased compared with systemic therapy. Approximately 62 mg of BCNU delivered as GLIADELŪ achieves substantially higher local brain tissue concentrations than a 3000 mg intravenous dose -- GLIADELŪ provides brain concentrations of BCNU that are 100-1,000 times higher than are possible with systemic administration. In the current GLIADEL formulation, the duration of drug delivery is 2-3 weeks (the ratio of PCPP:SA can be varied to shorten or lengthen the delivery).

Clinical Data

Prior to it's release, the treatment protocol was tested extensively in several studies worldwide.The first Phase III study was in 222 patients (at 27 centers) with malignant glioma undergoing reoperation for recurrent disease; 145 of these patients had glioblastoma multiforme. The primary endpoint of the reoperation trial was survival over 6 months, using a Cox multiple regression statistical analytical model to adjust for prognostic factors. At the 6 month time point, 60% of GLIADELŪ patients were alive, compared with 47% of placebo. These results are statistically significant at p = 0.01 adjusted for prognostic factors. Median survival time was increased from 24 weeks with placebo to 32 weeks with GLIADELŪ, statistically significant at p = 0.05. Independent statistical analysis, using 45-month survival as the primary endpoint, showed a statistically significant benefit for GLIADELŪ  at p = 0.005 in a multiple regression analysis. Long term follow-up through 71 months showed GLIADELŪ to continue to have a statistically significant benefit, p 0.05 (Cox regression model). No serious adverse effects caused by GLIADELŪ were identified. No clinically important adverse events attributable to GLIADELŪ were identified. The results of this clinical trial were published in The Lancet, April 22, 1995.

The second placebo-controlled Phase III study was conducted in patients undergoing surgery upon initial diagnosis of malignant glioma. This study was conducted in 32 patients in centers in Scandinavia. The primary endpoints used to assess efficacy in this study were one-year survival and overall survival. In this study, median survival was 58 weeks for GLIADELŪ and 40 weeks for placebo. This 18 week improvement in survival was statistically significant to p = 0.01. One-year survival was 63% for GLIADELŪ (10/16) and only 19% for placebo (3/16). This was also statistically significant to p = 0.029. After accounting for the effects of age, Karnofsky score (a measure of patient performance), and tumor type in a Cox regression model, the effects of GLIADELŪ treatment remained statistically significant (p = 0.006). The side effects profile for GLIADELŪ did not statistically differ from placebo.

Polymer Products for the Targeted Treatment of Other Cancers

The targeted treatment of cancer with polymer based products may be important for other cancers beyond brain cancer, to treat tumor recurrence after surgical resection. In this endeavor Guilford is also investigating a number of other next generation polyanhydride polymer oncology products for use in other cancers. Among other technologies, Guilford is developing a series of polyanhydride polymers in collaboration with The Hebrew University of Jerusalem, invented by Dr. Avi Domb, the original inventor of the PCPP:SA polymer used for GLIADELŪ. These polymers include polymers derived from hydrolyzable diacid fats, such as PRAM:SA (polyricinoleic acid maleate:sebacic acid). Guilford plans to develop these polymers with a variety of chemotherapeutic agents for the targeted treatment of other cancers including prostate, breast, head and neck, lung, esophageal, hepatic, pancreatic, colon, and others.

Guilford is also developing other physical formulations of polymers for stereotactic implantation. Such polymer products may potentially be used either for treatment of otherwise inoperable tumors, or for re-implantation of a polymer therapeutic after the initial surgery and implant. Such products, which may take the form of a gel or microspheres, would be implanted by stereotactic injection, without requiring conventional surgery. These stereotactic products will be explored both for brain and other forms of cancer.

For further information on  GLIADELŪ please visit Guilford Pharmaceuticals, www.gliadel.com, or call 1-800-701-9035 or P. Arjen Keuskamp, MD at (631) 265-2020.

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