Whole-Brain Radiation: Risks Outweigh Benefits for Limited Brain Metastases

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Jan C. Buckner, MD

Paul Brown, MD

We recommend [treating initially] with stereotactic radiosurgery and reserving whole-brain radiation therapy until the time of symptom progression.

—Jan C. Buckner, MD

New data from a phase III ­Alliance trial weighs in on a longstanding debate in the treatment of brain metastases: Should whole-brain radiation therapy be added to stereotactic radiosurgery? The study found that although whole-brain radiation therapy improved local tumor control in patients with one to three brain metastases, but it exacerbated cognitive decline and did not improve overall survival.1

“Adjuvant whole-brain radiation therapy improved control of brain metastases but had no impact on survival. We saw decline in cognitive function with whole-brain radiation therapy, and quality of life was worse. We recommend treating initially with stereotactic radiosurgery and reserving whole-brain radiation therapy until the time of symptom progression,” said senior study author Jan C. ­Buckner, MD, of Mayo Clinic, ­Rochester.

‘Which Is Worse: The Disease or the Treatment?’

Dr. Buckner spoke about the trial at a press conference during the 2015 ASCO Annual Meeting, and Paul Brown, MD, of The University of Texas MD Anderson Cancer Center, Houston, presented the data at the Plenary Session.

In the United States alone, up to 400,000 cancer patients are diagnosed with brain metastases each year. Although stereotactic radiosurgery is effective initial treatment, there is a high rate of recurrence at treated sites, and additional lesions develop after stereotactic radiosurgery.

Studies have shown that the addition of whole-brain radiation therapy to stereotactic radiosurgery can reduce the number of patients with recurrence in treated sites and the number of new metastases.

“New metastases have negative effects on cognitive function and may require additional therapy, so whole-brain radiation therapy is attractive. But on the other side, whole-brain radiation therapy carries risks. The question has been which is worse: the disease or the treatment,” Dr. Buckner continued.

“A clear understanding of the risks of whole-brain radiation therapy is essential in making treatment decisions,” Dr. Brown noted at the Plenary Session.

Study Details

The federally funded prospective randomized phase III trial was initiated 10 years ago and enrolled 213 patients at 34 institutions with one to three brain metastases stratified according to age, control of extracranial disease, number of brain metastases, and institution. Patients were randomized to receive stereotactic radiosurgery or whole-brain radiation therapy plus stereotactic radiosurgery.

Baseline characteristics were well distributed between the two arms. Seventy percent had primary lung cancer, and 50% had only one brain metastasis.

At a median follow-up of 7 months, whole-brain radiation therapy significantly decreased disease progression in the brain (P < .0001) yet had no impact on survival.

For the primary endpoint of cognitive function at 3 months, significantly greater decline was observed in the whole-brain radiation therapy group: 91.7% of patients who received whole-brain radiation therapy exhibited cognitive deterioration vs 63.5% of the stereotactic radiosurgery group (P = .0007), as measured by a battery of cognitive and neuropsychiatric tests. Cognitive domains affected were immediate recall, memory, and verbal ­communication.

Quality-of-life measurement scores were significantly worse with whole-brain radiation therapy, showing clinically and statistically significant decrements for functional well-being and quality of life, Dr. Brown noted.

“As initial treatment, we recommend stereotactic radiosurgery alone and close monitoring to better preserve cognitive function in patients with newly diagnosed brain metastases amenable to stereotactic radiosurgery,” Dr. Brown stated.

More acute radiation-induced side effects were seen in the whole-brain radiation therapy arm at 6 weeks, but there was no difference in radiation necrosis between the two arms.

The investigators also tested a smaller group of long-term survivors at 12 months who completed at least one cognitive test. These survivors represented about one-sixth of the original study population. Cognitive function remained worse in the whole-brain radiation therapy arm and was statistically inferior for recognition, with a strong trend toward worse word association compared with stereotactic radiosurgery.

“This shows that over time, patients treated with whole-brain radiation therapy continued to have worse cognitive function for up to 12 months,” Dr. Brown said. ■

Disclosure: Drs. Buckner and Brown reported no potential conflicts of interest.


1. Brown PD, Asher AL, Ballman KV, et al: NCCTG N0574 (Alliance). 2015 ASCO Annual Meeting. Abstract LBA4. Presented May 31, 2015.


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Formal discussant, Andrew B. ­Lassman, MD, of the Department of Neurology at Herbert Irving Comprehensive Cancer Center and Columbia University Medical Center in New York, congratulated Dr. Brown and his coauthors for undertaking and completing a “herculean task” that took 10 years.

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