User:Rdavis39/sandbox/Gliadel

Overview
The Gliadel Wafer is a Carmustine implant that is used in the treatment of malignant gliomas. Gliadel is currently the only local therapeutic treatment for malignant gliomas approved by both the Food and Drug Administration and the European Medicines Agency. Gliadel received FDA approval in 1996 for glioblastoma multiforme. After surgical resection of a brain tumor, up to 8 Gliadel wafers are placed in the tumor resection cavity to deliver a high, but local dose of Carmustine to the surrounding tissue to eliminate residual tumor cells.

Carmustine
The compound Carmustine, also called BCNU (bis-chloroethylnitrosourea), is a chemotherapeutic compound. BCNU is a β-chloro-nitrosurea [alkylating agent] that is related to mustard gas. Carmustine is used in the treatment of several kinds of brain tumors and gliomas. It treats brain cancer by preventing tumor cell proliferation by inhibiting DNA transcription and replication through the formation of interstrand crosslinks in DNA.

Implant Design
The Gliadel implant is a polyanhydride wafer made up of the copolymer polifeposan, which consists of 1,3-bis(p-carboxyphenoxy)propane and sebacic acid in a molar ratio of 80 to 20. The active ingredient, Carmustine, is distributed homogeneously throughout the implant's polymer matrix which allows for a controlled release. The disc-shaped implant has a diameter of 1.45 cm and a thickness of 1.00 mm. The bulk composition of each Gliadel Wafer is 192.3 mg of polifeprosan and 7.7mg of the active ingredient, BCNU.

The functional design of Gliadel is to deliver therapeutic levels of Carmustine that cannot be achieved via intravenous or oral administration. Biodegradable polymers, such as Gliadel, have several advantages over oral and intravenous drug administration in the central nervous system CNS. The first advantage is the avoidance of having to access the brain's prenchyma via the blood brain barrier (BBB). Secondly, since the polymer degrades in vivo, there is no need for surgical removal of the device after drug delivery is complete. Also, therapeutic levels of drug can be maintained over prolonged periods of time.

Drug Release and Delivery
A number of empirical and semi-empirical mathematical models have been developed to express drug release and delivery with regards to mass transport of in biodegradable polymers with varying degrees of accuracy. The design of the polymer itself affects the drug's release from the polymer. A number of factors affect drug delivery to the tissues such as "diffusion within the extra-cellular space", drug degradation, binding to the extra-cellular matrix, "elimination into the bloodstream, and anisotropy among other factors.

According to a study done by Dang et al., when the initial molecular weight of the polymer was varied between 20,000 Da and 110,000 Da, there was no difference in polymer degradation due to the initial molecular weight of the polymer. Hence, the polifeprosan matrix of the Gliadel Wafer will have the same decay profile regardless of the molecular weight of the matrix. This allows some flexibility in the manufacturing of the Gliadel Wafer as each wafer will biodegrade within the resection cavity with the same profile. The degradation proceeds in two phases, one of which occurs during the first 10h after 'in vitro' incubation or 'in vivo' introduction into the brain tissue and the other after the first 10 hrs. During the first period of degradation, the polymer matrix loses much of its molecular weight, degrading to a a molecular weight of <5000 Da. However, during the first degradation period, the polymer only loses <5% of of its bulk weight. The bulk polymer begins to degrade after about 10 hrs. and by the end of 1 week it has lost 80% of its bulk mass. The bulk weight loss of the wafer was inversely proportional to the wafer's molecular weight.

As mentioned earlier, the active ingredient of Gliadel, BCNU, is distributed homogeneously throughout the polifeprosan polymer matrix of the Gliadel Wafer. As the polymer matrix degrades, the BCNU is released from the matrix with a square root release profile with respect to time. This release profile infers that BCNU release from the polifeprosan matrix is diffusion controlled. Overall, the degradation of the polifeprosan matrix of Gliadel releases BCNU over an interval of 2-3 weeks.

Indications
Gliadel is used in the treatment of glioblastoma (Glioblastomas are high-grade forms of glioma classified as either grade IV astrocytoma or glioblastoma multiform). Glioblastomas are the most rapidly progressive and fatal form of brain cancer. It arises from the astrocyte cell line. Gliadel combined with surgery and radiation is approved in 18 countries worldwide. Gliadel plus the addition of temozolomide treatment has a median survival of 21 months.

Efficacy
The average survival time of a patient with Glioblastoma multiforme is between 6-8 months. The former primary treatment method for glioblastoma, surgical resection and systemic chemotherapy, was shown to be ineffective in double-blind, randomized controlled studiess. While the efficacy of Gliadel has been debate, it has been shown to have a small but statistically significant improvement in survival time.

Cysts
One of the main side effects of Gliadel treatment of malignant gliomas is is the development of cysts. Most cysts have been noted to appear between 9 and 30 days after tumor resection. Cyst development can lead to an increase in intracranial pressure (ICP) which can lead to further clinical deterioration of the patient. There are 3 lines of treatment for cysts developed by Gliadel treatment. The first line of treatment is a high dose of corticosteroids. The second line of treatment is transcutaneous puncture of the cyst. Finally, the third line of defense is Ommaya reservoir implantation.

Edema
Reactive brain edemas are also a known side effect of Gliadel implantation.

Other Side Effects
A study in France reported septic meningitis, cystic or aseptic abscess, thrombophlebitis, and pulmonary embolism in patients treated with Gliadel which could not be definitively linked to the Gliadel treatment. When Gliadel was combined with temozolomide and radiation therapy (Strupp Protocol) the instance of side effects went down and the survival expectancy increased making Gliadel safer and more efficacious. Gliadel has also been implicated in birth defects.

Systemic Chemotherapy
Gliadel wafer treatment is superior to systemic chemotherapy by delivering a higher drug concentration to tissue adjacent to the original tumor's location.

Surgical Implantation Procedure
The general procedure for Gliadel wafer treatment for brain cancer is resection of the the tumor. Resection is then followed up by placing Gliadel into the resection cavity. BCNU then diffuses into the parenchyma with peak release in the first 2 weeks.

According to the Gliadel Website sponsored by Eisai Inc., the following procedure is the current implantation guidelines for the Gliadel Wafer.


 * 1) Surgical Preparation
 * 2) Resect tumor
 * 3) Obtain hemostasis
 * 4) GLIADEL® Wafer pouches should remain unopened until ready for implantation
 * 5) Communication between resection cavity and ventricular system should be avoided
 * 6) Any communication larger than a wafer should be closed prior to implantation
 * 7) Confirm High-Grade Glioma (HGG) Pathology
 * 8) Mitotic activity is the most defining characteristic of HGGs
 * 9) Carefully Open Packaging
 * 10) Handling with double-layer surgical gloves is recommended
 * 11) Remove non-sterile outer pouch
 * 12) Slowly pull corners outward
 * 13) Grab crimped edge of inner pouch and pull upward
 * 14) Open sterile inner pouch
 * 15) Gently hold the crimped edge
 * 16) Cut inner pouch in an arc-like fashion around the wafer
 * 17) Remove wafer
 * 18) A dedicated surgical instrument should be used for handling
 * 19) Gently grasp wafer with forceps
 * 20) Place onto a designated sterile field
 * 21) Administer GLIADEL® Wafer
 * 22) Up to 8 wafers may be placed to cover as much of the resection cavity as possible
 * 23) Slight overlapping of wafers is acceptable
 * 24) Wafers broken in 2 may be used, but wafers broken in more than 2 pieces should be discarded
 * 25) Administer GLIADEL® Wafer
 * 26) Surgicel® may be placed over the wafers to secure them against the cavity surface
 * 27) After wafer implantation, irrigate cavity
 * 28) Close dura in a watertight fashion to minimize the risk of cerebrospinal fluid leak

According to a study by Bock et al., Gliadel is not recommended for treatment of high-grade malignant gliomas in the case of surgical opening of the ventricular system during microsurgical tumor resection because the wafer material may migrate from the resection cavity to the ventricular system. This will cause a blockage of fluid flow and lead to hydrocephalus. TachoSil is an adhesive collagen matrix used to seal the the ventricular system off from the resection cavity.

Alternative Glioma Treatments
One alternative treatment to Gliadel that made it to a phase 3 clinical trials is a convection-enhanced delivery system of the drug cintredekin besudotox. The convection-enhanced delivery system utilizes a "continuous pressure gradient" to delivery a therapeutic agent directly into the brain's interstitial space thereby bypassing the blood-brain barrier which inhibits the systemic delviery of drugs in the central nervous system. This delivery system operates over the course of several hours or days to increase the therapeutic agent's "distribution to the target tissue." Cintredekin besudotox is a cytotoxic agent, composed of both human interleukin 13 (IL-13) and a mutated form of Pseudomonas aeruginosa exotoxin A (PE38QQR), that kills tumor cells when it binds to receptors of IL-13. When comparing this treatment with Gliadel treatment in terms of both median survival (p=.476) and efficacy evaluable population (p=.310), this alternative treatment was not statistically significant different when compared with Gliadel. The risk for pulmonary embolism using this treatment was 8% compared with 1% for Gliadel wafers.

An alternative delivery mechanism to the Gliadel wafer for Carmustine was outlined in a paper by Vogelhuber, et al.. This delivery mechanism involves using a 'pulsatile' delivery mechanism to vary the rate of Carmustine delivery over time. Beads measuring 2mm in diamter and 1.8 mm in height could be loaded into the tumor resection cavity in place of the larger Gliadel wafers. It was suggested that 200 beads could account for the same amount of drug as 8 Gliadel wafers because both have a volume of 12 cu cm.

Recently, several studies have been conducted to assess the efficacy of Gliadel in conjunction with other treatments such as O6-Benzylguanine (O6-BG), temozolomide, and radation (cite quinn, noel, and Menei). O^6-BG helps with tumor treatment by suppressing the activity tumor O6-alkylguanine-DNA alkyltransferase (AGT) and O6-methylguanine-DNA methyltransferase (MGMT) levels. AGT helps to repair DNA damage by removing the "O6-alkylguanine lesions" "introduced by DNA to alkylating agents such as Carmustine". Hence, by suppressing the activity of AGT and MGMT which reverses the action of Carmustine in Gliadel, O6-BG enhances the action of Gliadel on tumor cells. In a phase II trial, the median survival of patients treated with localized Carmustine and systemically administered O6-BG showed a greater survival rate than patients treated with Gliadel alone. However, in addition to extending the average survival time of the population, systemic administration of O6-BG combined with local administration of Gliadel also increased the incidence of hydrocephalus, CSF leak, CSF/brain infection, and hematopoietic toxicity. Gliadel usage with Strupp Protocol also has a mechanism of proposed molecular synergism that increases the average survival of patients.