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Key words
Brain tumor, malignant glioma, surgery, radiation therapy, chemotherapy

Summary
Many patients diagnosed with malignant gliomas between 1997 and 2000 received treatment that did not conform with established practice guidelines for the care of adults with this type of brain tumor, according to a new study.

Source
Journal of the American Medical Association, February 2, 2005 (see the journal abstract).

Background
Malignant gliomas are the most common primary brain tumor, accounting for more than half of the more than 18,000 primary malignant brain tumors diagnosed each year in the United States. These tumors are the second-most common cause of cancer death in the 15 to 44 age group.

The outlook for patients with malignant gliomas is poor. Median survival for patients with moderately severe (grade III) malignant gliomas is three to five years. For patients with the most severe, aggressive form of malignant glioma (grade IV glioma or glioblastoma multiforme), median survival is less than a year.

Surgery is recommended for all operable brain tumors and is usually followed by radiation therapy. Several studies have shown that adding chemotherapy to radiation can improve patients' survival. In June 2004, after the completion of the current study, researchers announced that adding the drug temozolomide (Temodar®) to radiation therapy increased median survival in patients with glioblastoma multiforme by about two months (see related story). This approach is now considered the standard of care for the initial treatment of these tumors.

The Study
The Glioma Outcomes Project is a study that tracked how patients with grade III or IV malignant gliomas were treated and what the outcomes of that treatment were. A total of 565 patients with newly diagnosed malignant gliomas were enrolled in the study between 1997 and 2000; 74 percent of these patients had grade IV gliomas.

Patients were treated both at academic medical centers and by community oncologists. Information about their care and its outcomes was collected when patients enrolled, immediately after they had surgery, and at three-month intervals thereafter for two years or until the patient's death, whichever occurred sooner.

The study's lead author is Susan M. Chang, M.D., of the University of California, San Francisco.

Results
The treatment patients received conformed with practice guidelines in some respects and departed from them in others. For example, most patients underwent contrast-enhanced magnetic resonance imaging (MRI) at diagnosis. This imaging test is almost universally accepted as the test of choice for diagnosing malignant glioma.

Also in keeping with practice guidelines, most patients had surgery to remove as much of the tumor as possible, followed by postoperative radiation therapy. However, only 54 percent received chemotherapy, despite the fact that chemotherapy has been shown to improve survival.

Other aspects of patients' care conflicted with best practice recommendations. For example, the American Academy of Neurology (AAN) recommends treating glioma patients with anti-epileptic medications only if they have seizures as a symptom when their tumor is diagnosed. Because these drugs can have severe side effects, the AAN advises against prescribing them routinely to all patients with newly diagnosed malignant gliomas. Nevertheless, nearly 90 percent of patients in this study received anti-epileptic medications, although only 32 percent had seizures.

Several areas of patients' care reflected a lack of agreement on best practice. For example, studies of the safety and effectiveness of giving low-dose anticoagulants to prevent post-surgical blood clotting in glioma patients have produced conflicting findings. In this study, only 7 percent of patients received preventive anticoagulants, although as many as 60 percent developed blood clots within six weeks of surgery.

Thirteen percent of newly diagnosed patients reported symptoms of depression. However, only 28.6 percent of these patients received antidepressant medications. Patients' doctors may have been concerned about the possible side effects of giving antidepressants to patients who were also taking anti-epileptic medications, the study authors say. The likelihood of such adverse effects is not known.

Almost all patients received corticosteroid medications to reduce neurologic symptoms, although these medications may cause significant adverse effects such as diabetes, high blood pressure, muscle pain, and increased susceptibility to infections.

Limitations
This was an observational study, not a prospective clinical trial. (See Which Study Results Are the Most Helpful in Making Cancer Care Decisions? for an explanation of how observational studies differ from clinical trials.)

Patients in this study were diagnosed between 1997 and 2000, a time when there was little consensus about the best approach to treating newly diagnosed malignant gliomas, comments Howard Fine, M.D., Chief of the Neuro-Oncology Branch at the National Cancer Institute's (NCI's) Center for Cancer Research and the National Institute of Neurological Disorders and Stroke.

That situation has changed, particularly since the release of the temozolomide findings in 2004, he says. Surgery plus radiation therapy plus temozolomide chemotherapy is now the established standard of care in the United States for all patients with newly diagnosed grade III or IV malignant gliomas.

Comments
"The data presented [in this study] suggest that current clinical practice does not follow guidelines or evidence," write Paul Graham Fisher, M.D., and Patrician A. Buffler, M.D., in an accompanying editorial.

What's more, note the study's authors, "Variations in patterns of care were associated with differences in survival." Additional practice guidelines may help to reduce this variability, they suggest. Further research is needed to clarify the value of anticoagulants, antidepressants, and corticosteroids in the treatment of glioma patients, they add.

To ensure that they receive care consistent with current best practices, patients with a diagnosis of malignant glioma should always obtain a second opinion from a brain tumor specialty center, advises Fine. NCI supports brain tumor specialty centers around the country; some centers specialize in treating adults while others specialize in treating children.

Patients should also consider enrolling in a clinical trial, adds Fine. The Neuro-Oncology Branch offers free consultations and can provide information about NCI-directed and NCI-supported clinical trials around the country that are currently accepting patients.

To obtain information about clinical trials or treatment for glioma patients, call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) or call the Neuro-Oncology Branch directly at 301-402-6298.

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