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Background: Whole-brain radiotherapy (WBRT) to 30 grays (Gy) in 10 fractions is the standard treatment in patients with multiple brain metastases in the majority of treatment centers worldwide. The current study investigated the potential benefit of dose escalation beyond 30 Gy., Methods: Data regarding 416 patients who were treated with WBRT for multiple brain metastases were evaluated retrospectively. Survival and freedom from recurrent brain metastasis (local control) of 257 patients who were treated with 10 fractions of 3 Gy each for 2 weeks were compared with those of 159 patients treated with 45 Gy in 15 fractions for 3 weeks or 40 Gy in 20 fractions for 4 weeks. Eight additional potential prognostic factors were investigated including age, gender, Karnofsky performance score (KPS), tumor type, interval between tumor diagnosis and RT, number of metastases, extracranial metastases, and Recursive Partitioning Analysis (RPA) class., Results: On multivariate analysis, improved survival was found to be associated with lower RPA class (P < .001), age <60 years (P = .026), KPS >or=70 (P < .001), and absence of extracranial metastases (P = .003). A trend was observed for number of metastases (2-3 vs >or=4; P = .07). Improved local control was associated with a KPS >or=70 (P < .001) and breast cancer (P < .001). A trend was observed for number of metastases (P = .059). The RT schedule did not appear to have any significant impact on survival (P = .86) or local control (P = .61). The subgroup analyses, performed for each of the 3 RPA classes, did not demonstrate a significantly better outcome with dose escalation., Conclusions: Dose escalation beyond 30 Gy in 10 fractions does not appear to improve survival or local control in patients with multiple brain metastases but does increase the treatment time and cost of therapy., ((c) 2007 American Cancer Society.)