今日の臨床サポート

膠芽腫

著者: 園田順彦 山形大学医学部脳神経外科

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:2021/10/13
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
患者向け説明資料

概要・推奨   

  1. 症状の悪化を来たさない範囲での、可及的な摘出術が推奨される(推奨度2)。
  1. 70歳以下の成人に対しては、手術後、1日1回2Gy, 週5日間 計60Gyの放射線治療と経口内服薬テモゾロミドの投与を放射線治療期間中、ならびに放射線治療終了後に行う(Stuppプロトコール)(推奨度1)。
  1. 成人膠芽腫患者手術においてカルムスチン徐放性ポリマーの留置を考慮しても良い(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
  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。
  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
  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
  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
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:
園田順彦 : 未申告[2021年]
監修:甲村英二 : 特に申告事項無し[2021年]

病態・疫学・診察

病態・疫学・診察  
  1. 膠芽腫は、原発性脳腫瘍の約10%を占める、比較的頻度の高い疾患であり、国内ではおおよそ年間2000人程度が発症するといわれている。50歳以降の発症が80%を占めるが、小児・若年者の発症も多い。男女比は3:2で男性に多い。
  1. 浸潤性に急速に増大し、周囲に広範な浮腫性変化を伴うため、発症から診断までの期間はほとんどが半年以内である。
  1. 初発症状としては頭痛が最も多く、次いでけいれん、性格変化、見当識障害などが多い。しかしながら、運動麻痺などの巣症状や頭痛・吐き気・うっ血乳頭などの頭蓋内圧亢進症状が手術前に急速に悪化することがある。
問診・診察のポイント  
  1. 初期症状は、不定愁訴との鑑別が非常に困難であり、スクリーニングとして頭部単純CT、MRIを施行したとしても、CTでは小さな低吸収域病変、MRI T2強調画像でも高信号域病変を認めることが多く、その所見から確定診断をつけることは極めて難しい。脳梗塞との鑑別が困難な場合は2~3カ月後の、フォローアップCT、MRIを行い病変の拡大の有無を確認する。

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: M Lacroix, D Abi-Said, D R Fourney, Z L Gokaslan, W Shi, F DeMonte, F F Lang, I E McCutcheon, S J Hassenbusch, E Holland, K Hess, C Michael, D Miller, R Sawaya
雑誌名: J Neurosurg. 2001 Aug;95(2):190-8. doi: 10.3171/jns.2001.95.2.0190.
Abstract/Text OBJECT: The extent of tumor resection that should be undertaken in patients with glioblastoma multiforme (GBM) remains controversial. The purpose of this study was to identify significant independent predictors of survival in these patients and to determine whether the extent of resection was associated with increased survival time.
METHODS: The authors retrospectively analyzed 416 consecutive patients with histologically proven GBM who underwent tumor resection at the authors' institution between June 1993 and June 1999. Volumetric data and other tumor characteristics identified on magnetic resonance (MR) imaging were collected prospectively.
CONCLUSIONS: Five independent predictors of survival were identified: age, Karnofsky Performance Scale (KPS) score, extent of resection, and the degree of necrosis and enhancement on preoperative MR imaging studies. A significant survival advantage was associated with resection of 98% or more of the tumor volume (median survival 13 months, 95% confidence interval [CI] 11.4-14.6 months), compared with 8.8 months (95% CI 7.4-10.2 months; p < 0.0001) for resections of less than 98%. Using an outcome scale ranging from 0 to 5 based on age, KPS score, and tumor necrosis on MR imaging, we observed significantly longer survival in patients with lower scores (1-3) who underwent aggressive resections, and a trend toward slightly longer survival was found in patients with higher scores (4-5). Gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable.

PMID 11780887  J Neurosurg. 2001 Aug;95(2):190-8. doi: 10.3171/jns.200・・・
著者: Nader Sanai, Mei-Yin Polley, Michael W McDermott, Andrew T Parsa, Mitchel S Berger
雑誌名: J Neurosurg. 2011 Jul;115(1):3-8. doi: 10.3171/2011.2.jns10998. Epub 2011 Mar 18.
Abstract/Text OBJECT: The value of extent of resection (EOR) in improving survival in patients with glioblastoma multiforme (GBM) remains controversial. Specifically, it is unclear what proportion of contrast-enhancing tumor must be resected for a survival advantage and how much survival improves beyond this threshold. The authors attempt to define these values for the patient with newly diagnosed GBM in the modern neurosurgical era.
METHODS: The authors identified 500 consecutive newly diagnosed patients with supratentorial GBM treated at the University of California, San Francisco between 1997 and 2009. Clinical, radiographic, and outcome parameters were measured for each case, including MR imaging-based volumetric tumor analysis.
RESULTS: The patients had a median age of 60 years and presented with a median Karnofsky Performance Scale (KPS) score of 80. The mean clinical follow-up period was 15.3 months, and no patient was unaccounted for. All patients underwent resection followed by chemotherapy and radiation therapy. The median postoperative tumor volume was 2.3 cm(3), equating to a 96% EOR. The median overall survival was 12.2 months. Using Cox proportional hazards analysis, age, KPS score, and EOR were predictive of survival (p < 0.0001). A significant survival advantage was seen with as little as 78% EOR, and stepwise improvement in survival was evident even in the 95%-100% EOR range. A recursive partitioning analysis validated these findings and provided additional risk stratification parameters related to age, EOR, and tumor burden.
CONCLUSIONS: For patients with newly diagnosed GBMs, aggressive EOR equates to improvement in overall survival, even at the highest levels of resection. Interestingly, subtotal resections as low as 78% also correspond to a survival benefit.

PMID 21417701  J Neurosurg. 2011 Jul;115(1):3-8. doi: 10.3171/2011.2.j・・・
著者: Roger Stupp, Warren P Mason, Martin J van den Bent, Michael Weller, Barbara Fisher, Martin J B Taphoorn, Karl Belanger, Alba A Brandes, Christine Marosi, Ulrich Bogdahn, Jürgen Curschmann, Robert C Janzer, Samuel K Ludwin, Thierry Gorlia, Anouk Allgeier, Denis Lacombe, J Gregory Cairncross, Elizabeth Eisenhauer, René O Mirimanoff, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group
雑誌名: N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
Abstract/Text BACKGROUND: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety.
METHODS: Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival.
RESULTS: A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.
CONCLUSIONS: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.

Copyright 2005 Massachusetts Medical Society.
PMID 15758009  N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/・・・
著者: P Hau, D Koch, T Hundsberger, E Marg, B Bauer, R Rudolph, M Rauch, A Brenner, P Rieckmann, J Schuth, T Jauch, H Koch, U Bogdahn
雑誌名: Neurology. 2007 Feb 27;68(9):688-90. doi: 10.1212/01.wnl.0000255937.27012.ee.
Abstract/Text We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.

PMID 17325277  Neurology. 2007 Feb 27;68(9):688-90. doi: 10.1212/01.wn・・・
著者: Manfred Westphal, Dana C Hilt, Enoch Bortey, Patrick Delavault, Robert Olivares, Peter C Warnke, Ian R Whittle, Juha Jääskeläinen, Zvi Ram
雑誌名: Neuro Oncol. 2003 Apr;5(2):79-88. doi: 10.1093/neuonc/5.2.79.
Abstract/Text A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group ( P
PMID 12672279  Neuro Oncol. 2003 Apr;5(2):79-88. doi: 10.1093/neuonc/5・・・
著者: Masayuki Nitta, Yoshihiro Muragaki, Takashi Maruyama, Hiroshi Iseki, Takashi Komori, Soko Ikuta, Taiichi Saito, Takayuki Yasuda, Junji Hosono, Saori Okamoto, Shunichi Koriyama, Takakazu Kawamata
雑誌名: J Neurosurg. 2018 Dec 7;:1-8. doi: 10.3171/2018.7.JNS18422. Epub 2018 Dec 7.
Abstract/Text OBJECTIVE: In this study on the effectiveness and safety of photodynamic therapy (PDT) using talaporfin sodium and a semiconductor laser, the long-term follow-up results of 11 patients with glioblastoma enrolled in the authors' previous phase II clinical trial (March 2009-2012) and the clinical results of 19 consecutive patients with newly diagnosed glioblastoma prospectively enrolled in a postmarket surveillance (March 2014-December 2016) were analyzed and compared with those of 164 patients treated without PDT during the same period.
METHODS: The main outcome measures were the median overall survival (OS) and progression-free survival (PFS) times. Moreover, the adverse events and radiological changes after PDT, as well as the patterns of recurrence, were analyzed and compared between the groups. Kaplan-Meier curves were created to assess the differences in OS and PFS between the groups. Univariate and multivariate analyses were performed to identify the prognostic factors, including PDT, among patients with newly diagnosed glioblastoma.
RESULTS: The median PFS times of the PDT and control groups were 19.6 and 9.0 months, with 6-month PFS rates of 86.3% and 64.9%, respectively (p = 0.016). The median OS times were 27.4 and 22.1 months, with 1-year OS rates of 95.7% and 72.5%, respectively (p = 0.0327). Multivariate analyses found PDT, preoperative Karnofsky Performance Scale score, and IDH mutation to be significant independent prognostic factors for both OS and PFS. Eighteen of 30 patients in the PDT group experienced tumor recurrence, including local recurrence, distant recurrence, and dissemination in 10, 3, and 4 patients, respectively. Conversely, 141 of 164 patients in the control group experienced tumor recurrence, including 101 cases of local recurrence. The rate of local recurrence tended to be lower in the PDT group (p = 0.06).
CONCLUSIONS: The results of the present study suggest that PDT with talaporfin sodium and a semiconductor laser provides excellent local control, with few adverse effects even in cases of multiple laser irradiations, as well as potential survival benefits for patients with newly diagnosed glioblastoma.

PMID 30544336  J Neurosurg. 2018 Dec 7;:1-8. doi: 10.3171/2018.7.JNS18・・・
著者: Olivier L Chinot, Wolfgang Wick, Warren Mason, Roger Henriksson, Frank Saran, Ryo Nishikawa, Antoine F Carpentier, Khe Hoang-Xuan, Petr Kavan, Dana Cernea, Alba A Brandes, Magalie Hilton, Lauren Abrey, Timothy Cloughesy
雑誌名: N Engl J Med. 2014 Feb 20;370(8):709-22. doi: 10.1056/NEJMoa1308345.
Abstract/Text BACKGROUND: Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma.
METHODS: We randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival.
RESULTS: A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%).
CONCLUSIONS: The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT00943826.).

PMID 24552318  N Engl J Med. 2014 Feb 20;370(8):709-22. doi: 10.1056/N・・・
著者: Mark R Gilbert, James J Dignam, Terri S Armstrong, Jeffrey S Wefel, Deborah T Blumenthal, Michael A Vogelbaum, Howard Colman, Arnab Chakravarti, Stephanie Pugh, Minhee Won, Robert Jeraj, Paul D Brown, Kurt A Jaeckle, David Schiff, Volker W Stieber, David G Brachman, Maria Werner-Wasik, Ivo W Tremont-Lukats, Erik P Sulman, Kenneth D Aldape, Walter J Curran, Minesh P Mehta
雑誌名: N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573.
Abstract/Text BACKGROUND: Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known.
METHODS: In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25% reduction in the risk of death and a 30% reduction in the risk of progression or death, the two coprimary end points, with the addition of bevacizumab.
RESULTS: A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group.
CONCLUSIONS: First-line use of bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.).

PMID 24552317  N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/・・・
著者: Nobuhiro Hata, Koji Yoshimoto, Ryusuke Hatae, Daisuke Kuga, Yojiro Akagi, Yuhei Sangatsuda, Satoshi O Suzuki, Tadahisa Shono, Masahiro Mizoguchi, Koji Iihara
雑誌名: Onco Targets Ther. 2017;10:429-437. doi: 10.2147/OTT.S125587. Epub 2017 Jan 18.
Abstract/Text PURPOSE: The AVAglio trial established the beneficial effect of add-on bevacizumab (BEV) for the treatment of newly diagnosed glioblastomas (nd-GBMs) that led to the approval of BEV for the treatment of these patients in Japan. However, the rationality of using BEV as a first-line treatment for nd-GBMs remains controversial. The purpose of this study was to analyze the outcomes of a case series of nd-GBM patients.
PATIENTS AND METHODS: The outcomes of 69 nd-GBM patients treated after 2006 were retrospectively analyzed. Clinical and genetic analyses were performed, and estimates of progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Since add-on BEV therapy was only used for partially resected GBMs (pr-GBMs) after its approval in 2013, the patients were subdivided into 3 treatment groups: Type I, partial removal with temozolomide (TMZ)/BEV and concurrent radiotherapy (CCRT); Type II, partial removal with TMZ and CCRT; and Type III, gross total removal with TMZ and CCRT.
RESULTS: The PFS rate of Type I patients was significantly higher than that of Type II patients (P=0.014), but comparable to that of Type III patients. Differences in OS rates between Type I and Type II patients were less apparent (P=0.075), although the median OS of Type I patients was ~8 months higher than that of Type II patients (17.4 vs 9.8 months, respectively). The clinical deterioration rate during initial treatment was significantly (P=0.024) lower in Type I than in Type II patients (7.7% vs 47.4%, respectively). Differences in OS rates between Type I and Type II patients with a poor performance status (PS) were significant (P=0.017).
CONCLUSION: Our findings suggest that add-on BEV can prevent early clinical deterioration of pr-GBM patients and contribute to a prolonged survival, especially for those with a poor PS.

PMID 28176936  Onco Targets Ther. 2017;10:429-437. doi: 10.2147/OTT.S1・・・
著者: Roger Stupp, Sophie Taillibert, Andrew A Kanner, Santosh Kesari, David M Steinberg, Steven A Toms, Lynne P Taylor, Frank Lieberman, Antonio Silvani, Karen L Fink, Gene H Barnett, Jay-Jiguang Zhu, John W Henson, Herbert H Engelhard, Thomas C Chen, David D Tran, Jan Sroubek, Nam D Tran, Andreas F Hottinger, Joseph Landolfi, Rajiv Desai, Manuela Caroli, Yvonne Kew, Jerome Honnorat, Ahmed Idbaih, Eilon D Kirson, Uri Weinberg, Yoram Palti, Monika E Hegi, Zvi Ram
雑誌名: JAMA. 2015 Dec 15;314(23):2535-43. doi: 10.1001/jama.2015.16669.
Abstract/Text IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly.
OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma.
DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis.
INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle.
MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up.
RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004).
CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

PMID 26670971  JAMA. 2015 Dec 15;314(23):2535-43. doi: 10.1001/jama.20・・・
著者: W Roa, P M A Brasher, G Bauman, M Anthes, E Bruera, A Chan, B Fisher, D Fulton, S Gulavita, C Hao, S Husain, A Murtha, K Petruk, D Stewart, P Tai, R Urtasun, J G Cairncross, P Forsyth
雑誌名: J Clin Oncol. 2004 May 1;22(9):1583-8. doi: 10.1200/JCO.2004.06.082. Epub 2004 Mar 29.
Abstract/Text PURPOSE: To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM).
PATIENTS AND METHODS: One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br).
RESULTS: All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02).
CONCLUSION: There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.

PMID 15051755  J Clin Oncol. 2004 May 1;22(9):1583-8. doi: 10.1200/JCO・・・
著者: Wilson Roa, Lucyna Kepka, Narendra Kumar, Valery Sinaika, Juliana Matiello, Darejan Lomidze, Dalenda Hentati, Douglas Guedes de Castro, Katarzyna Dyttus-Cebulok, Suzanne Drodge, Sunita Ghosh, Branislav Jeremić, Eduardo Rosenblatt, Elena Fidarova
雑誌名: J Clin Oncol. 2015 Dec 10;33(35):4145-50. doi: 10.1200/JCO.2015.62.6606. Epub 2015 Sep 21.
Abstract/Text PURPOSE: The optimal radiotherapy regimen for elderly and/or frail patients with newly diagnosed glioblastoma remains to be established. This study compared two radiotherapy regimens on the outcome of these patients.
PATIENTS AND METHODS: Between 2010 and 2013, 98 patients (frail = age ≥ 50 years and Karnofsky performance status [KPS] of 50% to 70%; elderly and frail = age ≥ 65 years and KPS of 50% to 70%; elderly = age ≥ 65 years and KPS of 80% to 100%) were prospectively randomly assigned to two arms in a 1:1 ratio, stratified by age (< and ≥ 65 years old), KPS, and extent of surgical resection. Arm 1 received short-course radiotherapy (25 Gy in five daily fractions over 1 week), and arm 2 received commonly used radiotherapy (40 Gy in 15 daily fractions over 3 weeks).
RESULTS: The short-course radiotherapy was noninferior to commonly used radiotherapy. The median overall survival time was 7.9 months (95% CI, 6.3 to 9.6 months) in arm 1 and 6.4 months (95% CI, 5.1 to 7.6 months) in arm 2 (P = .988). Median progression-free survival time was 4.2 months (95% CI, 2.5 to 5.9) in arm 1 and 4.2 months (95% CI, 2.6 to 5.7) in arm B (P = .716). With a median follow-up time of 6.3 months, the quality of life between both arms at 4 weeks after treatment and 8 weeks after treatment was not different.
CONCLUSION: There were no differences in overall survival time, progression-free survival time, and quality of life between patients receiving the two radiotherapy regimens. In view of the reduced treatment time, the short 1-week radiotherapy regimen may be recommended as a treatment option for elderly and/or frail patients with newly diagnosed glioblastoma.

© 2015 by American Society of Clinical Oncology.
PMID 26392096  J Clin Oncol. 2015 Dec 10;33(35):4145-50. doi: 10.1200/・・・
著者: H Brem, S Piantadosi, P C Burger, M Walker, R Selker, N A Vick, K Black, M Sisti, S Brem, G Mohr
雑誌名: Lancet. 1995 Apr 22;345(8956):1008-12. doi: 10.1016/s0140-6736(95)90755-6.
Abstract/Text Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.

PMID 7723496  Lancet. 1995 Apr 22;345(8956):1008-12. doi: 10.1016/s01・・・
著者: Henry S Friedman, Michael D Prados, Patrick Y Wen, Tom Mikkelsen, David Schiff, Lauren E Abrey, W K Alfred Yung, Nina Paleologos, Martin K Nicholas, Randy Jensen, James Vredenburgh, Jane Huang, Maoxia Zheng, Timothy Cloughesy
雑誌名: J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31.
Abstract/Text PURPOSE: We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial.
PATIENTS AND METHODS: One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival.
RESULTS: In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade > or = 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively).
CONCLUSION: Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

PMID 19720927  J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 10.1200/J・・・
著者: Stephanie E Combs, Verena Widmer, Christoph Thilmann, Holger Hof, Juergen Debus, Daniela Schulz-Ertner
雑誌名: Cancer. 2005 Nov 15;104(10):2168-73. doi: 10.1002/cncr.21429.
Abstract/Text BACKGROUND: This article describes the results of a study of stereotactic radiosurgery (SRS) in the treatment of patients with recurrent malignant glioma.
METHODS: Thirty-two patients with recurrent glioblastoma multiforme (GBM) were treated for 36 lesions with SRS from 1993 to 2001. Nineteen patients were male and 13 were female. The median age at primary diagnosis of the tumor was 56 years (range, 33-76 yrs). At the time of initial diagnosis a total neurosurgical resection was performed in 7, a subtotal resection in 21, and a biopsy in 4 patients. Histology evaluations revealed glioblastoma multiforme (WHO Grade IV) in all 32 patients. In all patients radiotherapy was performed as the first-line therapy, applied as fractionated external beam radiotherapy. The median interval between primary irradiation and reirradiation was 10 months. The median dose applied was 15 Gy (range, 10-20 Gy) prescribed to the 80% isodose line that encompassed the target volume. No concomitant chemotherapy was applied.
RESULTS: Treatment was well tolerated by all patients. No acute toxicities > CTC Grade II occurred. No severe long-term toxicities including radionecrosis were observed. The median follow-up time was 13 months (range, 1-89 mo). All patients died of tumor progression during follow-up. The median overall survival from primary diagnosis of the tumor was 22 months (range, 9-133 mo). The survival rate at 1 year was 90%, and 49% and 26% at 2 and 3 years, respectively. Median overall survival after SRS was 10 months. At 6 and 12 months after SRS, survival rates were 72% and 28%, respectively. Median progression-free survival after SRS was 7 months.
CONCLUSIONS: SRS offers effective treatment as a salvage therapy for a subgroup of patients with smaller lesions of recurrent GBM.

Copyright 2005 American Cancer Society
PMID 16220556  Cancer. 2005 Nov 15;104(10):2168-73. doi: 10.1002/cncr.・・・

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