Malignant brain tumors are a relatively uncommon cancer, making up only about 1.5 percent of all forms of cancer. However, the most severe type of brain tumor, a glioblastoma, or GBM, is nearly uniformly fatal.
GBM is the brain tumor that in August ended the life of Sen. Ted Kennedy. Gina Kolata and Lawrence Altman focus on glioblastoma in the New York Times article “Weighing Hope and Reality in Kennedy’s Cancer Battle,” on page 6. If we ask whether we are better at treating these tumors than we were five years ago, or even 10, the answer is, “Yes, but not much.”
Glioblastomas are very aggressive tumors: They grow rapidly and diffusely, spreading through normal brain tissue. GBM is like a weed in your garden. You can cut the weed at the surface, but a spread of roots, some quite tiny, remains in the soil. Similarly, these tumors have small extensions in the brain—some are only microscopic. These cannot be removed by surgery without sacrificing a large amount of normal brain tissue, and even then unseen tumor is left behind. So the role of surgery is limited to: 1) obtaining tissue to characterize the tumor, a procedure called a biopsy; and 2) removing as much of the tumor as can be done safely, without causing further neurological damage. Surgery does not cure these tumors.
Radiation, introduced and evaluated about 30 years ago, was the first addition to surgery. The techniques have changed so that radiation can be directed much more precisely at the tumor and not the uninvolved brain. Taken alone, its value is limited, extending life for a few months.
The next step was the addition of chemotherapy, which has involved various agents over the years. The current drug of choice is temozolomide (Temodar), a drug that is taken by mouth and alters the tumor cells’ DNA to induce tumor-cell death. In the last year bevacizumab (Avastin), a drug used for many other cancers, has earned FDA approval for use in brain tumors. Avastin is different from most chemotherapeutic agents in that it is an antibody that affects the blood vessels of tumors, rather than a chemical agent that directly poisons tumor cells. It is still too early to say whether this addition to therapy will be a significant advance. While therapy directed against tumor blood vessels may limit tumor growth, its efficacy against the microscopic invading tumor cells is unclear.
Patients’ own circumstances also make a difference in how they fare with these tumors. Favorable factors include being younger; early tumor detection, with less neurological impairment; safe removal during the initial surgery of all tumor that was visible using magnetic resonance imaging; and the presence in the tumor of inherent genetic markers that are associated with longer survival.
Other factors make these tumors difficult to treat. Tumors are often large and advanced by the time they are diagnosed, and the cells of the tumor are resistant to chemotherapy. Many treatment components such as chemicals and antibodies do not reach the brain as well as they reach other organs. Normal brain tissue is sensitive to both radiation and chemicals, and the microscopic spread of tumor cells makes the true boundary of the tumor impossible to determine.
The current state of therapy is that regardless of which medical center is involved in a person’s care, the initial conventional approaches of surgery, radiation and chemotherapy are very similar. This field desperately needs new ideas and applications, such as the use of Avastin.
Many medical centers are participating in clinical trials of new treatment agents and combinations of agents. Other examples of new clinical trial approaches include creating anti-tumor vaccines using the patient’s immune cells to generate an immune response against the surgically removed tumor; delivering specific agents that block growth factors used by the tumor to grow; and administering chemotherapy directly into the area of brain invaded by tumor using a process called convection-enhanced delivery.
As scientific advisors at the Dana Foundation, Dr. Ralph Steinman, a world-class immunologist, and I have recognized the need for ingenuity and have initiated a grant program asking for new approaches to brain tumor therapy. The program is just starting, but the responses from our colleagues have been encouraging.
Patients can help, too. Few patients get involved in clinical trials, even though present therapies are so limited. The only way we will be able to evaluate new approaches is to study them in human patients, as there is no satisfactory animal model that can do more than suggest that something might help. If there is one area where participation in clinical trials is crucial, this is it.