NEW BRAIN TUMOR TREATMENTS EXTEND LIFE

SAN DIEGO—The term complete remission is never used for the deadliest of brain tumors, but new and ongoing studies reported at the 41st Annual Meeting of the American Society of Clinical Oncology are offering hope that in some cases, novel treatment modalities can extend survival.

During a special session on central nervous system tumors, Stuart Grossman, MD, said that a look at the survival in the group with the worst prognosis—patients with glioblastoma multiforme—indicates that it has changed little. Nevertheless, “This has been a year where there have been genuine advances in this disease, some surprises, and some significant implications for both clinical care and research.” Dr. Grossman is a medical oncologist at Johns Hopkins University in Baltimore, former President of the Society for Neuro-Oncology, and Chairman of the Eastern Cooperative Oncology’s Brain Tumor Working Group.

According to Dr. Grossman, “a whirlwind of the last 30 years” still shows that surgery and radiation therapy do help patients, and that radiotherapy plus daily oral temozolomide has been shown to increase median survival to 14.6 months as opposed to 12.1 months for patients given only radiotherapy. Furthermore, the two-year survival rate was 26.5% for radiotherapy plus temozolomide versus only 10.4% for radiotherapy alone, in a group of 573 glioblastoma patients.

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The study results Dr. Grossman referred to were reported in the March 10 New England Journal of Medicine by Stupp and colleagues. In another study in that same issue, Hegi and colleagues determined that temozolomide worked best in patients with a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. They determined the patient’s status in this regard by polymerase chain reaction analysis.

“One of the interesting things about this study was that two-year survival was only 2% in those who got radiotherapy alone,” Dr. Grossman said. “And in the patients who had a methylated MGMT promoter, it was 22%.” He noted, however, that in other studies, the response rate for temozolomide alone was only 10%.

Nevertheless, the radiotherapy-temozolomide combination has now become “the standard therapy for patients with newly diagnosed glioblastoma, and rightly so,” he said—though he cautioned that physicians should not get so comfortable with this new standard that they fail to refer patients to experimental therapies. “Even with new treatments, 75% of our patients are dead in two years, and that is not a comfortable stopping point.”

Dr. Grossman also remarked that drug adverse events must be considered with any new type of therapy for individual patients. “We have learned that there is a tremendous interaction with the P-450 anticonvulsants. If you give [temozolomide] orally or by IV to a patient on an anticonvulsant drug, you are not guaranteed to get the blood levels you would expect in other tumors.” In addition to that caveat, there is the problem of the blood-brain barrier. “We had taken it on faith that the drug gets through the blood-brain barrier, but now we know that is not always the case.”

While temozolomide has been shown to work in some patients, he added, there are still questions to be answered, such as the optimal amount to give to individual patients. “Our challenge is to continue to develop new therapies, to be very careful about our trial designs, and to be sure we are actually delivering drug to the tumor,” he concluded.

OTHER REPORTS

• Jan C. Buckner, MD, Chair of Medical Oncology at the Mayo Clinic in Rochester, Minnesota, and his group are also looking at the drug CCI-779, a small-molecule inhibitor of the mammalian target of rapamycin, as a “rational therapeutic target” for recurrent glioblastoma multiforme. Early studies have shown it to be well tolerated and that high levels of phosphorylated p70s6 kinase predicted a good response to this treatment.

Dr. Buckner also said that while temozolomide has been shown to work in some patients, other therapeutic remedies should continue to be explored, including nitrosourea-based options, such as BCNU (carmustine) or procarbazine and vincristine. “There is also some evidence that irinotecan and the platins may be active in this disease group,” he noted.

• Jonathan P. S. Knisely, MD, Assistant Professor in the Department of Radiology at Yale University, New Haven, and colleagues reported a phase III study by the Radiation Therapy Oncology Group that analyzed the results of a trial with thalidomide in combination with radiation therapy for patients with multiple brain metastases. The drug did not increase survival.

• Howard Fine, MD, Chief of the Neuro-Oncology Branch at the National Cancer Institute, reported that the investigational drug enzastaurin reduced blood flow to tumors in 92 patients with glioblastoma, in most cases causing tumors to shrink. The drug also inhibited the cell-signaling pathways PKC-beta and P13/kinase, thus having both antiangiogenic and apoptotic effects. A phase III trial of this drug is under way.

• Another drug, erlotinib—an epidermal growth factor antagonist—has shown a promising response rate and has improved median survival in recurrent glioblastoma multiforme, although the numbers are still small, according to Timothy Cloughesy, MD, Director of the Neuro-Oncology Program at the University of California, Los Angeles.

• Martin J. van den Bent, MD, PhD, Head of the Neuro-Oncology Unit at Erasmus University in Rotterdam, the Netherlands, reported that in patients with anaplastic oligodendrogliomas, six cycles of adjuvant PCV (procarbazine, lomustine, vincristine) chemotherapy after radiotherapy prolonged progression-free survival from 13 to 24 months but did not improve overall survival.

• Lynn S. Ashby, MD, a neurologist in Phoenix, studied 95 patients with oligodendrogliomas and 44 patients with oligoastrocytomas and found that improved survival did not correlate with the type of treatment—whether it was radiotherapy, chemotherapy, or a combination. Although these patients would be expected to survive longer than patients with high-grade tumors, “high proliferative activity or the presence of enhancement on MRI is associated with shortened survival.” Also, 1p deletion is a powerful prognostic tool, she said.