Stereotactic Radiotherapy with Immunotherapy for Treatment of Brain Metastases: Optimal Timing and Fractionation to Improve Disease Control and Minimize Toxicity

Abstract

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitors (ICI) are increasingly used to treat patients with brain metastases, while stereotactic radiosurgery (SRS, 1 fraction) and stereotactic radiotherapy (SRT, 3-5 fractions) are established modalities. Emerging data suggest that ICI and SRS/SRT may work synergistically, with reports of increased efficacy and toxicity. We characterized factors associated with intracranial control and radiation necrosis in patients receiving both ICI and SRS/SRT. <h3>Materials/Methods</h3> We retrospectively identified patients treated with ICI and SRS/SRT for intact brain metastases at two institutions from 2013-2020. Patients had diagnoses of non-small cell lung cancer, renal cell carcinoma, or melanoma and were followed for a minimum of 2 months after receipt of both SRS/SRT and ICI with brain MRI. The analysis was completed on a per-metastasis basis. Local failure (LF) and radiation necrosis (determined radiographically with clinical impression or pathologically; included grade 2 (symptomatic) or higher) were analyzed by univariate and multivariate logistic regression which included tumor diameter, timing of ICI relative to SRS/SRT, PD-L1 (positive defined as ≥ 1%), and SRT vs. SRS. Progression-free survival (PFS) was defined as time from SRS/SRT to local or distant brain failure, death, or last follow up for those without progression. <h3>Results</h3> There were 179 patients with 549 metastases, 492 metastases treated with SRS, and 57 metastases treated with SRT. Median follow up from the time of SRS/SRT was 14.7 months. Median tumor size was 7mm (< 5mm: 253, ≥ 5 & < 10mm: 159, ≥ 10 and < 20mm: 91, and ≥ 20mm: 46). Rates of LF and grade 2+ radiation necrosis for the entire cohort were 5.8% (32/549) and 6.9% (38/549), respectively (15.6% (28/179) rate of grade 2+ radiation necrosis per-patient). LF rates for those who received ICI outside +/- 3 months from SRS/SRT vs. within +/- 3 months from SRS/SRT were 9.0% and 4.4%, respectively. Rates of grade 2+ radiation necrosis for those with positive vs. negative PD-L1 were 9.2% vs. 1.6%, respectively. Positive PD-L1 status was associated with improved intracranial PFS (HR 0.53, p = 0.03). <h3>Conclusion</h3> Combination ICI and SRS/SRT is increasingly used to treat brain metastases. Our study showed improved local control when ICI is given within 3 months from time of SRS/SRT without an associated increase in radiation necrosis. Increasing tumor size was associated with LF and radiation necrosis. Positive PD-L1 was associated with improved intracranial PFS and increased radiation necrosis. We recommend further study, ideally prospectively, to better characterize this treatment combination.