CHICAGO – Patients with limited brain metastases treated with radiosurgery have a higher risk of cognitive decline if they then undergo whole-brain radiation therapy, researchers reported at the annual meeting of the American Society of Clinical Oncology.
The phase III North Central Cancer Treatment Group (NCCTG)/Alliance trial also found that although whole-brain radiation therapy (WBRT) roughly halved the likelihood of progression in the brain, it did not prolong survival. And quality of life was worse with its use as well.
Dr. Jan C. Buckner
“We recommend initial treatment with stereotactic radiation alone and close monitoring in order to better preserve cognitive function, and then reserving whole-brain radiation until the time of symptomatic progression,” senior study author Dr. Jan C. Buckner, professor of oncology at the Mayo Clinic, Rochester, Minnesota, said in a press briefing.
He ticked off a list of alternative approaches for avoiding cognitive problems in general for patients with brain tumors: “If at all possible, use either no radiation, low-dose radiation, hippocampal-sparing radiation, or a combination of radiation and memantine as a way to reduce the risk of cognitive decline because essentially, the brain does not like to be radiated.”
ASCO expert Dr. Brian Michael Alexander said, “This scenario is a pretty complex one, and one that I take a lot of time talking to my patients about.” The disconnect between local control and survival with whole-brain radiation may be due to the availability of very good salvage therapies when brain metastases recur (so that recurrence is irrelevant) or a situation wherein progressive disease outside the brain is driving mortality, he proposed.
Dr. Brian Michael Alexander
“If [the latter] is more of the answer, then … the population of patients who are unlikely to have deaths from progression of disease outside the brain may be the only place where you find a benefit for whole-brain radiation therapy,” according to Dr. Alexander, who is also Disease Center Leader of Radiation Oncology and a physician with the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, and an assistant professor of Radiation Oncology at Harvard Medical School, both in Boston.
Given the totality of data today on the risks and benefits of this therapy, “I think the burden of proof is now switched, to say, can we prove that whole-brain radiation therapy is beneficial in a subset of patients?” he maintained, adding that the calculus may be changing with better systemic therapies, such as targeted agents for lung cancer, that may reduce brain metastases.
In their National Institutes of Health–funded trial, Dr. Buckner and colleagues studied 213 adults who had one to three cerebral metastases measuring up to 3 cm in diameter. They were randomly assigned to receive radiosurgery alone or radiosurgery followed by WBRT. Cognitive progression, the trial’s primary endpoint, was assessed with a battery of tests.
With a median follow-up of 7.2 months, the 3-month rate of cognitive progression, defined as a decline of greater than one standard deviation from baseline in any of the six tests used, was 92% in the WBRT group and 64% in the control group (P = .0007). Specifically, the former were more likely to experience declines in immediate recall (30% vs. 8%), delayed recall (51% vs. 20%), and verbal fluency (19% vs. 2%).
The overall difference in cognitive decline persisted at 6 months and there was additionally a trend at 12 months among the small subset of patients still alive. The WBRT group also had significantly worse scores for patient-reported quality of life.
The 3-month rate of failure in the central nervous system was lower for the patients given WBRT (6% vs. 25%, P less than .0001), but overall survival did not differ significantly between groups, either in the entire population or in subgroups. “In spite of imaging evidence of disease control, there was no overall impact on survival in these patients as they died of other causes,” reported Dr. Buckner.
In the session where the results were presented, invited discussant Dr. Andrew B. Lassman, the John Harris Associate Professor of Neurology and the Chief of Neuro-oncology at Columbia University Medical Center, New York, said, “I think there are other interpretations [of the findings] when placing this study in the context of other trials for brain metastases.”
“First, whole-brain radiotherapy does increase survival in the appropriate context. Second, deferring whole-brain radiotherapy leads to more rapid and more numerous recurrences of brain metastases, which also cause neurocognitive injury,” he elaborated. “Accordingly, whole-brain radiotherapy should be used in selected cases when brain metastases are a life-limiting site of disease. This is a form of precision medicine.”