Silenced Gene May Make Temozolomide More Effective for Some Brain Cancer PatientsKey Words
Brain tumor, glioblastoma multiforme, malignant glioma, temozolomide (Temodar®). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
In 2004, a clinical trial confirmed that adding the drug temozolomide to radiation therapy for the treatment of a brain tumor called glioblastoma multiforme helped more patients to live longer. In this related study, researchers report that most of the patients who survived longer on temozolomide had tumors in which a particular gene was turned off. Though this finding is too preliminary to be used as a way to determine which patients should receive temozolomide, the results are a step in that direction.
Source
New England Journal of Medicine, March 10, 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.
The outlook for patients with these tumors is poor. Median survival for patients with moderately severe (grade III) malignant gliomas is three to five years. For patients with the most severe form of malignant glioma (grade IV glioma or glioblastoma multiforme), median survival is less than a year.
In June 2004, researchers announced the results of a large, international, randomized clinical trial in which addition of the drug temozolomide (Temodar®) to radiation therapy increased median survival in patients with glioblastoma multiforme by about two months (see related story). Adding temozolomide to radiation therapy is now considered the standard of care for the initial treatment of these tumors.
Laboratory studies had previously shown that cancer cells that overexpress (make too much of) a protein called MGMT were harder for drugs like temozolomide to kill. Cells that contained no MGMT protein because the gene that produces the protein was switched off succumbed more readily to the drugs. In addition, findings from preliminary clinical trials suggested that patients treated with temozolomide and radiation survived for longer if the MGMT gene was switched off in their tumors. The current study looked at whether this association held true among patients enrolled in the international randomized trial.
The Study
In the original trial, 573 patients were randomly assigned to receive either radiation therapy alone or temozolomide in addition to radiation therapy. Researchers performed genetic tests on tumor tissue from a subset of 307 patients from both groups to find out whether the MGMT gene was turned on or off in the patients’ tumors. Then they compared survival rates in the two groups of patients.
The study’s lead author is Monika E. Hegi, Ph.D., of University Hospital in Lausanne, Switzerland.
Results
For technical reasons, the researchers could determine whether the MGMT gene was switched on or off in only 206 of the 307 patients whose tumors were tested. Within that subgroup of 206 - and regardless of which treatment patients received - median survival was six months’ longer for patients with a switched-off MGMT gene (18.2 months) than for those with a switched-on gene (12.2 months).
The best outcomes of all were seen in patients with a switched-off MGMT gene who received temozolomide in addition to radiation. Their median survival was 21.7 months. By contrast, patients with a switched-off gene who received radiation alone survived for a median of 15.3 months.
Among patients with a switched-on MGMT gene, those treated with temozolomide survived for a median of 12.7 months; those treated with radiation alone survived for a median of 11.8 months - a difference that was barely more than might have occurred by chance.
The researchers saw similar trends when they looked at how long patients survived before their disease progressed. Patients with a switched-off gene who were treated with temozolomide had the longest progression-free survival: 10.3 months compared with 5.9 months for those with a switched-off gene who were treated with radiation alone. Among patients with a switched-on gene, those treated with temozolomide progressed after 5.3 months; those treated with radiation alone progressed after 4.4 months.
Limitations
The researchers could determine whether the MGMT gene was switched on or off in only about a third of the patients enrolled in the trial, says Howard Fine, M.D., Chief of the Neuro-Oncology Branch at the National Cancer Institute's Center for Cancer Research.
Furthermore, the test to determine the status of the MGMT gene has not been standardized, says Fine, which means that different researchers performing the test in another laboratory might get different results.
Other possible explanations for the survival advantage seen in patients with a switched-off MGMT gene have not been completely ruled out, Fine adds. For example, the switched-off gene might be an incidental marker for a less-aggressive form of the disease and/or one that is more responsive to radiation or chemotherapy, independent of the effects of the MGMT gene itself.
Comments
Although this study’s findings are “intriguing,” further studies need to be done to confirm them, comments Fine.
“If they are ultimately validated, these findings would represent an important step toward the goal of personalizing cancer therapy by identifying whether or not patients are likely to respond to a particular treatment,” he says. “For now, however, it is premature to base recommendations for therapy on the status of the MGMT gene.”
Fine recommends that all patients with glioblastoma multiforme receive chemotherapy with temozolomide in addition to radiation therapy. “Because the drug is well tolerated and because we have no effective alternative therapy to offer, it is reasonable to offer temozolomide to all patients,” he says.
That position is supported by Lisa M. DeAngelis, M.D., of Memorial Sloan-Kettering Cancer Center in New York, in an accompanying editorial. “The minimal toxicity associated with temozolomide and the clear benefit of its use makes it reasonable to give this drug to all patients now,” she writes.
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