Masaaki Yamamoto1, Toru Serizawa2, Takashi Shuto3, Atsuya Akabane4, Yoshinori Higuchi5, Jun Kawagishi6, Kazuhiro Yamanaka7, Yasunori Sato8, Hidefumi Jokura6, Shoji Yomo9, Osamu Nagano10, Hiroyuki Kenai11, Akihito Moriki12, Satoshi Suzuki13, Yoshihisa Kida14, Yoshiyasu Iwai15, Motohiro Hayashi16, Hiroaki Onishi17, Masazumi Gondo18, Mitsuya Sato19, Tomohide Akimitsu20, Kenji Kubo21, Yasuhiro Kikuchi22, Toru Shibasaki23, Tomoaki Goto24, Masami Takanashi25, Yoshimasa Mori26, Kintomo Takakura27, Naokatsu Saeki5, Etsuo Kunieda28, Hidefumi Aoyama29, Suketaka Momoshima30, Kazuhiro Tsuchiya31. 1. Katsuta Hospital Mito Gamma House, Hitachi-naka, Japan. Electronic address: BCD06275@nifty.com. 2. Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo, Japan. 3. Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan. 4. Gamma Knife Center, NTT Medical Center Tokyo, Tokyo, Japan. 5. Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan. 6. Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Japan. 7. Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan. 8. Clinical Research Center, Chiba University Graduate School of Medicine, Chiba, Japan. 9. Saitama Gamma Knife Center, Sanai Hospital, Saitama, Japan. 10. Gamma Knife House, Chiba Cardiovascular Center, Ichihara, Japan. 11. Department of Neurosurgery, Nagatomi Neurosurgical Hospital, Oita, Japan. 12. Department of Neurosurgery, Mominoki Hospital, Kochi, Japan. 13. Department of Neurosurgery, Steel Memorial Yawata Hospital, Kitakyushu, Japan. 14. Department of Neurosurgery, Komaki City Hospital, Komaki, Japan. 15. Department of Neurosurgery, Osaka City General Hospital, Osaka, Japan. 16. Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan. 17. Department of Neurosurgery, Asanogawa General Hospital, Kanazawa, Japan. 18. Gamma Center Kagoshima, Atsuchi Neurosurgical Hospital, Kagoshima, Japan. 19. Department of Neurosurgery, Kitanihon Neurosurgical Hospital, Gosen, Japan. 20. Department of Neurosurgery, Takanobashi Central Hospital, Hiroshima, Japan. 21. Department of Neurological Surgery, Koyo Hospital, Wakayama, Japan. 22. Department of Neurosurgery, Southern Tohoku Research Institute for Neuroscience, Southern Tohoku General Hospital, Koriyama, Japan. 23. Department of Neurosurgery, Hidaka Hospital, Takasaki, Japan. 24. Department of Neurosurgery, Saiseikai Kumamoto Hospital, Kumamoto, Japan. 25. Department of Neurosurgery, Nakamura Memorial Hospital, Sapporo, Japan. 26. Nagoya Radiosurgery Center, Nagoya Kyoritsu Hospital, Nagoya, Japan. 27. Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan. 28. Department of Radiation Oncology, Tokai University, Isehara, Japan. 29. Department of Radiology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan. 30. Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan. 31. Department of Radiology, Kyorin University Faculty of Medicine, Tokyo, Japan.
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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Japan Brain Foundation.
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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Japan Brain Foundation.
Authors: Louis Burt Nabors; Jana Portnow; Mario Ammirati; Henry Brem; Paul Brown; Nicholas Butowski; Marc C Chamberlain; Lisa M DeAngelis; Robert A Fenstermaker; Allan Friedman; Mark R Gilbert; Jona Hattangadi-Gluth; Deneen Hesser; Matthias Holdhoff; Larry Junck; Ronald Lawson; Jay S Loeffler; Paul L Moots; Maciej M Mrugala; Herbert B Newton; Jeffrey J Raizer; Lawrence Recht; Nicole Shonka; Dennis C Shrieve; Allen K Sills; Lode J Swinnen; David Tran; Nam Tran; Frank D Vrionis; Patrick Yung Wen; Nicole R McMillian; Maria Ho Journal: J Natl Compr Canc Netw Date: 2014-11 Impact factor: 11.908
Authors: Or Cohen-Inbar; Zhiyuan Xu; Blair Dodson; Tanvir Rizvi; Christopher R Durst; Sugoto Mukherjee; Jason P Sheehan Journal: J Neurooncol Date: 2016-08-27 Impact factor: 4.130