今日の臨床サポート

転移性脳腫瘍

著者: 成田善孝 国立がん研究センター中央病院 脳脊髄腫瘍科

監修: 甲村英二 公立学校共済組合 近畿中央病院

著者校正/監修レビュー済:2020/05/21
参考ガイドライン:
  1. 日本脳腫瘍学会:脳腫瘍診療ガイドライン 2019年版 第2版 1.成人脳腫瘍編 2.小児脳腫瘍編
患者向け説明資料

概要・推奨   

  1. JCOG0504試験によって、摘出術後に全脳照射を行う必要はなく、摘出後残存がない場合は経過観察、残存がある場合は定位放射線照射を行うことが標準治療となった。またBrown/Mahajanの臨床試験によると、摘出後に残存がなくとも定位放射線照射を行うことにより、有意に摘出腔の局所制御率が高くなることが報告された(推奨度1)。
  1. 3cm以上の大きさの腫瘍に対しては、分割定位放射線照射も行われるが、放射線壊死のリスクも高くなるため、全身状態が安定している患者に対しては手術が第1選択で行われる(推奨度2)。
  1. 10個までの転移性脳腫瘍に対しても、全脳照射ではなく、定位放射線照射でも十分であると結論された(推奨度3)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
成田善孝 : 未申告[2021年]
監修:甲村英二 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行った(変更なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 転移性脳腫瘍の発生頻度についての正確な統計は存在しない。しかし文献によると癌患者の少なくとも10%が転移性脳腫瘍を発症するといわれており、癌罹患数が100万人であることを考えると、少なくとも年間10万人の癌患者が新たに脳転移を発症すると考えられている。
  1. 転移性脳腫瘍の原発腫瘍は、日本脳神経外科学会脳腫瘍全国集計調査報告(14版)によると肺癌(46.1%)、乳癌(14.5%)、大腸癌(6.0%)、腎癌(4.2%)、胃癌(3.3%)、直腸癌(3.0%)が多い。
  1. 初回受診時の転移巣の個数に関しては、上述の報告で単発(54.1%)、2~4個(30.6%)、5~9個(8.1%)、10個以上(4.9%)、髄膜癌腫症(2.3%)であった。
問診・診察のポイント  
  1. 上述の報告による転移性脳腫瘍診断時の特徴をまとめると以下のようになる。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Eric L Chang, Jeffrey S Wefel, Kenneth R Hess, Pamela K Allen, Frederick F Lang, David G Kornguth, Rebecca B Arbuckle, J Michael Swint, Almon S Shiu, Moshe H Maor, Christina A Meyers
雑誌名: Lancet Oncol. 2009 Nov;10(11):1037-44. doi: 10.1016/S1470-2045(09)70263-3. Epub 2009 Oct 2.
Abstract/Text BACKGROUND: It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction.
METHODS: Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test-Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov, number NCT00548756.
FINDINGS: After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0.0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis.
INTERPRETATION: Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases.

PMID 19801201  Lancet Oncol. 2009 Nov;10(11):1037-44. doi: 10.1016/S14・・・
著者: Takamasa Kayama, Shinya Sato, Kaori Sakurada, Junki Mizusawa, Ryo Nishikawa, Yoshitaka Narita, Minako Sumi, Yasuji Miyakita, Toshihiro Kumabe, Yukihiko Sonoda, Yoshiki Arakawa, Susumu Miyamoto, Takaaki Beppu, Kazuhiko Sugiyama, Hirohiko Nakamura, Motoo Nagane, Yoko Nakasu, Naoya Hashimoto, Mizuhiko Terasaki, Akira Matsumura, Eiichi Ishikawa, Toshihiko Wakabayashi, Yasuo Iwadate, Shiro Ohue, Hiroyuki Kobayashi, Manabu Kinoshita, Kenichiro Asano, Akitake Mukasa, Katsuyuki Tanaka, Akio Asai, Hideo Nakamura, Tatsuya Abe, Yoshihiro Muragaki, Koichi Iwasaki, Tomokazu Aoki, Takao Watanabe, Hikaru Sasaki, Shuichi Izumoto, Masahiro Mizoguchi, Takayuki Matsuo, Hideo Takeshima, Motohiro Hayashi, Hidefumi Jokura, Takashi Mizowaki, Eiji Shimizu, Hiroki Shirato, Masao Tago, Hiroshi Katayama, Haruhiko Fukuda, Soichiro Shibui, Japan Clinical Oncology Group
雑誌名: J Clin Oncol. 2018 Jun 20;:JCO2018786186. doi: 10.1200/JCO.2018.78.6186. Epub 2018 Jun 20.
Abstract/Text Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2-and 3 if caused only by neurologic deficits-and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.

PMID 29924704  J Clin Oncol. 2018 Jun 20;:JCO2018786186. doi: 10.1200/・・・
著者: Paul D Brown, Kurt Jaeckle, Karla V Ballman, Elana Farace, Jane H Cerhan, S Keith Anderson, Xiomara W Carrero, Fred G Barker, Richard Deming, Stuart H Burri, Cynthia Ménard, Caroline Chung, Volker W Stieber, Bruce E Pollock, Evanthia Galanis, Jan C Buckner, Anthony L Asher
雑誌名: JAMA. 2016 Jul 26;316(4):401-9. doi: 10.1001/jama.2016.9839.
Abstract/Text IMPORTANCE: Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial.
OBJECTIVE: To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT.
DESIGN, SETTING, AND PARTICIPANTS: At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013.
INTERVENTIONS: The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone.
MAIN OUTCOMES AND MEASURES: The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival.
RESULTS: There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P < .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, -48.7%; 95% CI, -87.6% to -9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, -34.4%; 95% CI, -74.4% to 5.5%; P = .04).
CONCLUSIONS AND RELEVANCE: Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00377156.

PMID 27458945  JAMA. 2016 Jul 26;316(4):401-9. doi: 10.1001/jama.2016.・・・
著者: Yongshun Chen, Jing Yang, Xue Li, Daxuan Hao, Xiaoyuan Wu, Yuanyuan Yang, Chunyu He, Wen Wang, Jianhua Wang
雑誌名: Cancer Sci. 2016 Dec;107(12):1800-1805. doi: 10.1111/cas.13079. Epub 2016 Nov 25.
Abstract/Text We proposed to compare the outcomes of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) alone with EGFR-TKI plus whole-brain radiotherapy (WBRT) for the treatment of brain metastases (BM) in patients with EGFR-mutated lung adenocarcinoma. A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study. Among the 132 patients, 72 (54.5%) harbored a deletion in exon 19, 97 (73.5%) showed multiple intracranial lesions, and 67 (50.8%) had asymptomatic BM. Seventy-nine patients (59.8%) were treated with EGFR-TKI alone, 53 with concomitant WBRT. The intracranial objective response rate was significantly higher in the EGFR-TKI plus WBRT treatment group (67.9%) compared with the EGFR-TKI alone group (39.2%) (P = 0.001). After a median follow-up of 36.2 months, 62.1% of patients were still alive. The median intracranial TTP was 24.7 months (95% CI, 19.5-29.9) in patients who received WBRT, which was significantly longer than in those who received EGFR-TKI alone, with the median intracranial TTP of 18.2 months (95% CI, 12.5-23.9) (P = 0.004). There was no significant difference in overall survival between WBRT and EGFR-TKI alone groups, (median, 48.0 vs 41.1 months; P = 0.740). The overall survival is significantly prolonged in patients who had an intracranial TTP exceeding 22 months compared to those who developed intracranial progression <22 months after treatment, (median, 58.0 vs 28.0 months; P = 0.001). For EGFR-mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT achieved a higher response rate of BM and significant improvement in intracranial progression-free survival compared with EGFR-TKI alone.

© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PMID 27627582  Cancer Sci. 2016 Dec;107(12):1800-1805. doi: 10.1111/ca・・・
著者: William J Magnuson, Nataniel H Lester-Coll, Abraham J Wu, T Jonathan Yang, Natalie A Lockney, Naamit K Gerber, Kathryn Beal, Arya Amini, Tejas Patil, Brian D Kavanagh, D Ross Camidge, Steven E Braunstein, Lauren C Boreta, Suresh K Balasubramanian, Manmeet S Ahluwalia, Niteshkumar G Rana, Albert Attia, Scott N Gettinger, Joseph N Contessa, James B Yu, Veronica L Chiang
雑誌名: J Clin Oncol. 2017 Apr 1;35(10):1070-1077. doi: 10.1200/JCO.2016.69.7144. Epub 2017 Jan 23.
Abstract/Text Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

PMID 28113019  J Clin Oncol. 2017 Apr 1;35(10):1070-1077. doi: 10.1200・・・
著者: R A Patchell, P A Tibbs, J W Walsh, R J Dempsey, Y Maruyama, R J Kryscio, W R Markesbery, J S Macdonald, B Young
雑誌名: N Engl J Med. 1990 Feb 22;322(8):494-500. doi: 10.1056/NEJM199002223220802.
Abstract/Text To assess the efficacy of surgical resection of brain metastases from extracranial primary cancer, we randomly assigned patients with a single brain metastasis to either surgical removal of the brain tumor followed by radiotherapy (surgical group) or needle biopsy and radiotherapy (radiation group). Forty-eight patients (25 in the surgical group and 23 in the radiation group) formed the study group; 6 other patients (11 percent) were excluded from the study because on biopsy their lesions proved to be either second primary tumors or inflammatory or infectious processes. Recurrence at the site of the original metastasis was less frequent in the surgical group than in the radiation group (5 of 25 [20 percent] vs. 12 of 23 [52 percent]; P less than 0.02). The overall length of survival was significantly longer in the surgical group (median, 40 weeks vs. 15 weeks in the radiation group; P less than 0.01), and the patients treated with surgery remained functionally independent longer (median, 38 weeks vs. 8 weeks in the radiation group; P less than 0.005). We conclude that patients with cancer and a single metastasis to the brain who receive treatment with surgical resection plus radiotherapy live longer, have fewer recurrences of cancer in the brain, and have a better quality of life than similar patients treated with radiotherapy alone.

PMID 2405271  N Engl J Med. 1990 Feb 22;322(8):494-500. doi: 10.1056/・・・
著者: C J Vecht, H Haaxma-Reiche, E M Noordijk, G W Padberg, J H Voormolen, F H Hoekstra, J T Tans, N Lambooij, J A Metsaars, A R Wattendorff
雑誌名: Ann Neurol. 1993 Jun;33(6):583-90. doi: 10.1002/ana.410330605.
Abstract/Text Most patients treated for single or multiple brain metastases die from progression of extracranial tumor activity. This makes it uncertain whether the combination of neurosurgery and radiotherapy for treatment of single brain metastasis will lead to better results than less invasive treatment with radiotherapy alone. The effect of neurosurgical excision plus radiotherapy was compared with radiotherapy alone in a prospectively randomized trial with 63 evaluable patients with systemic cancer and a radiological diagnosis of single brain metastasis. Radiotherapy was given to the whole brain by a novel scheme of 2 fractions per day of each 2 Gy for a total of 40 Gy. Before randomization, patients were stratified by site (lung cancer vs nonlung cancer) and status of extracranial disease (progressive vs stable). Survival as such and functionally independent survival (FIS; defined as World Health Organization performance status < or = 1 and neurological function < or = 1) were compared between both treatment arms. The combined treatment compared with radiotherapy alone led to a longer survival (p = 0.04) and a longer FIS (p = 0.06). This was most pronounced in patients with stable extracranial disease (median survival, 12 vs 7 mo; median FIS, 9 vs 4 mo). Patients with progressive extracranial cancer had a median overall survival of 5 months and a FIS of 2.5 months irrespective of given treatment. Improvement in functional status occurred more rapidly and for longer periods of time after neurosurgical excision and radiotherapy than after radiotherapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 8498838  Ann Neurol. 1993 Jun;33(6):583-90. doi: 10.1002/ana.410・・・
著者: R A Patchell, P A Tibbs, W F Regine, R J Dempsey, M Mohiuddin, R J Kryscio, W R Markesbery, K A Foon, B Young
雑誌名: JAMA. 1998 Nov 4;280(17):1485-9.
Abstract/Text CONTEXT: For the treatment of a single metastasis to the brain, surgical resection combined with postoperative radiotherapy is more effective than treatment with radiotherapy alone. However, the efficacy of postoperative radiotherapy after complete surgical resection has not been established.
OBJECTIVE: To determine if postoperative radiotherapy resulted in improved neurologic control of disease and increased survival.
DESIGN: Multicenter, randomized, parallel group trial.
SETTING: University-affiliated cancer treatment facilities.
PATIENTS: Ninety-five patients who had single metastases to the brain that were treated with complete surgical resections (as verified by postoperative magnetic resonance imaging) between September 1989 and November 1997 were entered into the study.
INTERVENTIONS: Patients were randomly assigned to treatment with postoperative whole-brain radiotherapy (radiotherapy group, 49 patients) or no further treatment (observation group, 46 patients) for the brain metastasis, with median follow-up of 48 weeks and 43 weeks, respectively.
MAIN OUTCOME MEASURES: The primary end point was recurrence of tumor in the brain; secondary end points were length of survival, cause of death, and preservation of ability to function independently.
RESULTS: Recurrence of tumor anywhere in the brain was less frequent in the radiotherapy group than in the observation group (9 [18%] of 49 vs 32 [70%] of 46; P<.001). Postoperative radiotherapy prevented brain recurrence at the site of the original metastasis (5 [10%] of 49 vs 21 [46%] of 46; P<.001) and at other sites in the brain (7 [14%] of 49 vs 17 [37%] of 46; P<.01). Patients in the radiotherapy group were less likely to die of neurologic causes than patients in the observation group (6 [14%] of 43 who died vs 17 [44%] of 39; P=.003). There was no significant difference between the 2 groups in overall length of survival or the length of time that patients remained functionally independent.
CONCLUSIONS: Patients with cancer and single metastases to the brain who receive treatment with surgical resection and postoperative radiotherapy have fewer recurrences of cancer in the brain and are less likely to die of neurologic causes than similar patients treated with surgical resection alone.

PMID 9809728  JAMA. 1998 Nov 4;280(17):1485-9.
著者: Laurie E Gaspar, Minesh P Mehta, Roy A Patchell, Stuart H Burri, Paula D Robinson, Rachel E Morris, Mario Ammirati, David W Andrews, Anthony L Asher, Charles S Cobbs, Douglas Kondziolka, Mark E Linskey, Jay S Loeffler, Michael McDermott, Tom Mikkelsen, Jeffrey J Olson, Nina A Paleologos, Timothy C Ryken, Steven N Kalkanis
雑誌名: J Neurooncol. 2010 Jan;96(1):17-32. doi: 10.1007/s11060-009-0060-9. Epub 2009 Dec 4.
Abstract/Text QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings?
TARGET POPULATION: These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection.
RECOMMENDATIONS: Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS + or - WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below.

PMID 19960231  J Neurooncol. 2010 Jan;96(1):17-32. doi: 10.1007/s11060・・・
著者: Dirk Rades, Jan-Dirk Kueter, Theo Veninga, Jan Gliemroth, Steven E Schild
雑誌名: Eur J Cancer. 2009 Feb;45(3):400-4. doi: 10.1016/j.ejca.2008.10.033. Epub 2008 Dec 4.
Abstract/Text This study is the first one to compare WBRT+SRS to OP+WBRT for 1-3 brain metastases. Survival (OS), intracerebral control (IC) and local control (LC) of the treated metastases were retrospectively evaluated in 52 patients undergoing WBRT+SRS and in 52 patients undergoing OP+WBRT. Both groups were matched for WBRT schedule, age, gender, performance status, tumour, number of brain metastases, extracerebral metastases, RPA class and interval from tumour diagnosis to WBRT. One-year OS was 56% after WBRT+SRS and 47% after OP+WBRT (p=0.034). One-year IC was 66% and 50% (p=0.003). One-year LC was 82% and 66% (p=0.006). On multivariate analyses, it was found that improved OS was associated with younger age (p=0.044), no extracerebral metastases (p<0.001), RPA class 1 (p<0.001) and longer interval from tumour diagnosis to WBRT (p=0.001). IC was associated with younger age (p=0.002) and longer interval (p=0.004); WBRT+SRS achieved borderline significance (p=0.052). Improved LC was associated with longer interval (p=0.017); WBRT+SRS showed a trend (p=0.09). WBRT+SRS appears at least as effective as OP+WBRT.

PMID 19062269  Eur J Cancer. 2009 Feb;45(3):400-4. doi: 10.1016/j.ejca・・・
著者: David W Andrews, Charles B Scott, Paul W Sperduto, Adam E Flanders, Laurie E Gaspar, Michael C Schell, Maria Werner-Wasik, William Demas, Janice Ryu, Jean-Paul Bahary, Luis Souhami, Marvin Rotman, Minesh P Mehta, Walter J Curran
雑誌名: Lancet. 2004 May 22;363(9422):1665-72. doi: 10.1016/S0140-6736(04)16250-8.
Abstract/Text BACKGROUND: Brain metastases occur in up to 40% of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG).
METHODS: Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements.
FINDINGS: From January, 1996, to June, 2001, we enrolled 333 patients from 55 participating RTOG institutions--167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 vs 4.9 months, p=0.0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months' follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p=0.03). By multivariate analysis, survival improved in patients with an RPA class 1 (p<0.0001) or a favourable histological status (p=0.0121).
INTERPRETATION: WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.

PMID 15158627  Lancet. 2004 May 22;363(9422):1665-72. doi: 10.1016/S01・・・
著者: Chirag G Patil, Katie Pricola, Sachin K Garg, Andrew Bryant, Keith L Black
雑誌名: Cochrane Database Syst Rev. 2010 Jun 16;(6):CD006121. doi: 10.1002/14651858.CD006121.pub2. Epub 2010 Jun 16.
Abstract/Text BACKGROUND: Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding radiosurgery to WBRT is unclear.
OBJECTIVES: To assess the efficacy of WBRT plus radiosurgery versus WBRT alone in the treatment of of brain metastases.
SEARCH STRATEGY: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2009), MEDLINE (1966 to 2009), EMBASE (1980 to 2009) and CancerLit (1975 to 2009) in order to identify trials for inclusion in this review.
SELECTION CRITERIA: The review was restricted to randomised controlled trials (RCTs) that compared use of radiosurgery and WBRT versus WBRT alone for upfront treatment of adult patients with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer
DATA COLLECTION AND ANALYSIS: The Generic Inverse Variance method, random effects model in RevMan 5 was used for the meta-analysis.
MAIN RESULTS: A meta-analysis of two trials with a total of 358 participants, found no statistically significant difference in overall survival (OS) between WBRT plus radiosurgery and WBRT alone groups (HR = 0.82, 95% CI 0.65 to 1.02). For patients with one brain metastasis median survival was significantly longer in WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months, P = 0.04). Patients in the WBRT plus radiosurgery group had decreased local failure compared to patients who received WBRT alone (HR = 0.27, 95% CI 0.14 to 0.52). Furthermore, a statistically significant improvement in performance status scores and decrease in steroid use was seen in the WBRT plus SRS group. Unchanged or improved KPS at 6 months was seen in 43% of patients in the combined therapy group versus only 28% in WBRT group (P = 0.03). Overall, risk of bias in the included studies was unclear.
AUTHORS' CONCLUSIONS: Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. Analysis of all included patients, SRS plus WBRT, did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for RPA Class I patients as well as patients with single metastasis.

PMID 20556764  Cochrane Database Syst Rev. 2010 Jun 16;(6):CD006121. d・・・
著者: Hidefumi Aoyama, Hiroki Shirato, Masao Tago, Keiichi Nakagawa, Tatsuya Toyoda, Kazuo Hatano, Masahiro Kenjyo, Natsuo Oya, Saeko Hirota, Hiroki Shioura, Etsuo Kunieda, Taisuke Inomata, Kazushige Hayakawa, Norio Katoh, Gen Kobashi
雑誌名: JAMA. 2006 Jun 7;295(21):2483-91. doi: 10.1001/jama.295.21.2483.
Abstract/Text CONTEXT: In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone.
OBJECTIVE: To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death.
DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003.
INTERVENTIONS: Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients).
MAIN OUTCOME MEASURES: The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death.
RESULTS: The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation.
CONCLUSIONS: Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used.
TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000412.

PMID 16757720  JAMA. 2006 Jun 7;295(21):2483-91. doi: 10.1001/jama.295・・・
著者: Martin Kocher, Riccardo Soffietti, Ufuk Abacioglu, Salvador Villà, Francois Fauchon, Brigitta G Baumert, Laura Fariselli, Tzahala Tzuk-Shina, Rolf-Dieter Kortmann, Christian Carrie, Mohamed Ben Hassel, Mauri Kouri, Egils Valeinis, Dirk van den Berge, Sandra Collette, Laurence Collette, Rolf-Peter Mueller
雑誌名: J Clin Oncol. 2011 Jan 10;29(2):134-41. doi: 10.1200/JCO.2010.30.1655. Epub 2010 Nov 1.
Abstract/Text PURPOSE: This European Organisation for Research and Treatment of Cancer phase III trial assesses whether adjuvant whole-brain radiotherapy (WBRT) increases the duration of functional independence after surgery or radiosurgery of brain metastases.
PATIENTS AND METHODS: Patients with one to three brain metastases of solid tumors (small-cell lung cancer excluded) with stable systemic disease or asymptomatic primary tumors and WHO performance status (PS) of 0 to 2 were treated with complete surgery or radiosurgery and randomly assigned to adjuvant WBRT (30 Gy in 10 fractions) or observation (OBS). The primary end point was time to WHO PS deterioration to more than 2.
RESULTS: Of 359 patients, 199 underwent radiosurgery, and 160 underwent surgery. In the radiosurgery group, 100 patients were allocated to OBS, and 99 were allocated to WBRT. After surgery, 79 patients were allocated to OBS, and 81 were allocated to adjuvant WBRT. The median time to WHO PS more than 2 was 10.0 months (95% CI, 8.1 to 11.7 months) after OBS and 9.5 months (95% CI, 7.8 to 11.9 months) after WBRT (P = .71). Overall survival was similar in the WBRT and OBS arms (median, 10.9 v 10.7 months, respectively; P = .89). WBRT reduced the 2-year relapse rate both at initial sites (surgery: 59% to 27%, P < .001; radiosurgery: 31% to 19%, P = .040) and at new sites (surgery: 42% to 23%, P = .008; radiosurgery: 48% to 33%, P = .023). Salvage therapies were used more frequently after OBS than after WBRT. Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and in 50 (28%) of 180 patients in the WBRT arm.
CONCLUSION: After radiosurgery or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival.

PMID 21041710  J Clin Oncol. 2011 Jan 10;29(2):134-41. doi: 10.1200/JC・・・
著者: A H Mintz, J Kestle, M P Rathbone, L Gaspar, H Hugenholtz, B Fisher, G Duncan, P Skingley, G Foster, M Levine
雑誌名: Cancer. 1996 Oct 1;78(7):1470-6.
Abstract/Text BACKGROUND: Cerebral metastasis is a common oncologic problem that occurs in 15-30% of cancer patients; approximately half such metastases are single. Previous retrospective studies and two randomized trials reported that the addition of surgical extirpation prior to radiation therapy increased survival, neurologic function, and quality of life compared with radiation alone in patients with a single brain metastasis.
METHODS: A randomized controlled trial was conducted in which patients with a single brain metastasis were allocated to undergo radiation alone or surgery plus radiation. Radiation consisted of 3000 centigray to the whole brain in 10 fractions.
RESULTS: Forty-three patients received radiation alone and 41 patients surgery plus radiation. All but two of the study patients died. No difference in survival was detected between the groups; the median survival for the radiation group was 6.3 months (95% confidence interval, 3-11.4) compared with 5.6 months for the surgery plus radiation group (95% confidence interval, 3.9-7.2) (P = 0.24). Most patients died within the first year (69.8% in the radiation arm vs. 87.8% in the surgery plus radiation arm). There were no significant differences in the 30-day mortality, morbidity, or causes of death. Extracranial metastases was an important predictor of mortality (relative risk, 2.3). The mean proportion of days that the Karnofsky performance status was > or = 70% did not differ between the 2 groups.
CONCLUSIONS: This trial failed to demonstrate that the addition of surgery to radiation therapy improved outcome of patients with a single brain metastasis. Thus, the efficacy of surgery plus radiation compared with radiation alone needs to be addressed by further clinical trials and/or a meta-analysis.

PMID 8839553  Cancer. 1996 Oct 1;78(7):1470-6.
著者: Anita Mahajan, Salmaan Ahmed, Mary Frances McAleer, Jeffrey S Weinberg, Jing Li, Paul Brown, Stephen Settle, Sujit S Prabhu, Frederick F Lang, Nicholas Levine, Susan McGovern, Erik Sulman, Ian E McCutcheon, Syed Azeem, Daniel Cahill, Claudio Tatsui, Amy B Heimberger, Sherise Ferguson, Amol Ghia, Franco Demonte, Shaan Raza, Nandita Guha-Thakurta, James Yang, Raymond Sawaya, Kenneth R Hess, Ganesh Rao
雑誌名: Lancet Oncol. 2017 Aug;18(8):1040-1048. doi: 10.1016/S1470-2045(17)30414-X. Epub 2017 Jul 4.
Abstract/Text BACKGROUND: After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone.
METHODS: In this randomised, controlled, phase 3 trial, we recruited patients at a single tertiary cancer centre in the USA. Eligible patients were older than 3 years, had a Karnofsky Performance Score of 70 or higher, were able to have an MRI scan, and had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity ≤4 cm). Patients were randomly assigned (1:1) with a block size of four to either SRS of the resection cavity (within 30 days of surgery) or observation. Patients were stratified by histology of the primary tumour, metastatic tumour size, and number of metastases. The primary endpoint was time to local recurrence in the resection cavity, assessed by blinded central review of brain MRI scans by the study neuroradiologist in the modified intention-to-treat population that analysed patients by randomised allocation but excluded patients found ineligible after randomisation. Participants and other members of the treatment team (excluding the neuroradiologist) were not masked to treatment allocation. The trial is registered with ClinicalTrials.gov, number NCT00950001, and is closed to new participants.
FINDINGS: Between Aug 13, 2009, and Feb 16, 2016, 132 patients were randomly assigned to the observation group (n=68) or SRS group (n=64), with 128 patients available for analysis; four patients were ineligible (three from the SRS group and one from the observation group). Median follow-up was 11·1 months (IQR 4·8-20·4). 12-month freedom from local recurrence was 43% (95% CI 31-59) in the observation group and 72% (60-87) in the SRS group (hazard ratio 0·46 [95% CI 0·24-0·88]; p=0·015). There were no adverse events or treatment-related deaths in either group.
INTERPRETATION: SRS of the surgical cavity in patients who have had complete resection of one, two, or three brain metastases significantly lowers local recurrence compared with that noted for observation alone. Thus, the use of SRS after brain metastasis resection could be an alternative to whole-brain radiotherapy.
FUNDING: National Institutes of Health.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28687375  Lancet Oncol. 2017 Aug;18(8):1040-1048. doi: 10.1016/S1・・・
著者: Paul D Brown, Karla V Ballman, Jane H Cerhan, S Keith Anderson, Xiomara W Carrero, Anthony C Whitton, Jeffrey Greenspoon, Ian F Parney, Nadia N I Laack, Jonathan B Ashman, Jean-Paul Bahary, Costas G Hadjipanayis, James J Urbanic, Fred G Barker, Elana Farace, Deepak Khuntia, Caterina Giannini, Jan C Buckner, Evanthia Galanis, David Roberge
雑誌名: Lancet Oncol. 2017 Aug;18(8):1049-1060. doi: 10.1016/S1470-2045(17)30441-2. Epub 2017 Jul 4.
Abstract/Text BACKGROUND: Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis.
METHODS: In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12-20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774.
FINDINGS: Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1-18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45-5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86-3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35-0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS vs 41 [85%] of 48 evaluable patients assigned to WBRT; difference -33·6% [95% CI -45·3 to -21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7-16·0, 69 deaths) for SRS and 11·6 months (9·9-18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76-1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group vs eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] vs five [5%]). There were no treatment-related deaths.
INTERPRETATION: Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population.
FUNDING: National Cancer Institute.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28687377  Lancet Oncol. 2017 Aug;18(8):1049-1060. doi: 10.1016/S1・・・
著者: Brian Patrick O'Neill, Nancy J Iturria, Michael J Link, Bruce E Pollock, Karla V Ballman, Judith R O'Fallon
雑誌名: Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1169-76.
Abstract/Text PURPOSE: To determine whether neurosurgery (NS) or stereotactic radiosurgery (RS) provided better local tumor control and enhanced patient survival.
METHODS AND MATERIALS: Retrospective review of all solitary brain metastases (SBM) patients newly diagnosed at Mayo Clinic Rochester between 1991 and 1999. Eligible patients satisfied tumor size and SBM site criteria to qualify for both NS and RS.
RESULTS: There were no significant differences between 74 NS and 23 RS patients in terms of baseline characteristics (age, gender, systemic disease type, systemic disease status, signs/symptoms at SBM presentation) or percent of patients who received whole brain radiotherapy. Median follow-up for alive patients was 20 months (range 0-106 months). There was no significant difference in patient survival (p = 0.15); the 1-year survival rate was 56% for the RS patients and 62% for the NS patients. Multivariate Cox regression analysis found that a significant prognostic factor for survival was a performance score of 0 or 1. There was a significant (p = 0.020) difference in local tumor control between NS and RS for solitary brain metastasis; none of the RS group had local recurrence compared to 19 (58%) of the NS group.
CONCLUSION: The need for a Phase III study comparing these two techniques appears to be supported by the data from this study.

PMID 12654423  Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1169-76.・・・
著者: 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
雑誌名: Lancet Oncol. 2014 Apr;15(4):387-95. doi: 10.1016/S1470-2045(14)70061-0. Epub 2014 Mar 10.
Abstract/Text 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.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24621620  Lancet Oncol. 2014 Apr;15(4):387-95. doi: 10.1016/S1470・・・

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