Overview

Recent medical advances have led to new clinical trials for the treatment of brain tumors. One such advance is gene therapy. This therapy is being used for glioblastoma multiforme, a malignant, rapidly growing tumor of the brain that is difficult to treat. The effectiveness of this new therapy is being studied in clinical trials with adults and children. The following information explains more about gene therapy and participation in a clinical trial.

What treatments are available for glioblastoma multiforme?

The goal of treatment is to stop the growth of the glioblastoma. Conventional treatment for this tumor includes a combination of surgery, radiation, and chemotherapy.

Despite the use of these conventional treatments, many glioblastomas continue to grow. For this reason, investigational treatments, such as gene therapy, have been developed that offer new approaches for this malignant brain tumor.

The best treatment varies for each patient. Treatment depends on the size and location of the tumor, and the patient's age and overall health.

What is gene therapy?

Gene therapy is an investigational treatment for glioblastoma multiforme. In the laboratory, cells are specially treated for injection into patients with brain tumors (Figure 1).

With gene therapy, cells from a mouse are genetically altered to carry a harmless virus. During surgery to remove the tumor, these altered cells (vector-producer cells) are injected into the surrounding brain. The altered cells produce a harmless virus that carries a "suicide gene" to remaining tumor cells. When a tumor cell incorporates the suicide gene, it becomes sensitive to an anti-viral drug (ganciclovir), which is administered several weeks later. Because of this sensitivity, the tumor cells, which are actively dividing, are destroyed. Therefore, healthy brain cells, which do not divide, are normally unaffected. Thus, gene therapy should halt the growth of a glioblastoma multiforme.

Who should undergo gene therapy?

Gene therapy is being used in clinical trials for adults and children with glioblastoma multiforme. Your physician will discuss treatment options if the magnetic resonance imaging (MRI) scan detects a glioblastoma multiforme. Additionally, the tumor must be accessible by surgery and must have been treated only with medications.

What happens before undergoing gene therapy?

Patients interested in enrollment in a gene therapy trial review a consent form that describes the procedure, benefits, risks, discomforts, and precautions. Agreement to participate is not legally binding ­ a patient can withdraw from the study at any time.

Next, the patient undergoes a screening process to determine eligibility. Screening includes a neurologic examination, physical examination, Karnofsky assessment (ability to care for one's self), and laboratory tests to determine overall health. An eletrocardiogram is also performed.

Preparing for treatment

Patients in a gene therapy trial are assigned randomly to undergo one of two treatments: 1) surgical treatment for the removal of the tumor followed by gene therapy or 2) surgical treatment for the removal of the tumor without gene therapy.

Surgical treatment with gene therapy

Step 1 Tumor removal
In the operating room, the patient receives general anesthesia and is positioned on the operative table. The surgeon makes a skin incision and performs a craniotomy, which temporarily removes a piece of skull to expose the brain (Figure 2). After exposing the brain, the surgeon removes as much of the tumor as possible (Figure 3). A pathologist samples the brain tumor tissue to confirm that it is a glioblastoma.

Step 2 Injection of gene therapy
The surgeon identifies the margin of the tumor cavity. Any accessible and remaining tumor is injected with a small amount of the gene therapy, that is, the genetically altered cells or vector-producer cells (Figure 4). The craniotomy and skin incision are closed.

Step 3 Recovery from the operation
After 1 or 2 days in the Intensive Care Unit, the patient continues recovery in the neurosurgical ward. Within 2 days after surgery, the patient undergoes an MRI scan to detect any remnants of tumor. Patients are typically discharged from the hospital 4 days after the operation.

Step 4 Administration of ganciclovir
Two weeks after surgery, ganciclovir is given intravenously (in the arm) twice daily (Figure 5). A home health nurse administers the first dose and teaches a family member how to administer remaining doses of medication.

Step 5 Radiation treatment
Two to 3 weeks after surgery, the patient begins radiation treatment of the tumor site on outpatient visits to the hospital. Radiation directs high energy beams to the remaining cancer cells (Figure 6). The treatment period is generally 5 days a week for 6 to 7 weeks.

Conventional surgical treatment

Patients undergoing conventional surgical treatment, that is without gene therapy, will undergo Steps 1, 3, and 5 described above.

What happens after the treatment?

The patient's physician monitors overall progress. During the first year, an MRI scan is performed about every 2 months. These imaging studies will decrease in frequency over time.

What are the results of gene therapy?

The combination of surgical treatment and radiation has improved survival in patients with glioblastoma. Chemotherapy is used to kill tumor cells that are rapidly growing. However, it is unknown how gene therapy in combination with surgery and radiation may affect the growth of the brain tumors.

Gene therapy has been promising in animal studies and in early trials with patients in whom conventional therapies have failed. Its effectiveness in patients is being studied further in clinical trials.

Are there side effects?

Side effects associated with surgical treatment include hemorrhage, seizures, infection, deterioration of neurologic function, and death. Radiation therapy can cause hair loss, skin irritation, nausea, vomiting, and fatigue; permanent neurologic injury from radiation can also occur.

Some of the possible side effects of gene therapy itself are meningitis, which can develop if the gene therapy cells leak into the cerebrospinal fluid. Patients in the clinical trials are closely monitored for any adverse effects.

For more information on gene therapy

Talk to your personal physician about your interest in gene therapy as a possible treatment. If you would like information about this specific gene therapy trial, please call the Study Coordinator at the Mayfield Clinic at (513)558-0353 or (800)325-7787.

Support

Several organizations provide support and services. The American Brain Tumor Association (800-886-2282) provides information on a variety of brain tumors and treatments. The Wellness Community (513-791-4060) provides local support groups, educational workshops, and stress management sessions. Patients and their families can share experiences and learn about advances in treatments.

References

1) Pyles RB, Warnick RE, Chalk CL, et al.: A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors. Human Gene Therapy 8:533-544, 1997.

2) Berger MS, Prados M, Van Gilder JC, et al.: Gene therapy for the treatment of recurrent glioblastoma multiforme with in vivo transduction using the herpes simplex-thymiine kinase gene/ganciclovir system. J Neurosurg 86:378A-379A, 1997.

Glossary

Cerebrospinal fluid: fluid in the brain and around the spinal cord.

Clinical trial: a study that tests a new and potentially beneficial treatment in patients.

Gene: a piece of DNA, the coded information of the cell that controls the production of a protein. Each protein has a particular function within the cell.

Glioblastoma multiforme: a rapidly growing tumor that arises from the supporting cells of the brain.

Magnetic resonance scan: a large magnet, radio waves, and a computer produce detailed pictures of soft tissues, such as brain.

Neurological deficit: a loss of normal function in some part of the nervous system. Examples are weakness or loss of sensation, or loss of speech, memory, or comprehension.

Suicide gene: a gene that leads to the death of the tumor cell when exposed to a particular medication.

Vector-producer cell: mouse cells that are genetically altered to become factories for the production of a harmless virus. The virus carries the suicide gene to any tumor cells that remain after surgical treatment.

Questions to ask your doctor

1) Am I a candidate to undergo gene therapy?

2) What other treatments should I consider?

3) When and where are the steps of the gene therapy trial performed?

4) Can gene therapy injure my brain? Will treatment affect the way I think, feel, or look?

5) Will I have side effects from the treatment?

6) Can I go back to work or my daily routine?

7) If my tumor comes back, what options are available?

8) How long will I remain in the study?

9)What costs does insurance cover?

updated: 6.2004

 

 

 

 

 

 

 

 

 

 


Figure 1. Every cell in the body contains genetic material called DNA in the form of chromosomes. The DNA carries thousands of instructions, called genes,
for normal cell growth and function. For gene therapy, a piece of DNA is altered to change its normal cell function.

 

 

 

 

 

 

 

 

 

 

 


Figure 2. The patient undergoes surgical treatment to remove a glioblastoma.


Figure 3. After exposing the tumor, the surgeon removes as much tumor as possible, leaving a shelled-out tumor cavity.


Figure 4. The brain surrounding the tumor cavity is injected with the altered cells for gene therapy. This injection makes the tumor cell susceptible to an anti-tumor medication that is administered several weeks later.


Figure 5. Several weeks after the operation, the patient receives an anti-tumor medication called ganciclovir.
A home health nurse administers ganciclovir intravenously.


Figure 6. Radiation beams are directed to the remaining cancer cells at the tumor margin.