By Don M. Long, M.D., Ph.D., distinguished service professor in the department of neurology, The Johns Hopkins Hospital
Treating gliomas is difficult, but new and experimental treatments are extending the time people who develop these brain cancers can expect to survive. And treatments now in the lab and early testing have doctors and patients talking of cure.
Gliomas are tumors derived from cells in the brain called glia, which maintain and nourish nerve cells. As with other types of cancer, cancers of the glia are classified by type and by severity, but for gliomas the familiar words “malignant” and “benign” have a different meaning.
Some cancers of other organs are called malignant because they cause death by spreading throughout the body. Brain tumors rarely spread in this way. For brain tumors, the word malignant means they cause death because they grow (or grow back) rapidly in the same place where they originate, not because they affect other organs. The most malignant tumors are called glioblastoma multiforme. Less rapidly growing tumors look different under a microscope and are called anaplastic astrocytomas. The third type is benign astrocytomas. Another way to grade the tumors is by numbering: Grades 1 and 2 are benign; though 2 grows faster than 1; grade 3 is malignant but not the worst; grade 4 (the glioblastoma) is the most malignant.
Elsewhere in the body benign tumors can be cured by completely removing the tumor and, sometimes, a bit of the healthy tissue surrounding the tumor just to be sure. This does not often work for brain tumors for two reasons: In the brain, the location of the tumor often means even benign tumors cannot be removed without unacceptable damage to the patient. These tumors also infiltrate normal brain tissue; if all affected brain tissue were removed, the person would suffer severe neurological injury, making the cure as bad as the disease.
Thus, “benign” in brain tumors often doesn’t mean curable, but only that cancer’s growth will be slower. Patients may live for years with benign gliomas, but malignant astrocytomas and glioblastomas are usually fatal within two years with treatment and often within weeks if untreated.
Early work: Drugs and radiation
Harvey Cushing, the founder of neurosurgery, and his famous neuropathology colleagues Louise Eisenhardt and Orville Bailey, were the first to categorize gliomas into an understandable scheme. For some 30 years after the first attempt to remove a glioma (by Rickman Godlee in London in 1884), neurosurgeons could remove the tumors only partially to provide temporary relief. The tumors always recurred and nearly all patients died.
In the early 1960s Joseph Galicich, Lyle French and I (with several collaborators) introduced a new drug, dexamethasone, to treat the swelling of the brain that often surrounds this tumors. The brain swells because fluids leaks from the tumor and the injured sections throughout blood vessels into the normal brain. This cerebral edema may be a more serious, acute problem than the tumor itself, because the area of swollen brain can be bigger than the tumor. Brain tumor patients often die from the edema, not the tumor.
Treatment with steroids such as dexamethosone shrinks the swelling. Steroids can dramatically reduce swelling, providing both extra time and brain protection for other treatments. Steroid treatment was the first great breakthrough to help patients with malignant tumors.
Edema, steroids and removing at least some of the tumor are all important because the skull is a closed box with limited capacity. As the tumor grows and the brain swells, the pressure in the box (skull) goes up, leading to severe headache, coma and death. At least partial removal of the tumor and shrinking the swollen brain prevents this progression. Patients improve, and there is time to try other treatments.
The next major advance came in 1978 when Michael Walker, who directed the Baltimore Brain Tumor Research Center, and his colleagues proved that radiation treatments (X-ray therapy) significantly prolonged life for patients with malignant astrocytomas. Then standard treatment became steroids, surgery to remove as much tumor as safe, followed by radiation.
Zeroing in on the tumor itself
During the late 1960s, throughout the ’70s and for most of the ’80s, brain tumor therapy research focused on trying new drugs to kill tumor cells. This approach was showing definite progress with many kinds of cancers but for the most part failed with malignant gliomas.
After watching many of these trials fail, only to be repeated with more of the same drug and fail again, I decided in 1982 that the newly founded John Hopkins Neuro-oncology Center should explore new approaches. I was fortunate to recruit Dr. Henry Brem to head the new center. Henry had been a fellow in neurosurgery and ophthalmology at Hopkins earlier in his career. He was finishing neurosurgery training at The New York Neurological Institute at Columbia and came with two revolutionary new ideas:
Anti-angiogenesis: “Angiogenesis” is the creation of new blood vessels. Attacking tumors by preventing the growth of blood vessels they need to feed and grow was proposed in 1971 by Judah Folkman of Harvard and has been intensely studied by Dr. Brem and many others. Promising new therapies are now appearing.
Prolonged local chemotherapy: The concept of local therapy (delivered directly at the tumor site) as opposed to systemic chemotherapy (delivered through the bloodstream to the tumor) was original to Dr. Brem and Dr. Robert Langer, who in the mid-1970s invented the polymer substrates that make slow-release local chemotherapy possible. After extensive clinical trials, in 1995 Dr. Brem and many collaborators showed that Gliadel (the local anti-cancer agent) significantly prolonged life after surgery for patients with glioblastoma.
Now, surgery for tumor removal that is as complete as possible, radiation, and Gliadel all are standard therapies. A new drug, Temodar, also is effective and looks promising as both an adjunct and alternative to Gliadel.
In spite of these advances, malignant gliomas still are dangerous tumors and most patients will not survive them beyond a few years. Benign gliomas slowly grow, producing disabilities, and eventually are also fatal. Surgery might extend survival 9 or 10 months. Gliadel extends this by two to three months, on average. But there is a little more hope now—and there is a small group of people who survive much longer.
Current therapy provides at least some hope of meaningful survival and cure. Still it is clear that we need more effective treatment for gliomas of all kinds. Development of better therapies is critical.
There are some new avenues of treatment that appear to be especially promising (see sidebar stories). There also are newer forms of radiation that may be helpful. The Gamma Knife, the Cyber Knife and a focused linear accelerator beam are examples of radiation therapies that can closely target the tumor, delivering less (or no) radiation to the surrounding normal brain. The use of radiation with protons has been restricted to two centers but soon will be available commercially. Much research is under way in how to make tumor cells more sensitive to radiation. All have great promise to improve outcomes for patients with gliomas.
I think the genetic approaches exemplified by the work of Dr. Lesniak (first sidebar) and the novel techniques described by Dr. Gallia (second sidebar) are excellent examples of the future for treatment of malignant (and other) gliomas. Identifying and mass producing viral vectors that are safe is key to effective gene therapy in this area. Vaccines might become reality. More research with local delivery of improved drugs should follow Gliadel. Some or all of these newest concepts soon should offer more regular, dramatic successes than we see now.
Surgery, steroids, radiation therapy and local chemotherapy have all improved survival rates by small increments. A universally fatal disease has become treatable, with hope of cure for some. It is likely that the new treatments will provide a much greater chance of cure for all.