Indian Journal of Cancer Medknow Publications on behalf of Indian Cancer Society ISSN: 0019-509X EISSN: 1998-4774 Vol. 48, Num. 1, 2011, pp. 11-17

Indian Journal of Cancer, Vol. 48, No. 1, January-March, 2011, pp. 11-17

Symposium

Brain tumor and Gliadel wafer treatment

M Panigrahi¹, PK Das², PM Parikh³

¹ Department of Neurosurgery, Krishna Institute of Medical Sciences, Secunderabad, India
² Department of Medical Oncology, Indraprastha Apollo Hospital, New Delhi, India
³ Indian Co-operative Oncology Network, Mumbai, India

Correspondence Address:
P M Parikh
Indian Co-operative Oncology Network, Mumbai
India
purvish1@gmail.com

Abstract

Keywords: Biological therapy, 1,3-bis (2-chloroethyl)-1-nitrosourea or carmustine, brain tumor, chemotherapy, Gliadel wafer, glioblastoma, gliomas, polifeprosan 20

Introduction

Primary malignant brain tumors account for only 2% of all adult cancers, ^[1] but the survival rate in patients with malignant brain tumor is limited. The ontogenesis and management of glioblastoma, the most common type of malignant brain tumor, is one of the greatest challenges faced by oncologists. Nevertheless, advancements in medical research have come up with novel treatment strategies for these tumors and have brought optimism among oncologists.

Glioma

Gliomas are tumors that arise from the glial or supportive cells in the brain. They are the most common type of primary brain tumors and consist of 30% of all primary brain tumors. They are malignant with poor prognosis in most cases. The most common type of glioma is astrocytoma. The tumor is formed in the astrocytes that are star shaped cells. The function of astrocytes is providing nutrients, support and insulation to the neurons. Astrocytes also maintain the blood-brain barrier of the body that protects the brain from potentially dangerous substances, for example, virus and bacteria. In adults, astrocytomas are commonly found in the cerebrum, whereas in children they are found in the brain stem, cerebrum and cerebellum. According to the degree of malignancy, astrocytomas are classified into four types: pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma and glioblastoma ^[2],[3] [Table - 1].

Glioblastoma or grade IV astrocytoma, also known as glioblastoma multiforme (GBM), is the most common and aggressive form of glioma, claiming the lives of patients within an average of 1 year following diagnosis.^[4] About 50% of the gliomas are glioblastomas. It is most common in adults and commonly found in the cerebrum. It accounts for 60% of primary brain tumors with an annual incidence of 74,000 cases worldwide and 10,000 cases in the USA. Despite recent achievements in targeted therapeutics in oncology, management of patients with GBM is a tough challenge. Unraveling the biology of glioblastoma and its targeted therapeutics are areas of immense interest to the brain tumor research community. A multidisciplinary research approach is taken for the treatment of glioblastoma to identify environmental, occupational, familial, and genetic factors responsible for the disease. Scientists have identified abnormalities in chromosomes 10 and 17 in patients with GBM. But what causes this abnormality is still unknown. All glioblastomas do not show the same abnormalities. Hence, more treatment options are needed for this fatal form of cancer and scientists are exploring biological differences in glioblastoma as the basis for new treatments.

Current Trends and New Strategies in Brain Tumor Therapy

Diagnosing a clinical problem and finding a successful solution to it is one of the greatest satisfactions of medical practice. Survival after diagnosis of GBM is about 1 year. Personal or local experience of a physician has always been helpful in treating malignant brain tumors. Medical research in oncology has led to a large number of literature resources that are also available to the physicians. But identifying the best treatment strategy for anaplastic astrocytoma and GBM (the most common types of malignant brain tumors) is nevertheless challenging. In recent times, creation of guidelines for management of diseases has become increasing popular in medicine. These guidelines are especially useful in managing deadly diseases that do not have a cure, like GBM.

Surgery is the standard treatment strategy for high-grade malignant gliomas like GBM, once the exact location of the tumor is confirmed. High-powered microscopes assist the neurosurgeon to get a better view of the tumor. Brain mapping and functional magnetic resonance imaging (fMRI) are some of the tools used by the neurosurgeon to map the vital areas of the brain so as to avoid them during surgery. Stereotactic computerized equipment and image-guided techniques guide the surgeon′s access to the deeper areas in the brain. Ultrasonic aspirators are used to break up and suction out the tumor. Sometimes, lasers are used to vaporize tumor cells. The tumor tissue is used for diagnosis and subsequent treatment follows. In certain medical conditions where surgery is not possible, most likely due to a strategic location of the tumor, a biopsy is done and the tumor tissue is used to confirm diagnosis. Radiation and chemotherapy are administered if necessary. The aim of the surgery is to remove most of the tumor. But in most cases, it cannot remove the tumor completely because the tumor tends to spread into surrounding tissues. Hence, radiation therapy normally follows surgery to treat the remaining tumor.

Radiation is aimed at the tumor site and surrounding areas. The doses, schedules and techniques vary. Radiation treatment may be also given by placing radioactive material directly on the tumor (interstitial radiation). In order to potentiate the effectiveness of radiation therapy, drugs are also used. Monoclonal antibodies may also be used to locate tumor cells and deliver radioactive tumor-killing substances such as radioactive iodine to the tumor site, without harming normal cells. This technique, like many other radiation techniques, is still under investigation. Sometimes, MRI or computed tomography (CT) scans taken after radiation and chemotherapy treatment indicate findings that resemble tumor progression that actually may be due to radiation-induced injury. This phenomenon may cause unnecessary changes in an effective therapeutic schedule, which should be avoided. ^[5] More reliable differential diagnosis between neoplasia and radiation injury needs to be established for satisfactory outcome for patients. Guidelines for disease management may be of help in such cases.

Chemotherapy is used often along with radiation therapy in order to relieve the symptoms of brain tumor. However, in infants and young children with brain tumors, chemotherapy is the only therapy. At this young age, radiation therapy is not a preferred treatment. Clinical studies are being carried out in order to establish alternate effective ways to treat brain tumors in infants and children. With the exact cause of glioblastomas still undefined, researchers keep working to find novel ways to treat the deadly disease, and currently there are many drugs that are undergoing clinical trials. Chemotherapy drugs are broadly classified into two groups: cytotoxic and cytostatic. Cytotoxic drugs destroy tumor cells and make them unable to reproduce themselves. Some examples are 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU or carmustine), CCNU (lomustine), procarbazine, cisplatin, temozolomide, and irinotecan. Cytostatic drugs alter the physiological behavior of the tumor. They accomplish this by changing the cellular environment of the tumor. For instance, angiogenesis inhibitors such as bevacizumab, thalidomide and carboxyamidotriazole stop the growth of new blood vessels around a tumor. Cytotoxic and cytostatic drugs are sometimes used in combination for effective treatment. While intravenous chemotherapy administration is the traditional drug delivery system for brain tumors, research is underway to develop innovative ways of drug delivery to the tumor site as the blood-brain barrier hinders most drugs to reach the target tissue upon systemic administration. Paclitaxel-loaded microparticles and lipidic implants can directly be injected into the brain tissue, which release the drugs into the tumor at a pre-determined rate. ^[6] In convection-enhanced delivery (CED), there is a continuous injection of a fluid that contains a therapeutic agent, under positive pressure. However, the delivery devices in this therapy still need further development. ^[7] Another area of ongoing research for GBM treatment is the use of monoclonal antibodies (bevacizumab or Avastin) that may reduce the blood supply to the site of tumor, thereby slowing or disrupting its growth. TransMolecular, an oncology-focused biotechnology company, has developed novel drugs to diagnose and treat human diseases, using a novel tumor-targeting platform called TM601. TM601 is a synthetic version of chlorotoxin, a naturally occurring 36-amino acid peptide derived from scorpion venom, used to carry radioactive material directly to the tumor. It possesses some unique properties that make it a potential antineoplastic agent. TM601 has highly specific tumor cell binding and internalization properties and does not affect the neighboring healthy, normal tissues. TM601 interacts with a protein that is overexpressed on tumor cells. When administered systemically, TM601 has been shown to cross the blood-brain barrier and target tumors. Scientists have used this synthetic venom to deliver small doses of radioactive iodine to brain tumor cells in human patients by attaching it to TM601 that binds to the tumor cells. This technique ensures radiation to be localized to the vicinity of the tumor cells and results in selective killing of the cells. TM601 conjugated to the radioactive isotope ¹³¹ I has a Special Protocol Agreement (SPA) with the Food and Drug Administration (FDA) for a pivotal, Phase 3 trial in newly diagnosed GBM. ^[8],[9]

Biological therapy or immunotherapy is a relatively new therapy used in brain tumor treatment. This therapy uses the body′s own natural responses to get the immune system to recognize and fight cancer cells or to lessen the side effects that may be caused by some other cancer treatments. Its effectiveness to fight brain tumor is still under investigation. Antisense therapy inhibits the formation of the targeted protein involved in the formation of malignancy, through complementary oligonucleotide binding to target mRNA. Animal studies have demonstrated that a combination of immunization and gene delivery of transforming growth factor (TGF)-beta antisense oligonucleotides may be a promising approach for brain tumor therapy. Nanoparticles are useful to deliver antisense oligonucleotides to brain tumors. ^[10] On the other hand, use of protease inhibitors like tamoxifen blocks the ability of the tumor cells to make proteins necessary for cell division. In immunotoxin therapy, a toxin (e.g. Pseudomonas, diphtheria) is linked to an anti-tumor antibody. ^[11] Immunotoxins can locate tumor cells and kill them without harming normal healthy cells. Very recently, a Phase I/II clinical trial sponsored by National Cancer Institute to study the effectiveness of immunotoxin therapy (Cintredekin Besudotox, a recombinant toxin composed of the enzymatically active portion of Pseudomonas exotoxin A conjugated with human IL13) in treating patients who have malignant glioma was completed. Finally, gene therapy is a promising method for controlling tumor growth. This method delivers a cancer-fighting gene to normal brain tissue around the tumor to keep it from spreading. Specially engineered genes can make tumor cells more susceptible to drug therapy or stimulate the body′s natural production of immune substances or are used to restore the normal function of tumor suppressing genes within tumor cells. ^[12]

Cancer vaccines are a novel form of therapy but are controversial. Unlike other vaccines, they are administered to a person after the diagnosis of cancer. To make the vaccine, cells from a patient′s brain tumor are processed. Immune cells isolated from the patient′s blood are exposed to the tumor cells so that the immune cells could learn to recognize the brain tumor cells. Once made, the vaccine is injected under the patient′s skin. Clinical studies have demonstrated that patients with GBM who were given the vaccine survived almost four times as long as patients without the vaccine treatment. It also demonstrated the viability and safety of a vaccine for patients with GBM.

Targeted Drug Delivery of Chemotherapy Agents

The intent of the surgery is maximum removal of the malignant tumor as technically as possible and to reduce the risk of neurological impairment. But the invasive nature of the tumor makes it virtually impossible to remove the whole tumor and microscopic malignant cells still remain at the site. Hence, a trimodal approach of surgery followed by radiation and chemotherapy, administered either orally or intravenously, is common in treating GBM. Nitrosoureas like carmustine and temozolomide are the drugs frequently used in systemic chemotherapy. Temozolomide has emerged as an active chemotherapeutic agent for treating GBM. On the basis of studies by the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada, simultaneous radiotherapy and the oral temozolomide followed by adjuvant temozolomide has become the standard treatment for patients with newly diagnosed GBM. ^[4] Though this therapy has demonstrated low toxicity and promising survival rates, there are still some shortcomings of systemic chemotherapy treatment. The chemotherapeutic agents have difficulty crossing the blood-brain barrier, and often, therapeutic doses of the drug do not reach the tumor site. At the same time, short half-life and systemic side effects such as depletion of white blood cells are common. Moreover, the recurrence of malignant glioblastoma is often local, suggesting the need for a regional therapy. Targeted drug delivery of chemotherapy agents over a 3-4 week period at the level of the tumor bed is now possible via the Gliadel wafer.

Gliadel wafer treatment is the first brain cancer treatment to deliver chemotherapy drugs directly to the tumor site, thus increasing the clinical effectiveness. Animal studies have demonstrated that Gliadel wafers are capable of delivering 1000 times more chemotherapeutic agent (in this case, carmustine) to the tumor site than intravenous injection. The controlled delivery of carmustine from biodegradable polymer wafers enhances the therapeutic ratio by fully containing the drug within the boundaries of the brain tumor while minimizing systemic toxicities. ^[13] This product is the only US FDA approved chemotherapeutic implant for use during surgical procedures for newly diagnosed, high-grade malignant glioma, as well as for patients with recurrent GBM. Gliadel wafer with concurrent temozolomide and radiation followed by rotational chemotherapy is an effective therapy compared with radiation alone. ^[14]

Gliadel Wafer

Two unique features set the Gliadel wafer apart from other drug delivery systems. First, it is a localized drug delivery system that delivers high concentrations of the chemotherapeutic agent directly to the tumor cavity, thereby overcoming the adverse side effects associated with conventional systemic administration. Secondly, Gliadel wafers are biodegradable and dissolve slowly over time releasing high concentrations of the drug in a sustained fashion over an extended time interval. This drug delivery system is manufactured by Guilford Pharmaceuticals, a Baltimore based biopharmaceutical company engaged in the development of polymer-based therapeutics for cancer, and novel products for the diagnosis and treatment of neurological disorders.

Gliadel wafer or polifeprosan 20 with carmustine implant is a dime-sized sterile wafer, approximately 1.45 cm in diameter and 1 mm thick. It is off-white to pale yellow in color. Each wafer is made up of two components: 192.3 mg of polifeprosan 20 and 7.7 mg of carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea, or BCNU]. Polifeprosan 20 is a biodegradable polyanhydride copolymer and consists of poly [bis (p-carboxyphenoxy) propane:sebacic acid] in a 20:80 molar ratio. Its function is to control the local delivery of carmustine. Carmustine is a nitrosourea that is commonly used as a palliative therapy. It is also an antineoplastic agent. It is used in combination with other approved chemotherapeutic agents for treating brain tumors, multiple myeloma, Hodgkin′s disease, and non-Hodgkin′s lymphomas. It is homogeneously distributed in the copolymer matrix. Carmustine is highly lipophilic, and thus crosses the blood-brain barrier readily. Carmustine leads to the inhibition of DNA synthesis, RNA production and protein synthesis by crosslinking with DNA and RNA. It also carbamoylates proteins, including DNA repair enzymes, resulting in an enhanced cytotoxic effect. Gliadel wafer must be stored at or below −20°C (−4°F).

The Gliadel wafers are implanted into the tumor bed following surgical removal of the brain tumor. Up to eight wafers can be implanted in the resection cavity created by tumor removal. However, sometimes, the size and shape of the resection cavity does not allow implantation of eight wafers. In that case, the maximum number of wafers as allowed should be placed. As each wafer contains 7.7 mg of carmustine, it amounts to a total dose of 61.6 mg, with the implantation of eight wafers. The wafers deliver the drug, carmustine, directly to the site of tumor removal. As the wafers dissolve, they release high concentrations of BCNU at the tumor site to destroy residual tumor cells that have not been removed by the surgery. They slowly erode and deliver the drug over a 2-3 week period directly on the tumor site and, at the same time, minimize drug exposure to other areas of the body. While no direct pharmacokinetic measurements have been made in humans after implantation of a carmustine wafer, extensive animal studies have been conducted with respect to drug distribution and clearance at various time points after implantation. Gliadel wafers have been shown to release carmustine in vivo over a period of approximately 5 days. The wafers degrade completely in continuous contact with the interstitial fluid. More than 70% of the polyanhydride copolymer degrades by 3 weeks after implantation, although "wafer remnants" can be detected even several months after implantation. Metabolic elimination studies of the polymer degradation products have demonstrated that sebacic acid monomers are excreted from the body in the form of expired CO ₂ . The 1,3-bis-(p-carboxyphenoxy) propane monomers and carmustine degradation products are excreted primarily through the urine. ^[15] As exposure to carmustine can cause severe burning and hyperpigmentation of the skin, the wafers should be handled with care during implantation. Use of surgical instruments dedicated to the handling of the wafers and use of double surgical gloves are recommended during surgery.

In September 1996, Rhone-Poulenc Rorer Inc. and Guilford Pharmaceuticals Inc. announced that Gliadel 0 wafer, the first commercially available brain cancer treatment to deliver chemotherapy directly to the tumor site, had received clearance from the FDA for use as an adjunct to surgery for recurrent GBM patients for whom surgical resection is indicated. This decision was based on successful clinical trial results. The trial involved 222 patients with recurrent malignant glioma. The Phase III clinical trial was randomized, double-blinded, and placebo-controlled. The clinical trial was conducted at 38 study centers across 14 countries. The study showed that use of Gliadel wafer increased the survival in patients by more than 50%. ^[16] The results of clinical trials have shown that Gliadel wafer significantly prolonged the survival in both newly diagnosed patients and patients with recurrent GBM, when used as an adjunctive therapy to surgery and/or radiation therapy.

In February 2003, the US FDA approved Gliadel wafer for use in newly diagnosed patients with high-grade malignant gliomas as an adjunct to surgery and radiation therapy. This promising treatment is approved in 18 countries worldwide, primarily in North America, Europe, and Southeast Asia. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology refer to the use of Gliadel wafers as part of the treatment strategy for malignant gliomas. Since its launch in 1997, over 20,000 procedures have been performed with Gliadel wafer in the USA alone. There is very little information available on the incidence of brain tumors in India. According to unofficial sources, the estimated incidence of primary brain tumors in India is 2-5 new cases per 100,000 per year, while another source estimates the total number of cases to be around 21,000 per year. A significant 60-65% of these primary brain tumors are GBM. Early this year, Ranbaxy Laboratories received import permission for marketing the US FDA approved Gliadel wafer. The company has signed an exclusive licensing agreement with BioPro Pharmaceutical, USA, to promote and market Gliadel wafer in India.

Gliadel wafer treatment is used as an adjunct to other standard treatments for brain cancer. Studies have shown that temozolomide therapy in addition to Gliadel wafer implantation is associated with a median survival of nearly 21 months without increased perioperative morbidity. ^[17] Temozolomide can be safely given to GBM patients receiving Gliadel wafer treatment after tumor removal. In many cases, it is given for 6-12 months. ^[17] Gliadel is currently approved for use in patients with recurrent glioblastoma as an adjunct to surgery and in newly diagnosed patients with high-grade glioma as an adjunct to surgery and radiation after it was shown to be well tolerated and effective in clinical trials. ^[15]

Side effects

Preclinical and clinical studies have proven the safety and efficacy of gliadel in the management of glioblastoma. Nevertheless, the risks of using Gliadel wafers must be weighed against its beneficial effects. It is important that the physician checks for unwanted effects and makes sure that the medicine is working properly. Gliadel wafer treatment cannot be used on patients who are allergic to carmustine. Animal studies have shown that carmustine in other dosage forms causes birth defects and other problems, hence can cause fetal harm when administered to a pregnant woman. It is also recommended that patients receiving Gliadel wafer discontinue nursing. The presence of other medical problems may also affect the use of carmustine.

Multiple studies have demonstrated the successful use of Gliadel wafers in treating patients with malignant gliomas, with hardly any adverse effects. As it delivers the drug directly at the tumor site, it also minimizes drug levels elsewhere in the body. A 10-year institutional study to characterize Gliadel wafer associated morbidity showed that Gliadel wafer use was not associated with an increase in perioperative morbidity after surgical treatment of malignant astrocytoma. ^[18] However, Phase III studies have indicated local side effects with Gliadel wafer treatment in comparison to placebo treatment. The most common side effects of Gliadel wafer which were observed during clinical trials included seizures, brain edema, wound healing problems and intracranial infections. It was observed that patients receiving Gliadel wafer had a much earlier onset of seizures than the placebo group, but the incidence of seizures was the same as in the placebo. There have also been reports of significant ipsilateral cerebral edema and progressive neurological deficit post Gliadel wafer treatment. Hence, it is important to recognize two things when using this product: first, the need for use of high-dose corticosteroids early and continue them as needed to prevent cerebral edema, and second, the criticality of the time at which the cerebral edema presents clinically.^[19] Early presentation may require medical management only, while in the occurrence of late presentation, one may consider surgical management if initial medical management fails. There is an ongoing clinical study to determine the safety and efficacy of the combination of Gliadel wafers plus surgery and limited field radiation therapy with concomitant temozolomide followed by temozolomide given at an extended dose schedule (metronomic schedule) in patients undergoing initial surgery for newly diagnosed high-grade glioma.

Conclusions

Among approximately 20,000 primary brain tumors diagnosed in the USA each year, GBM is the most common type. It is the most devastating neoplasm and claims the life of a patient within a year of diagnosis. There is a gloomy and pessimistic attitude toward its diagnosis. The cause of malignant glioma is unknown and it is a poorly understood form of cancer. Patients with this type of cancer usually undergo surgery, traditional chemotherapy and radiation therapy, but in many cases, the cancer returns. However, scientific and medical research developments in the field of cell biology and molecular biology have helped in the better understanding of tumor biology. The aim of cancer therapeutics has become streamlined to target more specific biological pathways, genetic components, and/or cellular proteins. This has resulted in the evolution of innovative treatment strategies with new drugs that target steps in the molecular pathogenesis of the tumor. However, there are others strategies that use standard brain tumor drugs which are delivered in a different way and are more effective. A good example is use of Gliadel wafers. Gliadel wafer treatment has become increasingly popular for treating patients with GBM. It is clinically effective and has demonstrated significant increase in the overall survival rate in glioblastoma patients. The biodegradable wafers deliver the chemotherapeutic drug carmustine directly to the tumor site post surgery. It is the first FDA approved chemotherapeutic implant for use in newly diagnosed patients with high-grade malignant gliomas, as an adjunct to surgery and radiation therapy. While molecular targeted therapy and immunotherapy require more clinical development and are still under investigation, Gliadel wafer treatment provides a silver lining for glioblastoma patients and brings optimism to oncologists.

References

Copyright 2011 - Indian Journal of Cancer

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