The impact of whole brain radiation therapy on the long-term control and morbidity of patients treated with gamma knife radiosurgery for brain metastases

Purpose/Objective: To better evaluate long-term tumor control and toxicity from the initial treatment of brain metastases by the use of stereotactic radiosurgery with and without concurrent whole brain radiotherapy (WBXRT), we analyzed these outcomes in patients who had survived at least one year from radiosurgery. Materials/Methods: We evaluated the results of Gamma Knife radiosurgery for 160 brain metastases in 109 patients who were followed for a median of 18 months (range: 12–122) after radiosurgery. Eighty-two patients had solitary metastases. Twenty-seven patients presented with multiple tumors. Sixty-nine patients were treated with initial radiosurgery and WBXRT, while 40 received initial radiosurgery alone. Median treatment volume was 2.3 cc (range: 0.05–21.2). Median marginal tumor dose was 16 Gy (range: 12–21). Results: At 1, 3, & 5 years: local tumor control was 84.1±5.5%, 68.6±8.7%, & 68.6±8.7% with radiosurgery alone compared with 93.1±2.4%, 87.7±4.9% & 65.7±10.2% with concurrent WBXRT and radiosurgery (p = 0.064, univariate). Multivariate analysis demonstrated that better local control was associated with smaller tumor volumes (p = 0.005) and WBXRT (p = 0.0277). In subset analysis, WBXRT improved local control only with treatment volumes >2cc (p = 0.0105) or marginal doses ≤16 Gy (p = 0.0087). Distant intracranial failure developed at 1, 3, & 5 years in 26.0±7.1%, 74.5±9.4%, & 74.5±9.4% with radiosurgery alone compared to 20.7±4.9%, 49.0%±8.7%, & 61.8±12.8% with concurrent WBXRT and radiosurgery (p = 0.098, univariate). Distant intracranial relapse developed less commonly in non-small cell lung cancer patients (p = 0.0429) by multivariate analysis. In subset analysis, WBXRT improved distal control in patients with age ≥60 yrs (p = 0.0295) and with non-resistant histology (p = 0.054). No other factors correlated with local or distant intracranial relapse (other primaries, patient age, presence of extensive tumor edema, multiple vs. solitary metastases, resistant vs. sensitive tumor type, isodose, marginal dose, tumor enhancement pattern, patient performance status, and tumor location) by multivariate analysis. Post-radiosurgery complications developed in 2.8±1.2% & 10.7±3.5% at 1 and 3–5 years. Complications did not differ with concurrent WBXRT (p = 0.822). Volume, 12-Gy volume, and marginal dose were the only factors that correlated with complications in univariate analysis (p = 0.0167, 0.0273, & 0.0206, respectively). Conclusions: The addition of concurrent WBXRT to radiosurgery for the initial management of brain metastases improves local control of larger metastases (>2cc) or tumors treated with lower marginal doses of radiation (≤16 Gy). It also reduces distal intracranial relapse in patients ≥60 yrs, and with metastases that have non-resistant histologies. Distant intracranial relapse >1 yr post-treatment remains a significant problem with or without WBXRT.