Neurological Surgery 脳神経外科36巻4号

2008年04月発行

総説

膠芽腫に対する中性子捕捉療法

著者： 山本哲哉¹ 中井啓¹ 松村明¹

所属機関： ¹筑波大学大学院人間総合科学研究科機能制御医学（脳神経外科学）

ページ範囲：P.293 - P.302

Ⅰ．はじめに

　悪性神経膠腫に対する高線量の放射線治療は，標準的X線分割照射治療と比べ腫瘍本体（main tumor mass）に高い治療効果を期待できる一方で，浸潤域（infiltrating area）では浸潤腫瘍細胞に対する効果と正常組織障害が同時に起こってくることへの対策が必要である．これまでの報告では，線量集中性の高い定位照射を用いたboost法が最も一般的で，過分割照射法，強度変調法や陽子線を用いた治療法も試みられてきた．これらの臨床試験では，膠芽腫での生存期間が20カ月を超えるとする良好な結果も含まれるが^{4,12,13,26,34,35,45)}，小規模なcase seriesが多く，生存期間延長効果がないとする報告もあり^32,38,50)，十分な評価を得るには至っていない．

　1936年，Locherがアルファ線を利用した選択的な癌治療として，ホウ素の非放射性同位体（¹⁰B）と中性子の核反応の利用（中性子捕捉療法）を提唱してから70年余が経過した³⁰⁾．中性子を取り扱う技術的課題や原子炉施設の利便性から長い期間を要したが，近年になって実用的な中性子捕捉療法の治療シミュレーションが可能となり，従来の悪性新生物に対する放射線治療と同様，線量分布に基づいた臨床効果の判定ができるようになった．

　中性子捕捉療法は，治療に用いる中性子ビームの特殊性から，限られた研究用原子炉で行われているのが現状である．国内の臨床研究は日本原子力研究開発機構（JAEA，茨城県）のJRR-4において行われ，現在6大学の研究グループが参加している．JRR-4における中性子捕捉療法の治療件数は頭頸部癌への適応拡大を契機に年々増加してきており，2006年の治療件数は26例，うち半分の13例が膠芽腫をはじめとする悪性脳腫瘍となっている（Fig. 1）．また海外でも，HFR（High Flux Reactor，オランダ），FiR-1（Finnish Research Reactor，フィンランド），SRR（Studsvik Research Reactor，チェコ），NRIR（Nuclear Research Institute of Rez，アルゼンチン）などの研究用原子炉を中心に臨床研究が行われている．

　中性子捕捉療法は，中性子を直接治療に用いるのではなく，ホウ素と中性子の核反応により2次的に得られたアルファ粒子線（および⁷Li粒子）を治療に用いる．腫瘍細胞選択的照射を行いうるユニークな高LET（linear energy transfer）粒子線治療として研究が続けられ，近年，汎用性が高く簡便に本治療を行うための小型加速器中性子源の開発も本格化しつつある．本稿では膠芽腫に対する中性子捕捉療法の現状について概説する．

参考文献

1）Anderson AP：Postoperative irradiation of glioblastomas. Results in a randomized series. Acta Radiol Oncol Radiat Phys Biol 17：475-484, 1978

2）Barth RF, Yang W, Rotaru JH, Moeschberger ML, Joel DD, Nawrocky MM, Goodman JH, Soloway AH：Boron neutron capture therapy for brain tumors：enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption. Cancer Res 57：1129-1136, 1997

3）Barth RF, Grecula JC, Yang W, Rotaru JH, Nawrocky M, Gupta N, Alvertson BJ, Ferketick AK, Moeschberger ML, Coderre JA, Rofstad EK：Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors. Int J Radiat Oncol Biol Phys 58：267－277, 2004

4）Baumert BG, Lutterbach J, Bernays R, Davis JB, Heppner FL：Fractionated stereotactic radiotherapy boost after post-operative radiotherapy in patients with high-grade gliomas. Radiother Oncol 67：183-190, 2003

5）Bleehen NM, Stennning SP：A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Receach Council Brain Tumour Working Party. Br J Cancer 64：769-774, 1991

6）Capala J, Stenstam BH, Sköld K, af Rosenschöld PM, Giusti V, Persson C, Wallin E, Brun A, Franzen L, Carlsson J, Salford L, Ceberg C, Persson B, Pellettieri L, Henriksson R：Boron neutron capture therapy for glioblastoma multiforme：clinical studies in Sweden. J Neurooncol 62：135－144, 2003

7）Ceberg CP, Brun A, Kahl SB, Koo MS, Persson BR, Salford LG：A comparative study on the pharmacokinetics and biodistribution of boronated porphyrin (BOPP) and sulfhydryl boron hydride (BSH) in the RG2 rat glioma model. J Neurosurg 83：86－92, 1995

8）Chanana AD, Capala J, Chadha M, Coderre JA, Diaz AZ, Elowitz EH, Iwai J, Joel DD, Liu HB, Ma R, Pendzick N, Peress NS, Shady MS, Slatkin DN, Tyson GW, Wielopolski L：Boron neutron capture therapy for glioblastoma multiforme：interim results from the phaseⅠ/Ⅱdose-escalation studies. Neurosurgery 44：1182-1193, 1999

9）Colman H, Berkey BA, Maor MH, Groves MD, Schultz CJ, Vermeulen S, Nelson DF, Mehta MP, Yung WKA：PhaseⅡradiation therapy oncology group trial of conventional radiation therapy followed by treatment with recombinant interferon-β for supratentorial glioblastoma；resurls of RTOG 9710. Int J Radiat Oncol Biol Phys 66：819-824, 2006

10）Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson JS, Tsukaba Y：Comparison of postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group Study. Cancer 53：997-1007, 1983

11）Culbertson CN, Green S, Mason AJ, Picton D, Baugh G, Hugtenburg RP, Yin Z, Scott MC, Nelson JM：In-phantom characterization studies at the Birmingham Accelerator-Generated epIthermal Neutron Source (BAGINS) BNCT facility. Appl Radiat Isot 61：733-738, 2004

12）Fitzek MM, Thornton AF, Rabinov JD, Lev MH, Pardo FS, Munzenrider JE, Okunieff P, Bussiere M, Braun I, Hochberg FH, Hedley-Whyte ET, Liebsch NJ, Harsh GR 4th：Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme：results of a phase II prospective trial. J Neurosurg 91：251-260, 1999

13）Ganett D, Stea B, Lulu B, Adair T, Verdi C, Hamilton A：Stereotactic radiosurgery as an adjunct to surgery and external beam radiotherapy in the treatment of patients with malignant gliomas. Int J Radiat Oncol Biol Phys 33：461-468, 1995

14）Havu-Auren K, Kiiski J, Lehtio K, Eskola O, Kulvik M, Vuorinen V, Oikonen V, Vahatalo J, Jaaskelainen J, Minn H：Uptake of 4-borono-2-[(18)F]fluoro-L：-phenylalanine in sporadic and neurofibromatosis 2-related schwannoma and meningioma studied with PET. Eur J Nucl Med Mol Imaging 34：87-94, 2007

15）Horn V, Pharm D, Slansky J, Janku I, Strouf O, Sourek K, Tovarys F：Disposition and tissue distribution of boron after infusion of borocaptate sodium in patients with malignant brain tumors. Int J Radiat Oncol Biol Phys 41：631-638, 1998

16）Imahori Y, Ueda S, Ohmori Y, Sakae K, Kusuki T, Kobayashi T, Takagaki M, Ono K, Ido T, Fujii R：Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas：partⅡ. Clin Cancer Res 4：1833-1841, 1998

17）Isaac MF, Kahl SB：Synthesis of ether- and carbon-linked polycarboranyl porphyrin dimers for cancer therapies. J Organomet Chem 680：232－243, 2003

18）Joel DD, Coderre JA, Micca PL, Nawrocky MM：Effect of dose and infusion time on the delivery of p-boronophenylalanine for neutron capture therapy. J Neurooncol 41：213－221, 1999

19）Justus E, Awad D, Hohnholt M, Schaffran T, Edwards K, Karlsson G, Damian L, Gabel D：Synthesis, liposomal preparation, and in vitro toxicity of two novel dodecaborate cluster lipids for boron neutron capture therapy. Bioconjug Chem 18：1287-1293, 2007

20）Kageji T, Nagahiro S, Matsuzaki K, Mizobuchi Y, Toi H, Nakagawa Y, Kumada H：Boron neutron capture therapy using mixed epithermal and thermal neutron beams in patients with malignant glioma-correlation between radiation dose and radiation injury and clinical outcome. Int J Radiat Oncol Biol Phys 65：1446-1455, 2006

21）Kankaanranta L, Seppälä T, Koivunoro H, Saarilahti K, Atula T, Collan J, Salli E, Kortesniemi M, Uusi-Simola J, Mäkitie A, Seppänen M, Minn H, Kotiluoto P, Auterinen I, Savolainen S, Kouri M, Joensuu H：Boron neutron capture therapy in the treatment of locally recurred head and neck cancer. Int J Radiat Oncol Biol Phys 69：475-82, 2007

22）Kobayashi T, Kanda K：Analytical calculation of boron-10 dosage in cell nucleus for neutron capture therapy. Radiat Res 91：77-94, 1982

23）Kraft SL, Gavin PR, Leathers CW, DeHaan CE, Bauer WF, Miller DL, DornⅢRV, Griebenow ML：Biodistribution of boron in dogs with spontaneous intracranial tumors following borocaptate sodium administration. Cancer Res 54：1259-1263, 1994

24）Kumada H, Yamamoto K, Matsumura A, Yamamoto T, Nakagawa Y, Nakai K, Kageji T：Verification of the computational dosimetry system in JAERI (JCDS) for boron neutron capture therapy. Phys Med Biol 49：3353-3365, 2004

25）Kumada H, Yamamoto T, Yamamoto K, Nakai K, Nakagawa Y, Kageji T, Matsumura A：Improvement of dose calculation accuracy for BNCT dosimetry by the multi-voxel method in JCDS. Appl Radiat Isot 61：1045-1051, 2004

26）Kondziolka D, Flickinger JC, Bissonette DJ, Bozik M, Lunsford LD：Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 41：776-785, 1997

27）Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Nesbakken R, Hatlevoll R, Lindgren M, Brun A, Lindgren S, Notter G, Andersen AP, Elgen K：Combined modality therapy of operated astrocytomas gradeⅢand IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time：a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 47：649-652, 1981

28）Kumada H, Yamamoto K, Matsumura A, Yamamoto T, Nakagawa Y, Nakai K, Kageji T：Verification of the computational dosimetry system in JAERI (JCDS) for boron neutron capture therapy. Phys Med Biol 2004 49：3353-3365

29）小野公二：悪性神経膠腫の硼素中性子捕捉療法（原子炉医療）．脳外速報6：429-434, 1996

30）Locher GL：Biological effects and therapeutic possibilities of neutrons. Am J Roentgenol/Radium Ther 36：1-13, 1936

31）Miyatake S, Kawabata S, Kajimoto Y, Aoki A, Yokoyama K, Yamada M, Kuroiwa T, Tsuji M, Imahori Y, Kirihata M, Sakurai Y, Masunaga S, Nagata K, Maruhashi A, Ono K：Modified boron neutron capture therapy for malignant gliomas performed using epithermal neutron and two boron compounds with different accumulation mechanisms：an efficacy study based on findings on neuroimages. J Neurosurg 103：1000-1009, 2005

32）Mehta MP, Masciopinto J, Rozental J, Levin A, Chappell R, Bastin K, Miles J, Turski P, Kubsad S, Mackie T, Kinsella T：Stereotactic radiosurgery for glioblastoma multiforme：report of a prospective study evaluating prognostic factors and analyzing long-term survival advantage. Int J Radiat Oncol Biol Phys 30：541-549, 1994

33）Nakagawa Y, Hatanaka H：Boron neutron capture therapy. Clinical brain tumor studies. J Neurooncol 33：105-115, 1997

34）Nwokedi EC, DiBiase SJ, Jabbour S, Herman J, Amin P, Chin LS：Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery 50：41-47, 2002

35）Shrieve DC, Alexander III E, Black PM, Wen PY, Fine HA, Kooy HM, Loeffler JS：Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost：prognostic factors and long-term outcome. J Neurosurg 90：72-77, 1999

36）Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA, Pistenmaa DA：Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg 71：1-9, 1989

37）Smith D, Chandra S, Barth R, Yang W, Joel D, Coderre JA：Quantitative imaging and microlocalization of boron-10 in brain tumors and infiltrating tumor cells by SIMS ion microscopy：relevance to neutron capture therapy. Cancer Res 61：8179－8187, 2001

38）Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Suse W, Okunieff P, Buckner J, Zamorano L, Mehta M, Curran WJ：Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme：report of RadiationTherapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 60：853-860, 2004

39）Stenstam BH, Pellettieri L, Sorteberg W, Rezaei A, Skold K：BNCT for recurrent intracranial meningeal tumours - case reports. Acta Neurol Scand 115：243-247, 2007

40）Stragliotto G, Fankhauser H：Biodistribution and pharmacokinetics of boron-sulfhydryl for boron neutron capture therapy in patients with intracranial tumors. Neurosurgery 36：285-293, 1995

41）Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group：Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352：987-996, 2005

42）Sweet WH, Soloway AH, Brownell GL： Boron-slow neutron capture therapy of gliomas. Acta Radiol 1：114-121, 1963

43）Sweet WH：Early history of development of boron neutron capture therapy of tumors. J Neurooncol 33：19-26, 1997

44）Tamura Y, Miyatake S, Nonoguchi N, Miyata S, Yokoyama K, Doi A, Kuroiwa T, Asada M, Tanabe H, Ono K：Boron neutron capture therapy for recurrent malignant meningioma. Case report. J Neurosurg 105：898-903, 2006

45）Tanaka M, Ino Y, Nakagawa k, Tago M, Todo T：High-dose conformal radiotherapy for supratentorial malignant glioma：a historical comparison. Lancet Oncol 6：953-960, 2005

46）Yamamoto T, Matsumura A, Nakai K, Shibata Y, Endo K, Sakurai F, Kishi T, Kumada H, Yamamoto K, Torii Y：Current clinical results of Tsukuba BNCT trial. Appl Radiat Isot 61：1089-1093, 2004

47）Yamamoto T, Matsumura A, Yamamoto K, Kumada H, Hori N, Torii Y, Shibata Y, Nose T：Characterization of neutron beams for boron neutron capture therapy：in-air radiobiological dosimetry. Radiat Res 160：70-76, 2003

48）Yamamoto T, Matsumura A, Yamamoto K, Kumada H, Shibata Y, Nose T：In-phantom two-dimensional thermal neutron distribution for intraoperative boron neutron capture therapy of brain tumours. Phys Med Biol 47：2387-2396, 2002

49）Yoshida F, Matsumura A, Shibata Y, Yamamoto T, Nakauchi H, Okumura M, Nose T：Cell cycle dependence of boron uptake from two boron compounds used for clinical neutron capture therapy. Cancer Lett 187：135-141, 2002

50）Werner-Wasik M, Scott CB, Melson DF, Gasper LE, Murray KJJ, Fischbach JA, Nelson JS, Weinstein AS, Curran WJ：Final report of a PhaseⅠ/Ⅱtrial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Cancer 15：1535-1543, 1996

51）Walker MD, Strike TA, Sheline GE：An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5：1725-1731, 1979