Stereotactic radiosurgery may be new standard of care for four or more brain metastases
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Stereotactic radiosurgery conferred equivalent OS as whole-brain radiation but with less cognitive decline in patients with four or more nonmelanoma brain metastases, according to study results presented at the virtual ASTRO Annual Meeting.
“Up to 30% of [patients with cancer] develop brain metastases at some point during the disease process and these patients typically do not do well with current treatment modalities, including radiation and surgery,” Jing Li, MD, PhD, associate professor of radiation oncology and co-director of the Brain Metastasis Clinic at The University of Texas MD Anderson Cancer Center, said during a press conference. “Whole-brain radiation has been around for some time now; however, it is associated with significant side effects, which is why within the past decade there have been tremendous efforts to minimize the cognitive side effects of brain radiation.”
Stereotactic radiosurgery replaced whole-brain radiation therapy as the standard of care for patients with one to three brain metastases after a pair of randomized phase 3 studies showed it provided better preservation of cognitive function with no reduction in OS.
For the current phase 3 trial, Li and colleagues randomly assigned 72 adults with four to 15 untreated, nonmelanoma brain metastases (median at enrollment, 8) to either stereotactic radiosurgery (n = 36) dosed at 15 Gy to 24 Gy or whole-brain radiation therapy (n = 36) dosed at 30 Gy in 10 fractions. Researchers recommended memantine, a prescription drug used to treat dementia, to patients assigned whole-brain radiation therapy to help delay cognitive decline.
Memory function at 4 months, measured by Hopkins Verbal Learning Test-Revised Total Recall, and local control at 4 months served as primary endpoints. Other neurocognitive function tests, OS, distant brain failure, toxicity and time to systemic therapy served as secondary endpoints.
Researchers halted the trial early due to slow accrual. Thirty-one patients were evaluable at 4 months for Hopkins Verbal Learning Test-Revised Total Recall, including 18 patients in the radiosurgery group and 13 patients in the whole-brain radiation group.
At median follow-up of 6.6 months (range, 0.2-69.8), results showed patients in the stereotactic radiosurgery group scored higher on memory function compared with baseline (average z-score change, +0.21), whereas patients in the whole-brain radiation group scored worse compared with baseline (average z-score change, 0.74; P = .04). Researchers observed a clinically meaningful and statistically significant benefit with radiosurgery at 1 month (P = .033) and 6 months (P = .012).
Moreover, half of patients in the whole-brain radiation group experienced a clinically meaningful decline in cognitive function 4 months after treatment compared with only 6% of patients in the stereotactic radiosurgery group (P = .018).
The radiosurgery and whole-brain radiotherapy groups had similar local control rates at 4 months (95% vs. 87%), median OS (7.8 months vs. 8.9 months) and median time to distant brain failure (6.3 months vs. 10.5 months). However, patients assigned radiosurgery experienced shorter interruptions of systemic therapy, with time to systemic therapy of 1.7 weeks vs. 4.1 weeks with whole-brain radiation (P = .001).
“This is particularly important because patients with brain metastases often have metastases outside of the brain, as well,” Li said. “When these patients receive whole-brain radiation, we typically hold chemotherapy for 2 weeks and we continue to hold systemic therapy for up to 4 weeks for them to wash out before they can return to systemic therapy. These patients often need systemic therapy to control extracranial disease.”
Radiation necrosis occurred in 17% of patients in the radiosurgery group and in 4% of all treated lesions. Grade 3 or higher toxicities occurred among 8% of patients (n = 2) in the radiosurgery group and 15% of patients (n = 4) in the whole-brain radiation group.
“Despite early termination of the study and the use of memantine in the whole-brain radiation therapy arm, we were able to show that stereotactic radiosurgery was associated with reduced risk [for] cognitive deterioration compared with whole-brain radiation as demonstrated by a constellation of neurocognitive tests, individually or by composite scores,” Li said. “The results from this randomized, phase 3 trial strongly support the use of stereotactic radiosurgery in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising OS.”
Perspective
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Stephanie E. Weiss, MD, FASTRO
Radiosurgery alone without whole-brain radiation has been an accepted practice for patients with one to four (oligometastatic) brain metastases for the past 15 years.
A large phase 2 trial compared outcomes of stereotactic radiosurgery (SRS) alone for two groups — patients with five to 10 brain metastases, or those with four or fewer lesions — and showed survival was comparable, suggesting SRS alone was feasible for this group.
In this study, Li and colleagues compared outcomes for patients with four to 15 nonmelanomatous brain metastases who received SRS with those who received whole-brain radiotherapy (WBRT).
Researchers found neurocognitive function was superior for patients who received SRS compared with those who received WBRT, even though more than half of patients in the WBRT group received memantine, a cognitive-enhancing drug proven to benefit patients undergoing WBRT.
OS was slightly but not statistically significantly better for patients who received SRS; however, the trial was closed early because of slow accrual. It is most likely that earlier data, physician experience and patient preference to avoid WBRT made accrual with a randomized arm to WBRT challenging.
This study provides the highest level of evidence that WBRT may not be routinely needed and even may be detrimental from a neurocognitive standpoint compared with SRS for patients with up to 15 brain metastases.
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Li J, et al. Abstract 41. Presented at: American Society for Radiation Oncology Annual Meeting (virtual); Oct. 25-28, 2020.
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