BETTER TO AVOID WBRT AFTER STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES?

October 7, 2009 — Patients with brain metastases who were treated with whole-brain radiation therapy in addition to stereotactic radiosurgery were found to be at greater risk for cognitive decline, but did not show improved survival over surgery alone, according to a study published online October 2 in the Lancet Oncology.

"In our study, patients who received radiosurgery plus whole-brain radiation were at twice the risk of developing learning and memory problems at 4 months [than] patients getting radiosurgery alone," said lead study author Eric Chang, MD, associate professor in the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston.

In fact, the trial was stopped early by the data monitoring committee because there was a high probability (96%) that patients who were randomized to receive stereotactic radiosurgery plus whole-brain radiation therapy were significantly more likely to show a cognitive decline.

"Giving whole-brain radiation therapy in conjunction with stereotactic radiosurgery is highly controversial in the United States right now," said Dr. Chang. "Some might argue it is the standard treatment, but there is no consensus on this point. I would say there is a fair proportion of centers that do it, but there are many centers that do not."

Dr. Chang added that this study provides the strongest evidence to date that supports giving radiosurgery alone with close clinical monitoring as the preferred treatment strategy for patients newly diagnosed with a limited number of brain metastases. "We advocate the judicious and appropriate use of surgery, radiosurgery, or whole-brain irradiation only if needed for any recurrences that may develop later on in the brain," he told Medscape Oncology.

"I would advocate that physicians and their patients who are interested in preserving cognitive function and memory strongly consider using stereotactic surgery alone with close clinical monitoring in the initial management of their brain metastases," Dr. Chang said.

"Our strategy is consistent with the trend toward personalized medicine — tailoring therapies to the patient and their disease rather than applying a 'one size fits all' approach of giving whole-brain radiation therapy to all patients with brain metastases," he added.

Worse Neurocognitive Function With Combined Therapy

The trial was designed to enroll 90 patients and had about 80% power to detect a 30% difference in the neurocognitive end point of total recall, but the study was halted early by the data monitoring committee after the accrual of 58 patients. Patients with 1 to 3 newly diagnosed brain metastases were randomly assigned to receive stereotactic radiosurgery plus whole-brain radiation (n = 30) or stereotactic radiosurgery alone (n = 28) from January 2001 to September 2007.

The primary end point was neurocognitive function, objectively measured as a significant deterioration (5-point drop from baseline) in Hopkins Verbal Learning Test–Revised (HVLT-R) total recall at 4 months.

At 4 months, there was 96% confidence that total recall at 4 months for patients receiving the combination strategy (7 of 11 patients assessed [64%] deteriorated) was inferior to total recall for those who underwent stereotactic radiosurgery alone.

The researchers noted that a difference in total recall persisted at 6 months, with a mean posterior probability of decline of 28% for patients receiving the combination strategy and of 8% for those who underwent radiosurgery alone, with 90% confidence.

The HVLT–R delayed recall (22% in the combination group vs 6% in the radiosurgery-alone group; 86% confidence) and HVLT–R delayed recognition (11% vs 0%, respectively; 86% confidence) tests at 4 months indicated that it was highly probable that patients who underwent whole-brain radiation therapy had worse neurocognitive function than those who underwent surgery only.

Tumor Control Better, But Does Not Improve Survival

At 4 months, 4 patients (13%) in the radiosurgery-alone group had died, compared with 8 (29%) in the combination group. The researchers also observed that the median and 1-year overall survival was higher for patients in the radiosurgery-alone group than for those in the combination group (median survival, 15.2 vs 5.7 months; overall survival, 63% vs 21%; P = .003).

However, local tumor control at 1 year was higher for those in the combination group (100% vs 67%; P = .012), as was the distant brain tumor control rate (73% vs 45%; P = .02) and 1-year freedom from central nervous system recurrence (73% vs 27%; P = .0003).

Even though whole-brain radiation therapy reduced the risk for brain tumor recurrence, it did not increase overall survival. The authors note that the association between an increased risk for systemic deaths and whole-brain radiation therapy has been reported previously, and systemic deaths might be related to mechanisms involving central nervous system injury. That is a possibility that should be explored in future preclinical and clinical studies, they write.

There was 1 case of grade 3 toxicity in the combination group (seizures, motor neuropathy, depressed level of consciousness) that was attributed to radiation treatment. In the radiosurgery-alone group, there was 1 case of grade 3 toxicity (aphasia), which was attributed to radiation treatment, and 2 cases of grade 4 toxicity diagnosed as radiation necrosis.