10/16/2012. Neuro-Oncology The Beginnings. Neuro-Oncology The Beginnings. Primary Brain Tumors. Types of Primary Brain Tumors

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1 Neuro Oncology From Old to New Maciej M Mrugala, MD, PhD, MPH Associate Professor Department of Neurology and Neurosurgery University of Washington Medical Center Neuro-Oncology The Beginnings Galen (129 CE ca 199) De Tumoribus Hidden cancer without ulceration will not appear (on the surface) but remains in the depths of the body It is incurable and any attempt at removal will irritate the cancer still more and kill the patient faster Neuro-Oncology The Beginnings Primary Brain Tumors Incidence on the rise 41,130 new cases annually in US (both benign and malignant; CBTRUS data for 2004); 62,940 expected to be diagnosed in 2010 >180,000 new cases annually worldwide Risk factors still poorly understood Malignant glioma (22,070 primary malignant tumors to be diagnosed in 2010): 1. Glioblastoma (GBM) 2. Anaplastic tumors Low grade gliomas: 1. Astrocytoma 2. Oligodendroglioma 3. Mixed tumors Giovanni Andrea Della Croce, Chirurgiae 1573 Types of Primary Brain Tumors Incidence Rates of Primary Brain Tumors HGG LGG MENING VSCH PIT MIS HGG LGG MENING VSCH PIT MIS 1. High grade glioma (HGG) 2. Low grade glioma (LGG) 3. Meningioma i (MENING) 4. Vestibular schwannoma (VSCH) 5. Pituitary tumors (PIT) 6. Miscelanneous (MIS) CBTRUS , Wrensh et al.,

2 Do Cell Phones Cause Cancer or Not? The Latest Answer Is No By Bryan Walsh Cell phones and brain tumors (glioma) Swedish cell phone study First classification of brain tumors Pooled data from two case-controlled studies ( ) Association between use of mobile and cordless phones and malignant brain tumors only (GLIOMAS) Replies obtained from 85% of cases and 84% controls Immense surgical database of Harvey Cushing and pathological expertise of Percival Bailey - publication in Increased risk with latency period and with cumulative use in hours 2. Highest risk for astrocytoma (OR=2.7) in > 10 year latency group 3. Highest risk when wireless phone used before the age of 20 mobile phone OR=4.9, cordless phone OR=3.9 Hardell et al. International Journal of Oncology, Feb WHO Classification Prognostic Implications of Tumor Grade GRADE I - "BENIGN" or Low-Grade GRADE II - "BENIGN" or Low-Grade (more diffuse) GRADE III ANAPLASTIC (cellular atypia, etc. ) GRADE IV- MALIGNANT (necrosis, vascularity, mitoses) Median Tumor Type Survival, years Low-grade oligodendroglioma Low-grade astrocytoma 5 3 Anaplastic oligodendroglioma Anaplastic astrocytoma 3 3 Glioblastoma multiforme <1 1 1Bruce J, et al. Available at: 2 Hariharan S. Available at: 3DeAngelis LM. N Engl J Med. 2001;344:

3 Before we were able to see the tumor Identification: imaging (CT scan) Identification: imaging (MRI) Identification: imaging (MR Spectroscopy) T1 no contrast T1 with contrast FLAIR Low grade glioma High grade glioma Pathologic Diagnosis Low Grade Astrocytoma Stereotactic Biopsy CT or MRI guided biopsy 2% risk, sampling error Open Biopsy: Craniotomy Mortality <5% in major centers Mini tumor excision T1 + gad H&E Non-enhancing mass Cellular pleomorphic infiltrates 3

4 Anaplastic Astrocytoma (WHO III) Glioblastoma (WHO IV) T1 + gad H&E T1 + gad H&E May enhance, 30% don t enhance! Cellular, mitoses w/o vessels Enhancing cystic w. necrosis Cellular, vessels, necrosis, MIB-1 Beginnings of brain tumor surgery Surgery Goals: Accurate diagnosis Maximum tumor debulking: >98% advantage Preservation of neurologic function: mapping Reduces mass effect - palliation Increases survival by 2-3 mos. Newer techniques: Intraoperative MRI (low grade gliomas) Functional mapping, DWI To remove a glioma is to remove a piece of brain Daniel Silbergeld Extent of surgery is an important prognostic factor Surgical Implantation of Chemotherapy Wafers: Gliadel 13 mo P< mo P=0.02 >98% >98% All patients No prior treatment (n=416) (n=233) Lacroix M, et al. J Neurosurg. 2001;95: Data from Stummer et al, Neurosurgery 2008, confirmed benefit of more extensive resection. Gliadel is a trademark of Guilford Pharmaceuticals. N=240 (new GMB) 6-8 wafers Median Survival 13.9 vs Westphal et al, Neuro-Oncology

5 Polish contribution to neuro-oncology and the beginning of radiation-oncology Radiation Therapy Improved survival for anaplastic gliomas and GBM Prolonged time to progression for low grade gliomas XRT to the tumor and 1-2 cm margin Dose Gy = 5-6 weeks of therapy First chemotherapy trials Chemotherapy Chemotherapy prolongs survival At 1 year: 15% decrease in risk of death Increased survival of 6% (40% to 46%) 2 month increase in median survival time Effect of chemotherapy was independent of age, sex, histology, KPS or extent of resection Stewart et al, 2002 Meta-analysis of 12 Trials Limitations of Chemotherapy in Treating Brain Tumors: Perfusion and Hypoxia Temozolomide: Second-Generation Alkylating Agent TMZ spontaneously converts to MTIC at physiologic ph O C NH 2 ph > 7.0 O C NH 2 O N Spontaneous N NH 2 N N hydrolysis N C N + N N N N N NH 2 O CH CH 3 N 3 H N N CH 3 Temozolomide MTIC AIC Methyldiazonium ion Rieger J, et al MTIC, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide. Denny BJ, et al. Biochemistry. 1994;33: % oral bioavailability Crosses blood-brain barrier 20% of serum AUC found in CSF Minimal cytochrome P450 effect 5

6 Adjuvant Temozolomide Improves Survival in Glioblastoma Adjuvant Temozolomide Improves Survival in Glioblastoma Adjuvant Temozolomide Improves Survival in Glioblastoma Glioblastoma Current Standard of Care Maximal surgical resection Radiotherapy with concomitant and adjuvant chemotherapy (temozolomide) Stupp et all., 2005 (n=286) (n=287) Median OS = months 2-year OS = 15-27% of patients Median OS at recurrence = 6-7 months Median PFS at recurrence = 2-3 months Genetics and brain tumors Novel Therapies Gene Gene Function Chromosome Comment TP53 Tumor suppressor 17p % of all grades of astrocytomas, 65% of low grade astrocytomas MDM2 Oncogene 12q14.3-q15 10% of GBM p15 & p16 Tumor suppressor 9p21 Deleted in 67% of glioma cell lines CDK4 & CDK6 Promoter of 12q13-14 & Amplified in 15% of cases without p15 or p16 cell 7q21- proliferation i 22 mutations PTEN Tumor suppressor 10q % of glioblastomas MGMT DNA repair gene 10 Promoter methylation in 24-40% of gliomas Retinoblastoma Tumor suppressor 13q14 33% of high grade astrocytoma Frequent in high grade astrocytomas q 20-30% of all grades of astrocytomas EGFR Oncogene % of high grade astrocytomas, always associated with 10 loss Anti-angiogenic approach Overcoming resistance to chemotherapy Tumor treating fields (TTfields) PDGFR Oncogene - Expressed in all grades of astrocytomas 1p - Nearly all oligodendrogliomas, usually expressed with 19q loss 6

7 Vascular Endothelial Growth Factor Malignant Angiogenesis Gliomas in Generate glioma Abnormal Blood Vessels Normal human cortex From S. Stiver, Frontiers in Bioscience 9, , September 1, 2004 Anti-angiogenic Therapy in Malignant Glioma Anti-angiogenic Therapy in Malignant Glioma First generation angiogenesis inhibitors: 1. Thalidomide 2. Lenalidomide 3. Penicillamine 4. Carboxyamidotriazole Inhibitors of VEGF Bevacizumab Small-molecule inhibitors of VEGRF/PDGFR/ EGFR: 1. Cediranib (AZD 2171) 2. Vatalanib (PTK 787) 3. Pazopanib (GW ) 4. Sorafenib 5. Sunitinib 6. Vandetanib (ZD 6474) Metronomic temozolomide High rate of radiographic responses in recurrent GBM patients treated with bevacizumab N = 29 BEV + CPT-11 CR in 3 patients PR in 16 patients Overall radiographic response 66% Stark Vance, WFNO, May 2005 N = 32 BEV + CPT-11 CR in 1 patient PR in 19 patients Overall radiographic response 63% Vredenburgh et al. Clinical Cancer Research 2007 High Response Rate and Improved PFS Other benefits of anti-angiogenic therapy GBM: PFS-6 (30%) = 20 weeks (9 weeks hc) Anaplastic glioma: PFS-6 (56%) = 30 weeks (13 weeks hc) Vredenburgh et al. Clinical Cancer Research 2007 July 2009 September

8 Overcoming resistance to chemotherapy What is MGMT? Overall survival remains poor despite treatment Repairs alkylation DNA damage by removing adducts from the O-6 position on guanine Alkylating agents are used to treat GBM (temozolomide TMZ and carmustine BCNU) High O 6 methylguanine-dna-methyltransferase lt (MGMT) levels l in tumors confer TMZ and BCNU resistance (poor prognosis) MGMT promoter methylation status influences prognosis O 6 benzylguanine (O-6-BG) can inhibit wild type MGMT and enhance TMZ and BCNU activity in tumor cells BUT hematopoietic toxicity has been dose limiting DNA repair mechanism through O6-methylguanine-DNAmethyltransferase AGT = O 6 -Alkylguanine-DNA Alkyltransferase Chemotherapy Boosters Increasing efficacy of chemotherapy Direct protein inhibition O 6 -benzylguanine (O 6 -BG) AGT in mice tumors resistant to high doses of BCNU responded after treatment with O6-BG in humans, tumor AGT activity can be completely suppressed by O6-BG Friedman et al. found that 100 mg/m 2 of O6-BG depletes AGT activity to undetectable levels in gliomas 18 hours after administration Quinn et al. conducted Phase I trials of temozolomide plus O6-BG and determined the MTD of temozolomide at 472 mg/m2 Phase II study reported activity of this combination in recurrent malignant glioma Increasing efficacy of chemotherapy Efficient Ex Vivo Gene Transfer to CD34+ cells Weeks -7 to -1 Surgical Resection Radiation Therapy MGMT promoter methylation screening unmethylated = eligible Patient % Gene Transfer by MGMT Stain* Cells/kg Infused Day -7 Day -6 Day -5 Day -4 Day -3 G-CSF Mobilization Apheresis #1 Apheresis #2 CD34 Selection x x 10 6 Day -2 Day -1 Day 0 BCNU 600 mg/m 2 (Conditioning/chemotherapy) Stem Cell Infusion Gene Transfer x day cycles of O-6-BG (120 mg/m 2 bolus followed by 30mg/m 2 /day for 48h)+ TMZ (first dose 472 mg/m 2 ) *MGMT assessed by flow cytometry on day 3 after transduction 8

9 Sustained Presence of P140K in Peripheral White Blood Cells Treatment Course course and Response response Percent gene modifie ed cells (assuming one proviral cop py per cell) PATIENT # PATIENT # PATIENT # Days after cell infusion All three patients demonstrated presence of gene-modified granulocytes in peripheral blood by western blot and PCR up to 10 months after transplant PATIENT #1 PATIENT #2 PATIENT #3 SD stable disease PD progressive disease Number of treatment cycles Disease status at 6 and 12 mo Overall survival 9 SD/SD alive at 34 months 3 SD/PD 18 4 SD/SD 23 PATIENT #1 Treatment Course and Response Science Translational Medicine, May 9 th 2012 #1 Diagnosis 6 months 12 months #3 Outside the Box Effects of TTFields Alternating electric fields in therapy of cancer 1. Electric fields at low frequencies (<1kHz) have stimulatory effects stimulation of bone growth and fracture healing 2. At very high frequencies (MHz) tissue heating occurs diathermy, radio frequency tumor ablation 3. Electric fields at medium frequencies ( khz) have specific inhibitory effects on dividing cells TTFileds tumor treating fields 9

10 Metaphase Effect Tumor Treating Fields (in vitro) Application of TTFields to cancerous cell lines in-vitro leads to the formation of abnormal mitotic figures These figures are similar to the effects of taxanes in culture By analogy, TTFields also target the formation of the mitotic spindle Kirson et al., Cancer Research 2004 Kirson et al., Cancer Research 2004 TTField is targeted to a specific cancer cell Tumor Treating Fields (in vivo) Intestine 50kHz Breast cancer 120kHz GBM 200kHz TTField effect on cells is frequency specific and (inversely) related to cell size Cancer Research, 2004 Treated Untreated TTFields in brain tumor therapy TTFields in brain tumor therapy PNAS,

11 Clinical Trials with TTFields Recurrent GBM Clinical Trials with TTFields Surgery/Biopsy RT/TMZ + Maintenance TMZ Recurrence 10% - 1 st recurrence 90% th recurrence Phase III study of NovoTTF-100A comparing the device with the best standard of care (BSC) in recurrent GBM N=237 (28 international sites) TTFileds applied on average for 18h/day Frequency 220 khz, intensity 1-2 V/cm Outcome TTF group BSC OS p= months 6.0 months Randomization 1:1 OS; biopsy only patients; p= months 5.2 months NovoTTF-100A Monotherapy Active Chemotherapy OS; post anti-vegf therapy; p= months 3.2 months PFS6 p=ns 21.4% 15.2% Overall Survival Response to TTFields All Patients (n=120 vs. 117) Avastin Failures (n=21 vs. 23) Patient Baseline Patient months Fraction Overall Surv vival TTF Therapy BPC chemotherapy TTF Therapy BPC chemotherapy Fraction survival TTF Therapy BPC chemotherapy Months Overall Survival (months) Wong et al., SNO 2011 Ram et al., SNO 2010, 2011 Gliomas Summary The Team Significant advances in surgery and other treatment modalities over centuries decreased mortality in patients with brain tumors Prognosis for patients with malignant glioma remains poor but better than few decades ago Important prognostic factors have been identified (MGMT, 1p19q, EGFR, IDH1) Anti-angiogenic agents play an important role in therapy of recurrent tumors Novel approaches like gene therapy and TTFileds show promise PATIENTS and FAMILIES Kiem Lab Hans-Peter Kiem Jennifer Adair Brian Beard Grant Trobridge Christina Ironside Allie Evans Sum Ying Chiu Tera Matson Past and current members University of Washington Alex Spence Marc Chamberlain Jason Rockhill Dan Silbergeld Pam Becker Carrie Graham Laurie Lee Neuro Oncology Tumor Board NIH/NCI 5R01CA SCCA Gold Autologous Team CPF/GCTL Cathy Lindgren Chris Brown David Schneider Deanna Brown Duke University Henry Friedman NCI/CTEP O-6-BG NGVL/IUVPF Kenneth Cornetta CTL Shelly Heimfeld 11

12 The guilty trio 12