Articles Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study Masaaki Yamamoto*, Toru Serizawa*, Takashi Shuto, Atsuya Akabane, Yoshinori Higuchi, Jun Kawagishi, Kazuhiro Yamanaka, Yasunori Sato, Hidefumi Jokura, Shoji Yomo, Osamu Nagano, Hiroyuki Kenai, Akihito Moriki, Satoshi Suzuki, Yoshihisa Kida, Yoshiyasu Iwai, Motohiro Hayashi, Hiroaki Onishi, Masazumi Gondo, Mitsuya Sato, Tomohide Akimitsu, Kenji Kubo, Yasuhiro Kikuchi, Toru Shibasaki, Tomoaki Goto, Masami Takanashi, Yoshimasa Mori, Kintomo Takakura, Naokatsu Saeki, Etsuo Kunieda, Hidefumi Aoyama, Suketaka Momoshima, Kazuhiro Tsuchiya Summary Background We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the Lancet Oncol 2014 initial treatment for patients with fi ve to ten brain metastases is non-inferior to that for patients with two to four brain Published Online metastases in terms of overall survival. March 10, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70061-0 Methods This prospective observational study enrolled patients with one to ten newly diagnosed brain metastases (largest See Online/Comment tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL) and a Karnofsky performance http://dx.doi.org/10.1016/ status score of 70 or higher from 23 facilities in Japan. Standard stereotactic radiosurgery procedures were used in all S1470-2045(14)70076-2 patients; tumour volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery and those that were *Contributed equally 4–10 mL with 20 Gy. The primary endpoint was overall survival, for which the non-inferiority margin for the comparison Katsuta Hospital Mito of outcomes in patients with two to four brain metastases with those of patients with fi ve to ten brain metastases was set Gamma House, Hitachi-naka, 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 Japan (Prof M Yamamoto MD); study was fi nalised on Dec 31, 2012, for analysis of the primary endpoint; however, monitoring of stereotactic radiosurgery- Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, induced complications and neurocognitive function assessment will continue for the censored subset until the end of Tokyo, Japan (T Serizawa MD); 2014. This study is registered with the University Medical Information Network Clinical Trial Registry, number 000001812. Department of Neurosurgery, Yokohama Rosai Hospital, Findings Yokohama, Japan (T Shuto MD); We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after Gamma Knife Center, stereotactic radiosurgery was 13·9 months [95% CI 12·0–15·6] in the 455 patients with one tumour, 10·8 months NTT Medical Center Tokyo, [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 fi ve to ten Tokyo, Japan (A Akabane MD); tumours. Overall survival did not diff er between the patients with two to four tumours and those with fi ve to ten (HR 0·97, Department of Neurological Surgery (Y Higuchi MD, 95% CI 0·81–1·18 [less than non-inferiority margin], p=0·78; pnon-inferiority<0·0001). Stereotactic radiosurgery-induced Prof N Saeki MD), and Clinical adverse events occurred in 101 (8%) patients; nine (2%) patients with one tumour had one or more grade 3–4 event Research Center (Y Sato PhD), compared with 13 (2%) patients with two to four tumours and six (3%) patients with fi ve to ten tumours. The proportion Chiba University Graduate of patients who had one or more treatment-related adverse event of any grade did not diff er signifi cantly between the two School of Medicine, Chiba, Japan; Jiro Suzuki Memorial groups of patients with multiple tumours (50 [9%] patients with two to four tumours vs 18 [9%] with fi ve to ten; p=0·89). Gamma House, Furukawa Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumour and one each in Seiryo Hospital, Osaki, Japan the other two groups). (J Kawagishi MD, H Jokura MD); Department of Neurosurgery, Osaka City University Graduate Interpretation Our results suggest that stereotactic radiosurgery without WBRT in patients with fi ve to ten brain School of Medicine, Osaka, metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of Japan (K Yamanaka MD); stereotactic radiosurgery and the fewer side-eff ects than with WBRT, stereotactic radiosurgery might be a suitable Saitama Gamma Knife Center, alternative for patients with up to ten brain metastases. Sanai Hospital, Saitama, Japan (S Yomo MD); Gamma Knife House, Chiba Cardiovascular Funding Japan Brain Foundation. Center, Ichihara, Japan (O Nagano MD); Department Introduction neurological function if their brain metastases are well of Neurosurgery, Nagatomi 3 Neurosurgical Hospital, Brain metastases are a common, life-threatening controlled. Since Lindquist fi rst reported that a patient Oita, Japan (H Kenai MD); neurological problem for patients with cancer, in the with a brain metastasis had been successfully treated with Department of Neurosurgery, absence of eff ective treatment. Previously, outcomes in stereotactic radiosurgery, evidence of the eff ectiveness of Mominoki Hospital, Kochi, patients with brain metastases were uniformly poor, and this treatment has been accumulating, for both stereotactic Japan (A Moriki MD); Department of Neurosurgery, 4,5 palliative treatments—eg, steroids and whole-brain radiosurgery alone and in combination with WBRT. Steel Memorial Yawata radiotherapy (WBRT)—have dominated management Compared with WBRT, stereotactic radiosurgery has Hospital, Kitakyushu, Japan recommendations.1,2 However, mainly due to recent several benefi ts: it can be done in 1 day; more than 80% of (S Suzuki MD); Department advances in systemic cancer treatment, an appropriately patients will have their tumour controlled by this of Neurosurgery, Komaki City Hospital, Komaki, Japan selected subgroup of patients with brain metastases can treatment, which can lead to early symptom palliation, (Y Kida MD); Department of now achieve longer survival with maintenance of good even if the lesion is radioresistant; it can be repeated and Neurosurgery, Osaka City www.thelancet.com/oncology Published online March 10, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70061-0 1 Articles General Hospital, Osaka, Japan can be done after WBRT; it does not prevent radiation chose the observational study design described herein. If (Y Iwai MD); Department of therapy for other parts of the body, chemotherapy, or major this study failed to prove the non-inferiority hypothesis, a Neurosurgery (M Hayashi MD), surgery for another lesion; the incidence and magnitude of prospective randomised trial would be unnecessary. We and Institute of Advanced Biomedical Engineering and deterioration of neurocognitive function are much lower also took into consideration that the importance of Science (Prof K Takakura MD), than with WBRT;6 and the amount of radiation hair loss is validating non-inferiority has come to be widely accepted. Tokyo Women’s Medical minimal compared with WBRT. University, Tokyo, Japan; Department of Neurosurgery, Because many factors aff ect outcomes in patients with Methods Asanogawa General Hospital, brain metastases, a one-size-fi ts-all treatment framework Study design and participants Kanazawa, Japan (H Onishi MD); in which four or more tumours are automatically This prospective observational cohort study selected Gamma Center Kagoshima, recommended for WBRT is not appropriate. On the basis participants with several brain metastases from Atsuchi Neurosurgical Hospital, 4,5 Kagoshima, Japan of results from randomised controlled studies, 23 hospitals in Japan. Patients were eligible for inclusion (M Gondo MD); Department of stereotactic radiosurgery alone for patients with four or if, at the time that they underwent stereotactic radiosurgery, Neurosurgery, Kitanihon even fi ve or more tumours is not standard, and WBRT is they had newly diagnosed brain metastases that were Neurosurgical Hospital, Gosen, still strongly recommended in most industrialised confi rmed by contrast-enhanced MRI no more than Japan (M Sato MD); Department 7,8 of Neurosurgery, Takanobashi nations. However, evidence that patients with fi ve or 6 weeks before the procedure, they had ten or fewer Central Hospital, Hiroshima, more or even ten or more tumours might be potential tumours, their largest tumour was smaller than 10 mL in Japan (T Akimitsu MD); candidates for stereotactic radiosurgery alone has been volume and smaller than 3·0 cm in longest diameter, the Department of Neurological building since the early 21st century.9 Since Yamamoto cumulative volume of all their tumours was 15·0 mL or Surgery, Koyo Hospital, 10 Wakayama, Japan (K Kubo MD); and colleagues reported that two patients with brain smaller, they had no leptomeningeal dissemination Department of Neurosurgery, metastases with ten or more tumours were successfully fi ndings, and had a Karnofsky performance status (KPS) Southern Tohoku Research treated with stereotactic radiosurgery,10 retrospective score of 70 or higher or, in patients with a KPS score of less Institute for Neuroscience, studies of patients with many brain metastases who have than 70, a reasonable expectation of neurological function Southern Tohoku General been successfully treated with stereotactic radiosurgery