Stereotactic radiosurgery appears to be a new standard of care for patients with four or more nonmelanoma brain metastases, perhaps replacing whole-brain radiotherapy in this setting, according to a potentially practice-changing phase III study presented at the 2020 American Society for Radiation Oncology (ASTRO) Annual Meeting.¹

Highly focused radiation therapy with stereotactic radiosurgery led to less cognitive decline compared with whole-brain radiotherapy in patients with 4 to 15 brain metastases, with similar overall survival. Stereotactic radiosurgery allowed patients to continue systemic anticancer therapy with minimal interruption, whereas whole-brain radiotherapy required patients to take weeks off from their systemic therapy.

“Our study provides strong evidence to support replacing whole-brain radiotherapy with more focal radiation [stereotactic radiosurgery] for patients with multiple brain metastases.”

— Jing Li, MD, PhD

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“Up to 30% of all patients with cancer develop brain metastasis, and they typically do not have a good prognosis,” stated lead author, Jing Li, MD, PhD, Associate Professor of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston. “Whole-brain radiotherapy has been the standard radiation approach, and it is associated with significant cognitive side effects. Our study provides strong evidence to support replacing whole-brain radiotherapy with more focal radiation [stereotactic radiosurgery] for patients with multiple brain metastases. This approach preserves cognitive function and minimizes interruption of systemic therapy without compromising overall survival.”

The study presented at the 2020 ASTRO Annual Meeting builds on previous research aimed at preserving cognitive function in patients with brain metastasis. “Two phase III randomized trials have established stereotactic radiosurgery as standard of care for patients with one to three or four brain metastases. We wanted to extend this to patients with four or more brain metastases. The concern in using stereotactic radiosurgery in patients with a higher disease burden is that it cannot address microscopic disease,” she explained.

Stereotactic radiosurgery is more convenient than whole-brain radiotherapy for patients and minimizes interruption of systemic therapy to control cancer in the rest of the body. Whole-brain radiotherapy is typically delivered in 10 treatment sessions over 2 weeks, whereas stereotactic radiosurgery is generally completed in a single session, requiring just 1 day for planning and treatment.

Study Details

The study enrolled 72 patients with 4 to 15 untreated nonmelanoma brain metastases confirmed by neuroradiology. All lesions were amenable to treatment with stereotactic radiosurgery. Systemic therapy was allowed at the discretion of the treating physicians. Patients were randomly assigned in a 1:1 ratio to receive stereotactic radiosurgery (15–24 Gy) vs whole-brain radiotherapy (30 Gy in 10 fractions). Patients were stratified for histology, age, number of lesions (4–7 vs 8–15), performance status, extracranial disease status, and prior vs no prior stereotactic radiosurgery.

After the opening of the trial in 2012, a phase III trial published in 2013 showed that memantine (approved for dementia) slowed cognitive decline in patients treated with whole-brain radiotherapy. Memantine was therefore encouraged to be given to all patients randomly assigned to whole-brain radiotherapy, and about two-thirds of the patients in the WBRT arm received memantine.

The primary endpoints were memory function at 4 months (as measured by the Hopkins Verbal Learning Test [HVLT]) and local tumor control at 4 months.

Key Findings

At 4 months, memory function increased by 0.21 points with stereotactic radiosurgery vs a decrease of 0.74 points with whole-brain radiotherapy (P = .041). “At 1 month and at 6 months, a statistically significant and clinically meaningful benefit with stereotactic radiosurgery was also observed,” Dr. Li reported. Statistical significance favoring stereotactic radiosurgery over whole-brain radiotherapy was P = .033 at 1 month and P = .012 at 6 months.

According to a composite score reflecting cognitive function based on a battery of six cognitive tests, at 4 months after treatment, clinically meaningful cognitive decline was observed in 6% of those who underwent stereotactic radiosurgery vs 50% of those given whole-brain radiotherapy by using cognitive function composite scores (P = .018). Additionally, cognitive scores were significantly better with stereotactic radiosurgery at 1 month, 4 months, and 6 months (P = .024, P = .004, and P = .027, respectively). The battery of cognitive tests assessed learning and memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity.

In both groups, overall survival was similar, about 8 months, in an intent-to-treat analysis: a median of 7.8 months with stereotactic radiosurgery and a median of 8.9 months with whole-brain radiotherapy.

Other Study Endpoints

Local tumor control at 4 months was 95% with stereotactic radiosurgery vs 87% with whole-brain radiotherapy, numerically favoring stereotactic radiosurgery. Distant brain control was 60% with stereotactic radiosurgery vs 80% with whole-brain radiotherapy, numerically favoring WBRT. The median time to distant brain failure was 6.3 months with stereotactic radiosurgery and 10.5 months with whole-brain radiotherapy.

The time to systemic therapy was much shorter for patients who underwent stereotactic radiosurgery compared with whole-brain radiotherapy: 1.7 weeks vs 4.1 weeks (P = .001). “This is important for patients because they benefit from systemic therapy to control cancer outside the brain,” added Dr. Li.

Stereotactic radiosurgery–treated patients had fewer grade 3 or higher toxicities: 8% vs 15% for those treated with whole-brain radiotherapy.

“Our trial was conducted over a span of 7 years, with two practice changes occurring during that time,” continued Dr. Li. “Memantine was given to patients who received whole-brain radiotherapy, and hippocampal-avoidance WBRT, as assessed by NRG CC001 and published in early 2020, was adopted as a standard for selected patients who need WBRT, which led to the early termination of our study. Despite early termination after accruing 72 out of the targeted 100 patients, and two-thirds of those given whole-brain radiotherapy received memantine, we were able to show that stereotactic radiosurgery reduced the risk of neurocognitive deterioration compared with whole-brain radiotherapy, as demonstrated by a constellation of neurocognitive tests, individually or by composite score.”

Additional Commentary

Press conference moderator, Sue S. Yom, MD, PhD, of the University of California at San Francisco, commented on these trial findings: “Stereotactic radiosurgery can deliver very high doses of radiation safely with shorter treatment times. This may be a special advantage during the COVID-19 pandemic,” she noted.

“Stereotactic radiosurgery allowed patients to receive systemic therapy without an extended interruption.”

— Sue S. Yom, MD, PhD

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“One of the controversies is that stereotactic techniques such as stereotactic radiosurgery require technical precision, additional resources, and higher expense. Strong evidence is required to justify stereotactic radiosurgery in the palliative care setting,” Dr. Yom continued.

“The question in this study was should stereotactic radiosurgery be used to treat numerous metastases in the brain. Giving stereotactic radiosurgery to patients with 4 to 15 brain metastases clearly improved cognitive-function results, even in this setting with numerous metastases, compared with conventional whole-brain radiotherapy,” she said.

“It is possible that patients treated with stereotactic radiosurgery may have had more relapses in untreated areas of the brain, but they lived as long as patients treated with whole-brain radiotherapy, with improved cognitive function. And stereotactic radiosurgery allowed patients to receive systemic therapy without an extended interruption,” Dr. Yom explained.

“I consider it practice-changing that stereotactic radiosurgery can improve quality of life for patients with metastatic disease. The next study being planned will compare stereotactic radiosurgery with memory-sparing whole-brain radiotherapy,” she told the audience.

‘Appealing’ Strategy

Simon S. Lo, MB, ChB, FACR, FASTRO, Professor of Radiation Oncology and Neurological Surgery and Director of Stereotactic Body Radiation Therapy, University of Washington, Seattle, said: “Stereotactic radiosurgery is very appealing for patients with brain metastases who have a longer life expectancy.”

“Longer follow-up is required to better define the role of stereotactic radiosurgery alone for patients with 4 to 15 brain metastases.”

— Simon S. Lo, MB, ChB, FACR, FASTRO

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Dr. Lo continued: “This randomized phase III trial validates the approach used by Yamamoto et al in their multi-institutional prospective observational study, as published in TheLancet Oncology in 2014—namely stereotactic radiosurgery alone for 5 to 10 metastases.² Stereotactic radiosurgery alone for patients with 4 to 15 metastases offered the advantage of minimizing delay in systemic therapy and reduced the risk for neurocognitive deficit while yielding similar overall survival despite statistically nonsignificant shorter time to distant failure when compared with whole-brain radiotherapy.”

However, Dr. Lo offered a word of caution. “Longer follow-up is required to better define the role of stereotactic radiosurgery alone for patients with 4 to 15 brain metastases. Currently, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology [NCCN Guidelines^®] regard stereotactic radiosurgery alone as appropriate treatment for small-volume brain metastases without a hard cutoff number,” he noted.

Supportive Data Provided

Minesh Mehta, MD, Chair and Professor, Department of Radiation Oncology, Miami Cancer Institute at Baptist Health South Florida, noted that stereotactic radiosurgery has been shown to achieve similar survival as whole-brain radiotherapy with a lower risk of cognitive decline in patients with one to three brain metastases.

Minesh Mehta, MD

“This study provided further data to back up this finding and expands the results into the domain of four or more metastases. Similar to prior trials, radiosurgery produces comparable survival with lesser cognitive decline, but with a higher likelihood of in-brain failure, requiring salvage therapy. As the authors indicate, stereotactic radiosurgery will be compared with hippocampal-avoidant whole-brain radiotherapy in the future,” Dr. Mehta said.

DISCLOSURE: Dr. Li has received research grants from Bristol Myers Squibb and Medtronic and has received honoraria from Monteris and NovoCure. Dr. Yom has received research grants from Merck, Bristol Myers Squibb, and Genentech, and has received royalties from Springer and UpToDate. Dr. Lo has received institutional research funding from Elekta. Dr. Mehta has served as a consultant or advisor to Mevion Medical Systems, Karyopharm and Tocagen and has served on the Board of Directors for Oncoceutics.

REFERENCES

1. Li J, Ludmir EB, Wang Y, et al: Stereotactic radiosurgery vs whole-brain radiation therapy for patients with 4-15 brain metastases: A phase III randomized controlled trial. 2020 ASTRO Annual Meeting. Abstract 41. Presented October 24, 2020.

2. Yamamoto M, Serizawa T, Shuto T, et al: Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): A multi-institutional prospective observational study. Lancet Oncol 15:387-395, 2014.