Why this matters
Postoperative SRS is a standard treatment after resection of brain metastases, but local control becomes more difficult as the surgical cavity becomes larger.
Fractionating treatment is commonly used for larger cavities because it may permit a higher biologically effective dose while reducing the risk of normal brain toxicity. Until now, however, this practice has largely lacked randomized phase III evidence.
Alliance A071801 directly compared single-fraction SRS with fractionated SRS after resection of a brain metastasis larger than 2 cm.
The primary endpoint favored fractionation.
Study design
Alliance A071801 was a multi-institutional randomized phase III cooperative group trial.
Patients with 1-4 brain metastases were eligible after resection of one lesion larger than 2 cm.
Patients were randomized to:
- single-fraction SRS, 12-20 Gy depending on target volume
- fractionated SRS, 27 Gy in 3 fractions for targets below 30 cc or 30 Gy in 5 fractions for targets above 30 cc
Any unresected brain metastases were treated using the same assigned fractionation strategy.
Randomization was stratified by:
- age below 60 vs 60 years or older
- planned targeted therapy or immunotherapy within 4 weeks after radiotherapy
- maximal resection cavity diameter 3 cm or smaller vs greater than 3 cm
The primary endpoint was time to surgical bed failure.
Major secondary endpoints included:
- control of unresected metastases
- overall survival
- radiation necrosis
A total of 242 patients were randomized.
Median follow-up was 48 months.
Key results
Fractionated SRS significantly improved surgical bed control.
At 1 year, surgical bed control was:
- 87% with fSRS
- 81% with single-fraction SRS
- p=0.046
The absolute improvement was 6 percentage points.
Control of treated unresected brain metastases also numerically favored fractionation.
Failure of treated intact metastases occurred in:
- 4% with fSRS
- 11% with SRS
- p=0.063
This difference did not reach conventional statistical significance.
Overall survival
Overall survival unexpectedly favored fractionated SRS.
Median OS was:
- 29 months with fSRS
- 20 months with SRS
- p=0.035
The stratified Cox model showed:
- HR 0.69
A multivariable model adjusting for other baseline variables produced a similar result:
- HR 0.68
- p=0.032
This survival signal is notable, but OS was a secondary endpoint and should therefore be interpreted more cautiously than the primary local control result.
Radiation necrosis and toxicity
The improvement in surgical bed control did not come with a significant increase in adverse events.
Grade 1 or higher radiation necrosis occurred in:
- 14% with fSRS
- 10% with SRS
Cerebral edema occurred in:
- 8% with fSRS
- 9% with SRS
There were no significant differences in overall adverse event rates between treatment groups.
Interpretation
Alliance A071801 provides the randomized evidence that has been missing from postoperative brain metastasis practice.
The main result is straightforward: fractionated SRS provides better surgical cavity control than single-fraction SRS after resection of larger brain metastases.
The absolute difference at 1 year was modest at 6 percentage points, but this is clinically meaningful in a setting where local failure can lead to neurologic symptoms, additional treatment, or repeat surgery.
Importantly, better local control was not accompanied by a statistically significant increase in radiation necrosis.
That combination strengthens the rationale for fractionation. The theoretical advantage of spreading dose over several fractions now has phase III clinical support.
The OS result is more difficult to interpret.
A 9-month difference in median survival is substantial, and the association persisted after multivariable adjustment. However, local radiation fractionation would not normally be expected to generate such a large survival effect by itself.
Because OS was a secondary endpoint, the survival finding should be treated as supportive and hypothesis-generating rather than as the main basis for choosing fSRS.
The stronger conclusion is that fractionated SRS improves local control without a clear toxicity penalty.
Limitations
The primary endpoint reached statistical significance with a relatively modest absolute difference in 1-year surgical bed control.
Overall survival was a secondary endpoint, so the survival benefit requires cautious interpretation.
Radiation necrosis was numerically more frequent with fSRS, although the difference was not statistically significant.
The study population specifically included patients undergoing resection of lesions larger than 2 cm, so the results should not automatically be extrapolated to very small postoperative cavities.
The trial also allowed different fractionated schedules according to cavity volume, reflecting real-world practice but introducing some treatment heterogeneity.