By Debra Wood, RN

Dale Morse momentarily blacked out from a seizure while driving his tow truck, a frightening experience for the Avon Park, Florida, man. But more frightening was the cause of the seizure.

“I have the worst kind of brain cancer known to man,” says Morse, 46, who was diagnosed in May 2000 with a grade 4 glioma—a gliosarcoma, which is a rare type of brain cancer.

Brain tumors often strike without warning, turning a patient’s life upside down. About 18,000 people annually learn they have a primary brain tumor, one that develops in the brain. Another 150,000 will suffer from a metastatic brain tumor, in which cancer cells spread from a cancer located in another part of the body. Less than one-quarter of patients diagnosed with a malignant brain tumor survive five or more years. Median survival for glioblastoma multiforme remains less than one year. For anaplastic astrocytoma, it varies from 18 months to five years. And for low-grade gliomas, median survival improves to five to seven years, says Mark R. Gilbert, MD, associate professor of neurooncology, M. D. Anderson Cancer Center, Houston.

Like Morse, Greg Raver-Lampman has defied the odds. The Norfolk, Virginia, journalist suffered a seizure in 1992, falling and breaking a bone in his back. While doctors initially worried about the fractures, a neurosurgeon in the emergency room focused on the root of the problem—a grade 3 astrocytoma.

“I thought I was going to die,” Raver-Lampman recalls. “I had a 3-year-old and was very worried she would never know her dad. And I felt an overwhelming sense of guilt as though I was abandoning my daughter, more than being afraid of dying.”

Brain tumors represent less than 2% of all cancers, but the nature of the disease and their implications for patients and their families have led to international efforts to improve outcomes. “The approach is evolving,” Dr. Gilbert says. “More and more, we’re looking at taking laboratory discoveries and translating them into better treatments.”

A General Overview

Primary brain tumors develop from cells supporting and surrounding the neurons in the body’s main control center—the brain. Different parts of the brain enable thought, memory, movement, perception of sensations, and essential body functions such as breathing.

Secondary (metastatic) brain tumors occur in about one-fourth of all cancers that spread through the body. Tumors that commonly spread to the brain include lung, breast, and melanoma.

Depending on the tumor’s location, it may produce an array of symptoms as it increases in size and creates pressure within the skull, damages certain parts of the brain, or blocks the flow of cerebrospinal fluid.

Some patients will complain of headache, often at night or upon awaking in the morning. It may worsen with coughing or straining. Headache may be accompanied by nausea and vomiting. Seizures, such as those that affected
Morse and Raver-Lampman, result from disruption of normal electrical activity in the brain. Other symptoms include behavioral changes and difficulty thinking, communicating, speaking, or walking.

If symptoms are present, the physician will perform a neurological exam, checking reflexes, sensation, movement, balance, and coordination. If a tumor is suspected, the doctor likely will order a CT (computed tomography) scan or MRI (magnetic resonance imaging), which can visualize even small tumors. Specific patterns on the image may provide clues about the lesion, but determining the tumor type requires a biopsy for the purposes of obtaining a tissue sample for pathological examination.

In addition, scientists have identified specific protein patterns of gliomas, making it possible to more accurately classify and predict the aggressiveness of these tumors.

Finding the Right Treatment

Brain tumor patients do have options when it comes to treatment—surgery, chemotherapy, or radiation—with some patients receiving a combination of treatments. Surgery, the most common treatment for brain tumors, requires the neurosurgeon to remove the tumor without damaging healthy tissue in a craniotomy.

“A good surgeon is very much like a thief in the night,” says Keith L. Black, MD, director, Cedars-Sinai Maxine Dunitz Neurosurgical Institute, and director of neurosurgery, Cedars-Sinai Medical Center, Los Angeles. “He wants to sneak in and take the tumor out without the brain realizing he has been there.”

Morse and Raver-Lampman underwent surgery soon after diagnosis. Eliminating the tumor offers the greatest chance of survival and can relieve symptoms. “The location of the tumor clearly is a major determining factor as to what can be done,” says Marc C. Chamberlain, MD, professor of neurology and neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles. “The brain, unlike other organs, has eloquent regions that don’t always permit an aggressive surgical resection.”

New technologies and navigational systems linked to CT or MRI aid neurosurgeons during the surgical procedure. Images are taken during surgery to better define the extent of the tumor and help surgeons avoid areas controlling critical functions.

“It improves our ability to get real-time updates of the surgical resection,” Dr. Black says. “It allows us to make sure we’ve removed all of the tumor and haven’t left 10 percent or 15 percent of the tumor behind.”

Other tools exist in surgeons’ arsenals to help decrease risk of postsurgical problems. Though most craniotomies are performed under general anesthesia, intraoperative brain mapping lets the operating team wake the patient long enough to test speech or movement and determine the exact location for their control.

In a promising, although still experimental technique, Dr. Black says physicians at Cedars-Sinai Medical Center in Los Angeles are investigating the use of natural fluorescence to differentiate between normal and tumor tissue. Knowing what is healthy and not will help surgeons remove as much as possible without complications.

Raver-Lampman suffered no major deficits related to surgery. It took about a year for him to resume writing, but sometimes retrieving the right word still poses difficulty.

Zapping the Tumor

Limited-field radiation therapy and chemotherapy typically follow surgery to kill cancer cells left behind. The patient receives a small daily dose of radiation for about six weeks. The beams also damage normal cells and can leave patients with significantly altered functioning. In addition, dead tissue, called radiation necrosis, might form at the tumor site years after treatment.

Radiosurgery may be used instead of surgery if the tumor is inoperable because it lies too close to critical areas of the brain. Morse underwent a second surgery in 2000 after unsuccessful radiation, followed by gamma ray treatments in January 2001 and November 2003.

Leksell Gamma Knife® (see CURE, Fall 2002) is the best-known radiosurgical tool. Others ways of delivering targeted radiation include the linear accelerator (LINAC) and CyberKnife®.

With Gamma Knife, a frame attached to the skull holds the patient’s head still. An MRI provides high-resolution images that aid physicians in plotting delivery of 201 beams of high-intensity radiation to the tumor, leaving most normal tissue unharmed.

“Where all those beams meet is extremely intense, and it is able to kill whatever is at that point,” says neurosurgeon Melvin Field, MD, Florida Hospital Neuroscience Institute, Orlando.

The patient usually goes home the same day. The tumor typically shrinks over a period of weeks and months. However, there are certain criteria to be considered for radiosurgery, which can include size of tumor, number of tumors, and the patient’s functional status.

As with surgery, stereotactic radiosurgery can produce neurological deficits, depending on the tumor’s location. Dr. Chamberlain says stereotactic radiosurgery’s role following an initial surgery for malignant gliomas remains investigational because the only randomized cooperative group study did not show benefit. However, research tends to support its effectiveness in treatment recurrences and for metastatic lesions.

Drug Therapy

Chemotherapy drugs have difficulty reaching the brain because of the blood-brain barrier, which protects the brain and prevents certain molecules from passing through.

Direct delivery of chemotherapy agents to the tumor provides an attractive alternative. In some situations, neurosurgeons may place disc-shaped drug wafers called Gliadel® Wafers in the cavity created during removal of the tumor. In early 2003, the U.S. Food and Drug Administration (FDA) approved the wafer for use at time of inital surgery for newly diagnosed high-grade malignant glioma patients.

“The benefits are very modest, measured in weeks,” says Dr. Chamberlain. And using the wafer adds about $10,000 to the cost of surgery.

Research continues to determine if increasing the dose will improve results. Other scientists are investigating using a wafer-delivery system with different drugs. Researchers also are exploring injection of agents into the tumor during the surgery or through catheters placed during the operation.

The most commonly used chemotherapeutic agents are alkylating agents, particularly nitrosoureas. Patients with brain tumors frequently receive the nitrosourea drugs carmustine (BCNU), the active agent in Gliadel Wafers, and lomustine (CCNU). (The value of the wafer has never been directly compared to intravenous BCNU.) Oligodendrogliomas, especially those with a particular molecular makeup, can be highly responsive to chemotherapy with PCV (procarbazine, CCNU, and vincristine).

Temodar® (temozolomide) crosses the blood-brain barrier and is the most widely used chemotherapy agent for brain tumors in the world, says Dr. Gilbert. The FDA approved Temodar for treating anaplastic astrocytomas not responding to other treatments. Approved in 1999, Temodar was the first new chemotherapy agent for brain tumors approved by the FDA in 20 years. Side effects may include nausea, vomiting, fatigue, and constipation.

“It’s oral, easy to take, and patients tolerate it extremely well,” Dr. Gilbert says. “We’ve given it for as long as three years. Patients take it as long as it keeps working.”

Emerging Treatments

Although five-year survival rates for brain cancer have increased since the 1970s, researchers are not letting up on their quest to find new, more effective treatments. Calling this the molecular-biologic era, Dr. Gilbert says scientists now better understand how tumor cells function, which should lead to greater advances in the next five to 10 years.

Drugs that interfere with signaling pathways needed by tumor cells to grow represent one exciting area of research. These types of drugs, called epidermal growth factor inhibitors, have led to successful treatment of other cancers, such as childhood leukemia. But unlike that disease, brain tumors typically have multiple mutations and may require more than one drug, each targeted at a specific signaling pathway.

Examples of signal-blocking agents include:

Tarceva™ (erlotinib) Granted FDA orphan drug designation in August 2003 for patients with malignant glioma, a recent study of Tarceva found 16% of malignant glioma patients who were given Tarceva alone or in combination with Temodar showed tumor shrinkage. The main side effect was an acne-like rash.

Iressa™ (gefitinib) Already approved for non—small-cell lung cancer that has progressed, a recent phase II trial of Iressa in patients with relapsed glioblastoma resulted in one of 52 patients achieving a partial response and 22 patients achieving stable disease. Side effects were limited to rash and diarrhea.

Zarnestra® (tipifarnib) In addition to early-phase trials of Zarnestra for brain tumors, the drug is also being studied in patients with leukemia and breast or lung cancers.

Another advance is the ability to profile the molecular characteristics of each patient’s tumor, which down the road will allow physicians to customize therapies, using only those proven to work on the patient’s tumor cells. Such tailored treatments will help doctors overcome the challenges associated with the many different types of brain tumors.

Darell Bigner, MD, PhD, deputy director, Duke Comprehensive Cancer Center, is investigating 81C6, an antitenascin radioactive monoclonal antibody treatment that is injected into a cavity created by the neurosurgeon after removal of the tumor. The antibodies deliver radiation to kill the tumor cells with less radiation to normal brain tissue than conventional radiotherapy.

More than 400 patients have received the antitenascin radiolabeled monoclonal therapy during early clinical trials. In a phase I study, the median survival rate for patients with recurrent glioblastomas was 59 weeks, twice as high as patients receiving only surgery. Dr. Bigner has seen similar rates in phase II trials.

Treatment with radioactive antibodies can produce radiation necrosis, but it occurs at a lower rate than with brachytherapy (placing radioactive seeds near the tumor) or stereotactic radiosurgery. Duke researchers must forge an alliance with a commercial partner before proceeding with trials needed to obtain FDA approval.

Once Initial Therapy Ends

Patients should undergo imaging to check for recurrences every two to three months, says David A. Diamond, MD, Florida Hospital Cancer Institute, Orlando.

“We know these things almost always will come back,” Dr. Diamond says. “The key is aggressive surveillance so that when there is evidence of recurrence, you detect it when it is small—you can do something about it.”

Morse hopes his next MRI shows progress in fighting the recurring tumors. Cancer forced him to give up his tow-trucking business, but he maintains a pragmatic “let’s-just-get-it-done” approach.

Even after more than a decade, Raver-Lampman accepts that his cancer may return any time. He says he makes the most of every day and plans to travel and spend time with his family.

“Whatever the doctors tell you, you can take control of your own life,” he says. “Never give up hope and never give in. I’ve enjoyed the best years of my life since this diagnosis. I’ve lived much more consciously.”