title: Hypofractionated radiosurgery for intact or resected brain metastases: defining the optimal dose and fractionation.
abstract: BACKGROUND
  Hypofractionated Radiosurgery (HR) is a therapeutic option for delivering partial brain radiotherapy (RT) to large brain metastases or resection cavities otherwise not amenable to single fraction radiosurgery (SRS). The use, safety and efficacy of HR for brain metastases is not well characterized and the optimal RT dose-fractionation schedule is undefined.
  
  
  METHODS
  Forty-two patients treated with HR in 3-5 fractions for 20 (48%) intact and 22 (52%) resected brain metastases with a median maximum dimension of 3.9 cm (0.8-6.4 cm) between May 2008 and August 2011 were reviewed. Twenty-two patients (52%) had received prior radiation therapy. Local (LC), intracranial progression free survival (PFS) and overall survival (OS) are reported and analyzed for relationship to multiple RT variables through Cox-regression analysis.
  
  
  RESULTS
  The most common dose-fractionation schedules were 21 Gy in 3 fractions (67%), 24 Gy in 4 fractions (14%) and 30 Gy in 5 fractions (12%). After a median follow-up time of 15 months (range 2-41), local failure occurred in 13 patients (29%) and was a first site of failure in 6 patients (14%). Kaplan-Meier estimates of 1 year LC, intracranial PFS, and OS are: 61% (95% CI 0.53 - 0.70), 55% (95% CI 0.47 - 0.63), and 73% (95% CI 0.65 - 0.79), respectively. Local tumor control was negatively associated with PTV volume (p = 0.007) and was a significant predictor of OS (HR 0.57, 95% CI 0.33 - 0.98, p = 0.04). Symptomatic radiation necrosis occurred in 3 patients (7%).
  
  
  CONCLUSIONS
  HR is well tolerated in both new and recurrent, previously irradiated intact or resected brain metastases. Local control is negatively associated with PTV volume and a significant predictor of overall survival, suggesting a need for dose escalation when using HR for large intracranial lesions.
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Rd, NE, Building A, Suite CT 104, Atlanta, GA 30322, USA. brupper@emory.edu
authors.forename: Bree R
authors.initials: BR
authors.lastname: Eaton
authors.forename: Brian
authors.initials: B
authors.lastname: Gebhardt
authors.forename: Roshan
authors.initials: R
authors.lastname: Prabhu
authors.forename: Hui-Kuo
authors.initials: HK
authors.lastname: Shu
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.forename: Ian
authors.initials: I
authors.lastname: Crocker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000401:mortality / Q000556:secondary* / Q000601:surgery*; D016371:Cranial Irradiation / Q000379:methods*; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016634:Radiosurgery / Q000009:adverse effects / Q000379:methods*; D011879:Radiotherapy Dosage; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult