title: Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.
abstract: BACKGROUND
  We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the initial treatment for patients with five to ten brain metastases is non-inferior to that for patients with two to four brain metastases in terms of overall survival.
  
  
  METHODS
  This prospective observational study enrolled patients with one to ten newly diagnosed brain metastases (largest tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL) and a Karnofsky performance status score of 70 or higher from 23 facilities in Japan. Standard stereotactic radiosurgery procedures were used in all patients; tumour volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery and those that were 4-10 mL with 20 Gy. The primary endpoint was overall survival, for which the non-inferiority margin for the comparison of outcomes in patients with two to four brain metastases with those of patients with five to ten brain metastases was set as the value of the upper 95% CI for a hazard ratio (HR) of 1·30, and all data were analysed by intention to treat. The study was finalised on Dec 31, 2012, for analysis of the primary endpoint; however, monitoring of stereotactic radiosurgery-induced complications and neurocognitive function assessment will continue for the censored subset until the end of 2014. This study is registered with the University Medical Information Network Clinical Trial Registry, number 000001812.
  
  
  RESULTS
  We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after stereotactic radiosurgery was 13·9 months [95% CI 12·0-15·6] in the 455 patients with one tumour, 10·8 months [9·4-12·4] in the 531 patients with two to four tumours, and 10·8 months [9·1-12·7] in the 208 patients with five to ten tumours. Overall survival did not differ between the patients with two to four tumours and those with five to ten (HR 0·97, 95% CI 0·81-1·18 [less than non-inferiority margin], p=0·78; pnon-inferiority<0·0001). Stereotactic radiosurgery-induced adverse events occurred in 101 (8%) patients; nine (2%) patients with one tumour had one or more grade 3-4 event compared with 13 (2%) patients with two to four tumours and six (3%) patients with five to ten tumours. The proportion of patients who had one or more treatment-related adverse event of any grade did not differ significantly between the two groups of patients with multiple tumours (50 [9%] patients with two to four tumours vs 18 [9%] with five to ten; p=0·89). Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumour and one each in the other two groups).
  
  
  CONCLUSIONS
  Our results suggest that stereotactic radiosurgery without WBRT in patients with five to ten brain metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of stereotactic radiosurgery and the fewer side-effects than with WBRT, stereotactic radiosurgery might be a suitable alternative for patients with up to ten brain metastases.
  
  
  BACKGROUND
  Japan Brain Foundation.
authors.affiliation: Katsuta Hospital Mito Gamma House, Hitachi-naka, Japan. Electronic address: BCD06275@nifty.com.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Serizawa
authors.affiliation: Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shuto
authors.affiliation: Gamma Knife Center, NTT Medical Center Tokyo, Tokyo, Japan.
authors.forename: Atsuya
authors.initials: A
authors.lastname: Akabane
authors.affiliation: Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kawagishi
authors.affiliation: Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Clinical Research Center, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Jokura
authors.affiliation: Saitama Gamma Knife Center, Sanai Hospital, Saitama, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yomo
authors.affiliation: Gamma Knife House, Chiba Cardiovascular Center, Ichihara, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.affiliation: Department of Neurosurgery, Nagatomi Neurosurgical Hospital, Oita, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kenai
authors.affiliation: Department of Neurosurgery, Mominoki Hospital, Kochi, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Moriki
authors.affiliation: Department of Neurosurgery, Steel Memorial Yawata Hospital, Kitakyushu, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Neurosurgery, Komaki City Hospital, Komaki, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kida
authors.affiliation: Department of Neurosurgery, Osaka City General Hospital, Osaka, Japan.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Iwai
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Neurosurgery, Asanogawa General Hospital, Kanazawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Onishi
authors.affiliation: Gamma Center Kagoshima, Atsuchi Neurosurgical Hospital, Kagoshima, Japan.
authors.forename: Masazumi
authors.initials: M
authors.lastname: Gondo
authors.affiliation: Department of Neurosurgery, Kitanihon Neurosurgical Hospital, Gosen, Japan.
authors.forename: Mitsuya
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Neurosurgery, Takanobashi Central Hospital, Hiroshima, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Akimitsu
authors.affiliation: Department of Neurological Surgery, Koyo Hospital, Wakayama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kubo
authors.affiliation: Department of Neurosurgery, Southern Tohoku Research Institute for Neuroscience, Southern Tohoku General Hospital, Koriyama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: Department of Neurosurgery, Hidaka Hospital, Takasaki, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Shibasaki
authors.affiliation: Department of Neurosurgery, Saiseikai Kumamoto Hospital, Kumamoto, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Goto
authors.affiliation: Department of Neurosurgery, Nakamura Memorial Hospital, Sapporo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Takanashi
authors.affiliation: Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital, Nagoya, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kintomo
authors.initials: K
authors.lastname: Takakura
authors.affiliation: Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Naokatsu
authors.initials: N
authors.lastname: Saeki
authors.affiliation: Department of Radiation Oncology, Tokai University, Isehara, Japan.
authors.forename: Etsuo
authors.initials: E
authors.lastname: Kunieda
authors.affiliation: Department of Radiology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Aoyama
authors.affiliation: Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Suketaka
authors.initials: S
authors.lastname: Momoshima
authors.affiliation: Department of Radiology, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuchiya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000401:mortality / Q000556:secondary* / Q000601:surgery*; D005260:Female; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D016016:Proportional Hazards Models; D011829:Radiation Dosage; D016634:Radiosurgery / Q000009:adverse effects / Q000401:mortality; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden