Objectives: Prior studies have produced mixed conclusions regarding whether anti-PD-1 therapy increases radiosurgery toxicity. The objective of this study is to determine the high-grade toxicity of radiosurgery and anti-PD-1 immunotherapy for patients with renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and melanoma brain metastases (BM).

Methods: This study retrospectively assessed high grade toxicity in patients treated at UAB since 2014 for NSCLC, RCC, and melanoma BM with radiosurgery and anti-PD-1 immunotherapy. Similar to the dose-limiting toxicity definition in RTOG 9005, high grade toxicity was defined as irreversible grade 3 or any grade 4/5 neurologic events. Patients undergoing salvage resection with a pathologic mixture of necrosis and viable tumor were scored as both grade 4 toxicity and local failure. All patients received pembrolizumab and/or nivolumab and radiosurgery for at least one brain metastasis. No patient had whole brain radiation or prior radiosurgery to the index lesion(s). Median follow-up was 11.3 months (1-32.4), and the majority of patients received immunotherapy within 1 month of radiosurgery.

Results: Forty-three patients with median 2 (1-21) tumors each for a total of 126 tumors were followed for median 11.3 (0.7-32) months. Median tumor volume was 0.16 (0.01-24) cc and median radiation dose was 20 Gy (single fraction) and 30 Gy (five fractions). Thirty-six patients received single fraction radiosurgery, and 7 received hypofractionated therapy, most commonly 6 Gy x 5 fx. Five patients (11.6% of patients, 4% of tumors) experienced high-grade CNS toxicity including three patients requiring resection and two patients with irreversible brain edema associated with a decline in performance status and initiation of palliative care. All of these patients had melanoma with largest tumor volumes of 24.0 cc, 4.2 cc, 12.0 cc, 3.8 cc, and 2.3 cc with 3 of 5 receiving single fraction treatment. All but one event occurred within the first month of radiosurgery. In all five cases, patients worsened when treating physicians minimized or limited steroids due to concerns regarding the impact on immunotherapy.

Conclusions: Combination radiosurgery-immunotherapy (anti-PD1) appears tolerable for RCC, NSCLC, and melanoma BM with a level of high-grade toxicity that should not change treatment recommendations. Traditional factors such as treatment volume continue to drive the risk of high-grade toxicity, but variations in steroid prescribing patterns for immunotherapy patients may exacerbate toxicity.