ATLANTA—Cancer patients age 35 to 50 with brain metastasis had increased overall survival when treated with stereotactic radiosurgery alone, compared with stereotactic radiosurgery plus whole brain radiotherapy (WBRT), in an individual-patient-data meta-analysis of three published randomized controlled trials. As reported here at the ASTRO Annual Meeting (Abstract LBA3—accessible via http://online.myiwf.com/astro2013/Abstract.aspx), the results showed that beyond age 50 there was no difference in the two arms of the meta-analysis.
The three randomized trials—EORTC 22952-26001, JRSOG99-1, and MDACC NCT00460395—included newly diagnosed patients who had one to four brain metastases, treated with either stereotactic radiosurgery alone or stereotactic radiosurgery plus whole brain radiotherapy.
Those trials by themselves, however, were each under-powered for overall survival comparisons, said the first author of the new meta-analysis, Arjun Sahgal, MD, Associate Professor in the Department of Radiation Oncology at the University of Toronto and Deputy Chief of Radiation Oncology at Odette Cancer Center, also in Toronto.
Analyzing the raw patient data in this new meta-analysis allowed the researchers to formulate conclusions that could not be done through an aggregate meta-analysis previously performed earlier by the same group, he explained. “What we see now is that overall survival is significantly increased with radiosurgery alone in patients age 35 to 50 years, relative to an age-matched cohort treated with whole brain radiation plus radiosurgery.”
In the new meta-analysis, the risk of distant brain failure was significantly higher with radiosurgery alone, but only for patients 55 and older. The risk of new metastasis was also greater in patients with more than one metastasis.
Sahgal noted that previous research by his group showed that the addition of whole-brain radiation to radiosurgery improves distant brain control and local control but makes no difference on overall survival (Tsao et al: Cancer 2012; 118: 2486-2493).Therefore, he said, radiosurgery alone is a reasonable option because it spares the patient the adverse effects of whole brain radiation. In addition, the new meta-analysis expands on the results by age.
Patient Data Detailed
Sahgal reported a median time to death of 10 months for use of stereotactic radiosurgery vs. 8.2 months for radiosurgery plus whole brain irradiation; local failure was 6.6 vs. 7.4 months, respectively; and distant brain failure was 4.5 vs. 6.5 months, respectively.
The only significant treatment effect modifier was age.
Patients with a single metastasis also had significantly longer overall survival than those with two to four metastases. Those with more than one brain metastasis had a significantly greater risk of distant brain failure. Distant brain control and local control significantly favored the addition of whole brain irradiation, but multivariable analysis showed significant increases in distant brain failures in the radiosurgery-alone cohort only in patients older than 50.
“Therefore, based on our individual patient data of randomized controlled trials from three continents, we conclude that stereotactic radiosurgery alone is the preferred treatment for patients presenting with one to four brain metastases, recursive partitioning analysis score class 1 or 2, Karnofsky performance score of 70 or above, and age 50 years or younger,” Sahgal said.
“This conclusion allows radiosurgery alone to be offered and the patient potentially spared the adverse effects of whole brain radiation.”
Patient inclusion was limited to those with a recursive partitioning analysis score of 1 or 2, and Karnofsky performance score of 70 or above. The meta-analysis was based on one-stage time-to-event individual patient data.
Among 364 patients from the three randomized controlled trials who met the inclusion criteria, 51 percent had been treated with stereotactic radiosurgery alone; 19 percent were age 50 or younger; 41 percent were recursive partitioning analysis class 1; and 60 percent had a single brain metastasis.
In total, 21 percent of patients had a local failure, 44 percent had distant brain failure, and 86 percent died during follow-up.
Sahgal said the survival advantage with radiosurgery alone in younger patients may be explained by the lack of benefit in those receiving whole brain radiation in reducing the risk of brain metastases, while still exposing patients to the toxicities of worse memory function and harming quality of life, which ultimately translated into shorter survival.
Moving Away from Whole Brain Radiation Therapy
The moderator of a news briefing at the meeting, Daphne Haas-Kogan, MD, Professor of Radiation Oncology and Neurologic Surgery and Program Director of the Department of Radiation Oncology at the University of California, San Francisco, said the strength of the study is that it identified a cohort of patients in which the risk of distant brain metastases is not great, and that those patients might not need whole brain radiotherapy on top of stereotactic radiosurgery.
“The study provides us with results we would not otherwise have had if we had examined the individual studies separately,” she said. “These survival results have the potential to change practice as our field moves away from whole brain radiation.”
She added that it is not understood why the younger age group has less risk of dying. Her first thought on reading the abstract, she said, was that there were perhaps more breast cancer patients in the younger age group since they tend to have less risk for distant brain metastases. But in fact, more patients had lung cancer than breast cancer.
“We're going deeper into the data to understand it better,” Sahgal said, noting that the majority of the patients were treated before the era of molecular tests, and molecular predictors such as EGFR status is not known, “but the data are there and we can make some strong inferences.”
WBRT still has a role to play, however—the majority of patients will be offered whole brain irradiation because most present with a large number of brain metastases.”