Recent Advances and Updates in Multimodal Treatment for Gliomas

Transcription

1 14 th Asian Australasian Congress of Neurosurgical Surgeons (AACNS 2015) Controvercies in Brain Tumor Treatment Recent Advances and Updates in Multimodal Treatment for Gliomas Toshihiko Wakabayashi Department of Neurosurgery, Graduate School of Medicine, Nagoya University,JAPAN Apr, Nagoya, Japan

2 Introduction: Background Gliomas account for approximately 40% of all brain tumors and are thus the most common primary tumors of the central nervous system (CNS). High-grade (WHO grades III and IV) malignant gliomas that include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), and glioblastoma multiforme (GBM) are often resistant to treatment. Especially, GBM, the most common glioma in adults, kills patients within a median time span of a year after diagnosis despite treatment with aggressive surgical resection, chemotherapy, and radiotherapy.

3 Characteristic Biology of Malignant Glioma Aggressive infiltration into normal brain tissue including subependymal, subpial and CSF dissemination but not extra neural tissue Induction of marked peri-tumoral edema Resistant to current adjuvant therapy: chemotherapy, immunotherapy and radiotherapy Poor response of host immune system Uncontrolled rapid growth Lest than 2 years of average survival time

4 Current therapeutic strategy Image Guided tumor resection (operation) with Neuronavigation system, Functional brain mapping, Intraoperative neuro-physiological monitoring and Awake surgery Post operative radiation therapy whole brain 50Gy + local boost 10Gy Additional adjuvant chemotherapy Temozolomide, BCNU wafer, Bevasizumab, PCZ+CCNU+VCR(PCV) IFN-β and MCNU/ACNU (BCNU/CCNU) Cisplatinum, Etoposide, Vincristine

5 Key Words for Further Development of Neuro-Science Molecular Imaging Probe Targeting image by PET Highly Qualified Robotics Accurate approach to the target Molecular Targeting Therapy New drugs and materials

6 Key Words for Further Development of Neuro-Science Highly Qualified Robotics Accurate approach to the target High Quality Robot Intra-operative image-guided surgery Improvement of neuro-navigation system Combination with neuro-endoscope Robotic surgery (Neuro-Mate & Neuro-Convect)

7 Design concept of intraoperative MRI units imri (intraoperative MRI) units Magnetic field Low ( tesla) High( tesla) Different concepts with respect to scanner and operating room design Surgery directly in the scanner Patient transport system Dedicated system for intraoperative use Hybrid systems combining intraoperative use with routine radiologic diagnostics.

8 Automatic image fusion

9 Fusion image technology Pre-ope(3 tesra) Fusion image Intra -ope(0.4 tesra) Fusion tech.

10 Development of advanced image computation Various 3D virtual images :virtual operative field etc Enhance surgeons understanding of operative field and information about anatomy and critical function. Image fusion Especially important technique for low magnetic field scanner Preoperative anatomical, functional and tissue information (3-T high resolution image, fmri, DTI, MEG, PET, MRS) available on shifted intraoperative MRI

11 Pre-operative planning by image fusions Meth-PET

12 Pre-operative planning image; How to reach to tumor without damage of tract

13 Intraoperative MRI (Nagoya central hospital; An affiliated hospital of Nagoya Univ.) BrainSUITE is the state-of-the art operating room, a neurosurgical OR that integrates all the surgical and diagnostic tools Brain Suite 1.5-T Symphony (SIEMENS)

14 Brain THEATER:operation-supporting network Network of intra-operative microscopic and 3D virtual endoscopic Images Head Quarter (Department of Neurosurgery) Nagoya Central Hosp. Brain SUITE Graduate School of Information Science Nagoya University Nagoya Univ. Hosp. Department of Radiological Technology imri OR iplan server Novalis

15 Future prospect for development of operative accuracy Navigation combined with intra-operative image-guided surgery supported by imri imri Remnant mass Total removal Pre-MRI imri Remnant mass imri Total removal Post-MRI Pre-operative mass 55.4ml Post-operative mass 3.4ml Removal rate 93.8% Solve the problems 1) Non-visible remnant mass on MRI 2) Non-resectable remnant mass 3) Eloquent area near by remnant

16 Challenge for last one mile by newly developed neurosurgical technology Intelligent Neurosurgical equipments Remocal rate:93.8% Challenge to the Removal rate:100% New process approach For neurosurgery Sensing Operation Informatics Real time changing image guided surgery

17 Newly developed neuro-endoscope (Proto-type) Sensing Informatics Operation 3D image endoscope, sensor for mass, irrigation and suction, light guide, flexible neck for 360 degree, 2 device holder 3D endoscope 360 degree flexible Light-guide Compact and smooth Suction Operative tool port Diameter Φ15 Tip size Φ10

18 Challenge for last one mile by newly developed neurosurgical technology 18

19 Challenge for last one mile by newly developed neurosurgical technology 19

20 Challenge for last one mile by newly developed neurosurgical technology 20

21 Challenge for last one mile by newly developed neurosurgical technology 21

22 Convection Enhanced Delivery (CED) system

23 Trial Model of Nucleic Acid Therapy by means of Convectionenhanced Delivery System

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25 Key Words for Further Development of Neuro-Science Molecular Targeting Therapy New drugs and materials Molecular targeting therapy Gene therapy/ Nucleic acid therapy Cell therapy/regenerative therapy (ips) Nanotechnology for DDS Stem cell therapy

26 Temozolomide Temozolomide (TMZ), an oral alkylating agent, has been demonstrated to possess antitumor activity against malignant gliomas, with minimal additional toxicity; furthermore, in a previous study, treatment with this agent significantly prolonged the median survival time. However, its clinical outcomes depend on the O 6 - methylguanine-dna methyltransferase (MGMT) status, and MGMT modification is one of the key factors to obtain greater clinical benefits in the future.

27 Stupp R, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III Study; 5-years analysis on the EORTC-NCIC trial. Lancet Oncol 10(5): 434-5, 2009 Regimen 2 yrs 3 yrs 4 yrs 5 yrs Ratiotherapy alone 10.9% 4.4% 3.0% 1.9% Combined with TMZ 27.2% 16.0% 12.1% 9.8%

28 Stupp R, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III Study; 5-years analysis on the EORTC-NCIC trial. Lancet Oncol 10(5): 434-5, 2009 Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy MGMT unmethylated 2 yrs 3 yrs 4 yrs 5 yrs Ratiotherapy alone 1.8% 0% 0% 0% Combined with TMZ 14.8% 11.1% 11.1% 8.3% MGMT methylated 2 yrs 3 yrs 4 yrs 5 yrs Ratiotherapy alone 29.3% 7.8% 7.8% 5.2% Combined with TMZ 48.9% 27.6% 22.1% 13.8%

29 Current Reports of Combination Chemotherapy with Temozolomide Drug Phase Reference BCNU Phase I Raizer JJ et al. Neurooncology 2004 CCNU Phase II Herrlinger U et al. J. Clin. Oncol Thalidomide Phase II Chang SM et al. Int. J. Radiat. Oncol. Biol. Phys Retinoic acid Phase II Butowski N et al. Int. J. Radiat. Oncol. Biol. Phys Tamoxifen Phase II Spence AM et al. J. Neurooncology 2004 Interferon-b Phase I Wakabayashi T et al. JJCO 2008, Cancer Sci.2011 Cisplatinum Phase II Silvani A et al. J Neurooncology 2004 O 6 -BG Phase I Quinn JA et al. J. Clin. Oncol Marimastat Phase II Groves MD et al. J. Clin. Oncol. 2002

30 Interferon-b (IFN-b) Interferon-b ((IFN-b)) exhibits pleiotropic biological effects and has been widely used either alone or in combination with other antitumor agents in the treatment of malignant gliomas and melanomas. In the treatment of malignant gliomas, IFN-b can act as a drug sensitizer, enhancing toxicity against various neoplasms when administered in combination with nitrosourea. IFN-b and nitrosourea combination therapy has been particularly used for the treatment of gliomas in Japan.

31 IFN- b IFN type I receptor ISGF3,IRF-1 CBP/p300 IRF-3complex formation p53 MGMT Cancer Res. 65(17): , 2005 Interferon-beta (IFN-β) sensitized temozolomide (TMZ)-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via TP53 induction.

32 Cancer. 117(8), , 2011

33 Clinical, genetic, and epigenetic parameters associated with survival in GBM patients p=0.032 p=0.029 The log-rank tests demonstrated that 1) tumor localization (p=0.032), 2) the MGMT methylation status (p=0.029), 3) and TP53 mutation or loss ( p=0.035) were associated with the OS of patients with GBM p=0.035

34 The combination of IFN-β with TMZ ( Overall survival ) p=0.007 The median OS of the combination group was significantly greater with 19.9 months (95% CI, 15.3 to 24.5) as compared to the TMZ alone group, which was 12.7 months (95% CI, 10.5 to 14.9)

35 Benefits of IFN-β for GBM patients with the unmethylated MGMT promoter p=0.017 Even in patients whose tumors had the unmethylated MGMT promoter, the median OS was prolonged to 17.2 months (95% CI, 13.9 to 20.6) when receiving TMZ with IFN-β as compared to the 12.5 months (95% CI, 11.3 to 13.7) in those receiving TMZ without IFN-β (p = 0.003).

36 Estimated effect of TMZ with IFN-β versus TMZ without IFN-β In the subpopulation analysis, the use of IFN-β combination had significant associations with patients under 40 years of age (p=0.025), with ECOG PS <1 (p=0.004), deep tumor location (p=0.028), non-gtr (p=0.048), and ummethylated MGMT status (p=0.02).

37 Development of molecular targeted treatment In the Temozolomide era, Methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter has been closed up as a molecular target. MGMT proficient gliomas show a poorer prognosis. Inhibition of MGMT expression may induce a better prognosis. Silencing of MGMT expression by molecular targeted therapy by genomic therapy has been developed.

38 Gene therapy for brain tumors by means of liposome entrapped human interferon-b gene

39 Advance Medicine and Clinical Study Managing Center Gene Therapy Gene therapy The first gene therapy for malignant glioma opened, which made in Japan technology ( Interferon-beta gene /cationic liposomes) 2000 Regenerative therapy Artificial mucosa, skin, tooth, bone etc Cell therapy Dendritic cells (DC), CTLs Center for Genetic and Regenerative Medicine since 2002 Bio-material Division based on GMP (- 450 m2 ) Unit for Gene Therapy Unit for Regenerative Medicine Unit for Cell Therapy Collabaration Unit Division of genetic Analysis Division of Information Network Supported by ISO 9001:2000 & ISO 13485:2003

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41 Future prospects Enhancement effects for anti-tumor drug Temozolomide by means of MGMT-siRNA Neural stem cell therapy transduced with the IFN-b and cytosine deaminase genes Genetically engineered armed T-cell therapy (T-body therapy)

42 Future prospects Enhancement effects for anti-tumor drug Temozolomide by means of MGMT-siRNA Neural stem cell therapy transduced with the IFN-b and cytosine deaminase genes Genetically engineered armed T-cell therapy (T-body therapy)

43 Development of Nucleic Acid Medicine Antisense Ribozyme sirna Decoy DNA Aptamer Structure Single strand DNA/RNA (13-25 mer) Single strand RNA Double strand RNA (21-23 mer) Double strand DNA Target mrna mrna mrna Transfer factor Function Productizati on Inhibition of transfer Virtavene (CMV retinitis 1998) Enzymatic function Inhibition of expression Inhibition of transfer Single or Double strand RNA (15-60 mer) Protein Inhibition of function MACUGEN (VEGF;agerelated macular degeneration 2008)

44 Liposomes could be used by DDS in vivo MGMT Exp. Pre Post Collabolator:Hokkaido System Science UCSF Results: Nat Rev Drug Dsicov, 2009 に紹介 Priority: PCT/JP2007/ (HSS) Kato et al. Gene Therapy, 2010.

45 Conclusion Combination treatments strategy with newly developed molecular targeting image by PET, robotics and medical technology with molecular targeting therapy may constitute a new advance to induce further therapeutic strategy for malignant brain tumors.

46 Collaborator Dept. of Neurosurg. Nagoya Univ. Sch. Med. Atsushi Natsume, Kazuya Motomura, Hiromichi Suzuki, Kosuke Aoki, Yasukazu Kajita, Masato Hara, Syou Okamoto, Masazumi Fujii, Dai Ishii, Masasuke Ohno, Satoshi Itoh, Takenori Katou, Keiko Maeda, Motokazu Itoh, Shinji Shimato, Center for genetic and Regenerative Med., Nagoya Univ., Masaaki Mizuno, Katsuyoshi Kato Dept. of Med. Tech., Nagoya Univ., Sch. Med., Masatoshi Tsusaka, Miciko Hata, Youhei Watanabe, Yukari Hara, Dept. of Industrial technology, Nagoya Univ. Sch. Tech. Kensaku Mori, Yuichiro Hayashi Brain and Mind Research Center, Nagoya University Satoshi Maezawa, HIrohisa Watanabe, Gen Sobue Nagoya Central Hosp. Norimoto Nakahara, Narinori Takebayashi Dept. of Neurosurg., UCSF.USA Hideho Okada Jun Yoshida