Alliance A071801 Supports Fractionated SRS After Brain Metastasis Surgery

CancerNetwork® spoke with Ayal Aizer, MD, MHS, director of Central Nervous System Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute and associate professor of radiation oncology at Harvard Medical School, about findings from the phase 3 Alliance A071801 trial (NCT04114981), which he presented as a late-breaking abstract during the plenary session at the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting.¹

The trial randomly assigned 242 patients with 1 to 4 brain metastases, including a resected lesion, to postoperative single-fraction stereotactic radiosurgery (SRS) at 12 Gy to 20 Gy or fractionated SRS at 27 Gy in 3 fractions or 30 Gy in 5 fractions. At 1-year, surgical bed control was 87% with fractionated SRS vs 81% with single-fraction SRS (P = .046), and the median overall survival was 29 vs 20 months, respectively (P = .035).¹ Aizer discussed why fractionation may be more effective, how toxicity compared between arms, which patients may still be candidates for a single fraction, and how he counsels patients on the change. He also looked ahead to open questions in the field, including fractionated SRS for intact metastases and the role of preoperative SRS, and shared his perspective on local recurrence as an end point and the evolution of radiation oncology.

CancerNetwork: Your data showed that fractionated SRS beat single-fraction SRS for local control after resection. Did that surprise you, given the momentum single-fraction SRS has had?

The result was not a surprise per se, but it was nice to see that the study hypothesis in fact came to fruition. We know that when metastases are resected, the cavities can be large, and you can’t give a large amount of dose to a big target in the brain without causing significant necrosis. Dosing is an issue with single-fraction stereotactic radiosurgery. What fractionation can accomplish is a more tolerable dose, but one that can be effective against the tumor as well. There had been prior retrospective series supporting fractionated radiosurgery with good control rates, whereas the single-fraction data, which came mainly from prospective randomized series, were not as encouraging. The study confirmed the hypothesis, and in some ways, the study designers should be commended, Dr Paul D. Brown, in particular, for constructing the hypothesis that they did.¹

What was the driving difference: dose-fractionation biology, or something about how the resection cavity behaves?

We ultimately don’t know, and that needs to be investigated further. It may be the case that the biologic dose that’s imparted with single-fraction SRS is simply too low to achieve durable control. It may be something about the way people contour when they have to administer 1 fraction vs multiple fractions. Although there were no meaningful differences in the size of the target by arm, there may be subtleties in the way people do the contouring with regard to 1 vs multiple fractions, or there could be some sort of interaction with the fractionation. Ultimately, it can’t be determined with certainty, but this is something that needs to be explored further.

Does this mean single-fraction SRS should no longer be the default after resection?

That’s correct. When a typical patient with a larger brain metastasis has a resection, the standard of care should be adjuvant fractionated stereotactic radiosurgery; some people call that stereotactic radiotherapy. The study results were pretty conclusive: better local control in the surgical bed without an apparent increase in toxicity.For your typical patient who meets those criteria, fractionation seems important.

What did toxicity and radiation necrosis rates look like between the 2 arms?

They appear to be comparable. So far, crude rates of radiation necrosis have been analyzed. We’re still awaiting time-to-event analyses, but on average, about 10% to 15% of patients in both arms experienced radiation necrosis. There didn’t appear to be any meaningful differences, but that analysis is in preliminary form at the moment and will be finalized in the coming weeks.

Are there cavity sizes or locations where single-fraction SRS still makes sense?

Single fraction may still have a role. Patients on this trial had to have a metastasis that was over 2 cm in size. For metastases that are smaller, do the results apply to them? Perhaps or perhaps not. We also have to be cognizant that every patient is different, and there are some patients who have a guarded lifespan. If a patient with a smaller metastasis but a poor prognosis when it comes to extracranial disease says, “I want 1 treatment rather than 3 or 5,” it’s still reasonable to offer that treatment. For your typical patient, fractionation makes a lot of sense and probably should be the standard of care. There could be select patients who didn’t meet the eligibility criteria, or cases based on the preferences of patients, families, and caregivers, where it still seems reasonable to consider 1 fraction.

How does this change how you counsel patients and coordinate with neurosurgery?

We tell our patients that we would like to extend the radiation beyond the historically typical single day to now between 3 and 5 days, depending on the parameters of the surgical cavity and the nature of their disease. We try to say that yes, it’s an extra 2 to 4 treatments, but we think that the prevention of local recurrence is important. Local recurrences after SRS, whether fractionated or single fraction, are very complex to manage. They can impart symptoms for patients, and we often don’t even know that it’s a recurrence. It could be radiation necrosis, and trying to make that delineation is difficult initially. It causes stress, waiting, and more testing in many cases, and that can be problematic for patients. Ultimately, if there is a recurrence, the management of a post-SRS recurrence is nuanced, tricky, and sometimes morbid. Sometimes we need neurosurgical resection, and that can have associated complications. It does seem worthwhile to have a few extra days of treatment to prevent the downstream effects that manifest in cases of local recurrence.

The first thing is understanding why the results are what they are: What is the true driving mechanism? Then the next question comes about. Dr. Brown and colleagues have shown that fractionation is optimal for surgical cavities, but what about intact metastases? This study did look at that question, because patients could have up to 3 unresected brain metastases and enroll on the study. Interestingly, there was a trend toward better local control with fractionated stereotactic radiosurgery, even in unresected metastases. The P value was .06, so it didn’t quite meet statistical significance, but it was an encouraging trend. There is [a phase 3] NRG study (NCT06500455) that has completed accrual, and results are pending.² That will answer this question about fractionation more definitively in intact brain metastases. That’s an important question: Does what we see in cavities apply to intact metastases or not?

The next big question, though, is how much we should be doing postoperative radiation at all, relative to preoperative radiation. There’s a lot of encouraging data that suggest preoperative stereotactic radiation may be a better paradigm than postoperative SRS because of minimization of meningeal seeding, perhaps improved local control, and perhaps reduced necrosis. None of these issues have been answered definitively, but a multitude of randomized trials have presented preliminary data, more on the safety side and less on the efficacy side, and other trials are ongoing and have not yet presented results. I suspect within a few years we’ll have a multitude of trials reporting out on the role of preoperative SRS in lieu of postoperative SRS. That is another big question for the field.

References

1. Brown PD, Ballman KV, Aizer AA, et al. Alliance A071801 phase III trial postoperative single fraction stereotactic radiosurgery (SRS) vs fractionated SRS (fSRS) for resected brain metastasis. Presented at: 2026 ASTRO Annual Meeting; September 26–30, 2026; Boston, MA. Abstract LBA 01.

2. NRG-BN013: phase III trial of single fraction stereotactic radiosurgery (SRS) versus fractionated SRS (FSRS) for intact brain metastases. ClinicalTrials.gov. Accessed September 28, 2026. https://tinyurl.com/bdfypwdz