Objectives. Presenter Disclosure Information 11/29/2016

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1 Current State of Neurosurgical Treatment of Cerebral Glioma and Clinical Trials Testing Future Advances John D. Heiss, M.D. Chair, Surgical Neurology Branch, NINDS, National Institutes of Health Presenter Disclosure Information John D. Heiss, M.D. Title: Current State of Neurosurgical Treatment of Cerebral Glioma and Clinical Trials Testing Future Advances Research Support: This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. All Unlabeled/Unapproved Uses are Disclosed as Such. Objectives Upon completion of my presentation, participants should be better able to: 1. Describe standard treatment for glioblastoma 2. Describe the impact of surgical neurological deficit and extent of resection on patient survival in glioblastoma 3. Describe the impact of functional brain mapping on surgical outcome and long-term prognosis in different types and grades of glioma 4. Name a few agents and methods that are being tested in glioma clinical trials 1

2 Role of Radiotherapy in Glioblastoma Treatment Radiation dose correlates with Survival Time (mean) 0 rad 18 weeks 5000 rad 28 weeks 5500 rad 36 weeks 6000 rad 42 weeks 6 month (24 week) radiation treatment effect on survival Walker MD, Strike TA, Sheline GE: An analysis of doseeffect relationship in the radiotherapy of malignant gliomas. Int J Radiation Oncology Biol. Phys. 1979; 5: Standard Glioblastoma (GBM) Treatment 573 patients with glioblastoma 286 radiotherapy* 287 radiotherapy* plus temozolomide Prior surgical procedure 84% debulking surgery 40% complete resection 44% partial resection 16% biopsy Median survival Radiotherapy plus temozolomide 14.6 months Radiotherapy alone 12.1 months Stupp R, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. NEJM 2005; 352(10): *Radiotherapy 60g over 6 weeks to gross tumor volume with 2-3 cm margin for the clinical target volume Temozolomide, 75 mg per square meter per day, 7 days per week during radiotherapy period (no more than 49 days), followed by a 4 week break, and then adjuvant dosing at mg per square meter per day for 5 days every 28 days Standard Glioma Surgery Surgical procedure selected that makes the diagnosis and removes tumor tissue from non-eloquent brain areas 1) Preserving neurological function 2) Preserving survival quality 3) Maximal tumor removal from non-eloquent areas a) Complete excision with Grade I Tumors b) Maximal cytoreduction with Grade II-IV (infiltrative) tumors Choice of surgical procedures include a) Biopsy 16% of patients (Stupp 2005 study) b) Debulking 84% of patients (Stupp 2005 study) a) Partial resection 44% b) Complete (MRI) resection 40% 2

3 Extensive surgery for glioblastoma Extensive tumor resection improves Survival time (treatment effect about 5 months) 7.5 months extensive resection & post-operative radiation 2.5 months limited resection & post-operative radiation Quality of Survival Proportion of excellent or good condition patients increases after surgery in patients with extensive resections Removes tumor mass effect Reverses ICP elevation Jelsma R, Bucy PC. Glioblastoma multiforme: its treatment and some factors effecting survival. Arch Neurol 1969 Feb;20 (2): Non-central GBM location associated with greater tumor resection, survival time & quality Central vs. non-central tumor Survival time (6.5 months longer in noncentral vs. central tumors) 10.5 months non-central tumors 4.0 months central tumors Quality of Survival Proportion of excellent or good condition patients much better in patients with tumor outside the central area comprising the precentral gyri, Broca s area, or the Sylvian fissure of the dominant hemisphere. Jelsma R, Bucy PC. Glioblastoma multiforme: its treatment and some factors effecting survival. Arch Neurol 1969 Feb;20 (2): Longer survival with more tumor debulking, better WHO performance status, & corticosteroid independence 573 patients with glioblastoma 286 radiotherapy 287 radiotherapy plus temozolomide Median overall survival months longer in the patients with tumor debulking compared to biopsy only Patients not requiring baseline steroids survived months longer than patients requiring steroids Stupp R, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. NEJM 2005; 352(10):

4 Brain Tumor WHO Grade Prognostic impact of extent of resection I Neuronal DNET Ganglioglioma Pilocytic astrocytoma II Low grade astrocytoma & oligodendroglioma III Anaplastic astrocytoma & oligodendroglioma IV Glioblastoma multiforme Invasive No Complete Resection Possible Yes; if outside eloquent structures Life Expectancy (Months) Biopsy Life Expectancy (Months) MR Incomplete Resection Life Expectancy (Months) MR Complete Resection Increased Life Expectancy (Months) with MR- Complete Resection Prolonged Prolonged Prolonged Residual tumors require additional surgery Yes No * Yes No * Yes No * *Sinai N, Berger MS: Glioma extent of resection and its impact on patient outcome. Neurosurgery 62: , 2008 Stupp R, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. NEJM 2005; 352(10): Surgically-Induced Neurological Deficit in GBM 306 consecutive patients with newly diagnosed GBM y.o. Good performance status (KPS ) Retrospective review 15 patients (5%) with new language deficit perioperatively 9.6 month median survival 19 patients (6%) with new motor deficit perioperatively 9.0 month median survival 272 patients without neurological deficits (89%) 12.8 month median survival A permanent deficit reduced quality of life immediately and shortened survival by 3-4 months compared to patients without deficits. McGirt MJ, Mukherjee D, Chaichana KL, Than KD, Weingart JD, Quinones-Hinojosa A. Association of surgically acquired motor and language deficits on overall survival after resection of glioblastoma multiforme. Neurosurgery. 2009; 65: Maximizing Tumor Removal from Non-Eloquent Brain Remove all tumor from non-eloquent areas Establish non-eloquent margins by functional brain mapping and anatomic MRI Avoid injury to eloquent brain areas Direct injury Eloquent brain area mapping Eloquent cerebral cortex Subcortical white matter tracts Secondary injury Anatomic knowledge and MRI Arteries Local vessels Arteries of passage Major veins Vein of Labbé Figure from: Hervey- Jumper SL, Berger MS: Maximizing safe resection of low- and high-grade glioma. J Neurooncol (2016) 130:

5 Intraoperative Electrical Mapping Hughes Duffau: Intraoperative electrical mapping of eloquent cortical and white matter pathways is the standard of care for supratentorial glioma surgery, particularly for tumors adjacent to eloquent brain Acta Neurochir (Wien) 155:1803-4, 2013 Fewer permanent neurologic deficits (2-3.5%) More extensive resection Anesthetic technique Duffau (2013): Asleep-awake-asleep Patient asleep for opening & last part of resection and closure Pain range on 0-10 analogue scale Anxiety Sanai, Mirzadeh, Berger (2008): Sedation-awake-sedation Hansen et al. (2013): Awake-awake-awake Patient awake entire procedure 2/3rds of patients requested remifentanil No sedation needed except for seizures Therapeutic communication between anesthesiologist and patient Intraoperative Stimulation Mapping Identifies regions of eloquent function during surgery Craniotomy with mapping under local anesthesia using electrical cortical stimulation Positive effects of stimulation Motor cortex--movement Somatosensory cortex--localized dysesthesias Negative effects of stimulation Language--Disruption of language task Memory--Disruption of memory task Maintain a Margin of Safety Between Resection and Language Sites Cortical Localization of Temporal Lobe Language Sites in Patients with Gliomas. Haglund, Michael; Berger, Mitchel; Shamseldin, Michael; Lettich, Etorre; Ojemann, George Neurosurgery. 34(4): , April Figure 5. The distance of the resection margin to the nearest language site is analyzed with regard to the number of days a language deficit is present after tumor removal. Error bars represent the standard error of the mean. Copyright by the Congress of Neurological Surgeons. Published by Lippincott Williams & Wilkins, Inc. 2 5

6 Intraoperative Language Mapping Sanai N, Mirzadeh Z, Berger MS: Functional outcome after language mapping for glioma resection. N Engl J Med 358:18-27, 2008 Method: 250 consecutive glioma cases Intraoperative electrical stimulation mapping to identify language areas Resection of tumor up to 1 cm away from cortical areas that demonstrated language disturbance with electrical stimulation Results A total of 145 of the 250 patients (58.0%) had at least one site with an intraoperative stimulation-induced speech arrest, 82 patients had anomia, and 23 patients had alexia. Overall, 3094 of 3281 cortical sites (94.3%) were not associated with stimulation induced language deficits. A total of 159 patients (63.6%) had intact speech preoperatively. One week after surgery, baseline language function remained in 194 patients (77.6%), it worsened in 21 patients (8.4%), and 35 patients (14.0%) had new speech deficits. However, 6 months after surgery, only 4 of 243 surviving patients (1.6%) had a persistent language deficit. GTR (MRI) in 51.6% Grade I & II tumors; 65% Grade III tumors; 69% Grade IV tumors Intraoperative MRI guidance to highlight tumor Adjunct measure to identify more high-grade glioma tissue during the operative procedure Assessment Trend toward imri increasing tumor removal from non-eloquent brain Randomized trial of 58 patients with high-grade glioma* (All Grade 3 or 4, except for 1 ganglioglioma in the MRI groups) Microsurgery imri guided Gross total resection 68% 96% (p=0.023) Progression free survival 154 days 226 days (p=0.083) No apparent effect on neurological funcron Preserves survival quality No difference in SAEs and AE between 2 groups *Senft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V: Intraoperative MRI guidance and extend of resection in glioma surgery: a randomized, controlled trial. Lancet Oncol 2011 OCT; 12: Cortical Mapping in the IMR Suite 6

7 Cortical Mapping in the imri Imaging Suite Operating Outside the 5G Field Operative Procedure A) MR-Compatible 3-pin head holder that extends off the table; Surface coil between head holder and head; B) MR-compatible patient reference frame; C) MR-imaging coil wrapped in sterile plastic sheet and placed around surgical field; D) Position in MRscanner 7

8 Graduate student with new onset of complex partial seizures T1 -Weighted Image T2-Weighted Images Left Temporal Lobe Tumor Modified from Figure in Hansebout RR: Surgery of epilepsy current technique of cortical resection. In: Schmidek HH & Sweet WH, eds. Operative Neurosurgical Techniques: Indications, Methods, and Results. 2nd ed. New York: WB Saunders Co., Cortical stimulation testing: Mandarin primary, English second language;1,2: Sensation in Mouth; 21: Broca s area; 24: Wernicke s area in English; 23-27: Wernicke s area in Mandarin; Letters: Negative Stimulation imri Guides Tumor Resection Before Craniotomy After Initial Resection 6 Months After Surgery 8

9 57 year old woman with partial seizures Pre T1 With Gd Superior temporal gyrus tumor Inferior Ant. Negative Stimulation: Letters Broca s Area: 20, 24, 26 Mouth Sensation: 17 Wernicke s Area: 21, 22, 23, 25, 28 Blue Thread Surrounds Area of Tumor to be Removed Sylvian Fissure IMRI to Assess Extent of Resection Pre T1 With Gd Intraop T2 T1 With Gd 2 yrs After Surgery 9

10 45 y.o. man with new contrast enhancement 21 months after right frontal craniotomy T1 With Gd FLAIR With Gd Cortical Mapping Site of Surgery Performed 21 Months Previous to Present Surgery Silent Cortex (Sup. Frontal Gyrus) Letters (F, G, J, H, V, P, U, K, S, R, T, A) Motor Cortex (Precentral Gyrus) 7, Shoulder Motion; 4,2, & 1, Wrist Motion; 3 & 8, Finger Flexion Localize Tumor Margins In Relation to Motor Cortex Non-Ferromagnetic Bronze Probe 10

11 After Initial Tumor Resection IMRI to Detect Residual Tumor Pre T1 With Gd Intraop T1 Without Gd T1 With Gd After Medial Resection IMRI and Cortical Mapping Yr Sex Lobe(s) Dx WHO Motor Sensory Speech MR Complete Resection IMR Improved Resection Neuro Deficit Mixed Oligoastrocytoma 1 29 M Left frontal 3 Y Y Y N 1 Y N Rt frontoparietal 2 25 M GBM 4 Y Y N N 2 N N Lt temporal & Mixed Oligoastrocytoma 3 40 M insular 3 Y N Y N 3 Y Temporary Lt Anaplastic 4 27 F temporal astrocytoma 3 N Y Y Y Y Temporary Lt Anaplastic 5 57 F temporal astrocytoma 3 N N Y Y Y Temporary 6 49 M Rt parietal GBM 4 Y Y N Y N N 7 33 M Lt temporal DNET 1 Y Y Y Y Y N Rt frontal GBM 4 Y N N Y N N 8 54 F 9 45 M Mixed Oligoastrocytoma Rt frontal 3 Y N N Y Y N F Lt parietal GBM 4 N Y N Y Y N 1. Frozen section diagnosis was high grade glioma and tumor infiltrated deep white matter. 2. Tumor that infiltrated corticospinal tract in deep white matter was not removed. 3. Mass effect relieved; insular tumor not removed because patient was restless and frozen section diagnosis was high grade glioma. HIV(+) patient. From: Weingarten DM, et al. J Neurosurg 111(6): ,

12 Mapping in imri Suite vs. Standard OR Advantage of imri suite vs. Standard Neurosurgical OR Intraoperative evaluation of completeness of resection of tumors is possible in imri suite but not in conventional OR Recognize and remove residual tumor during the same procedure Improved resections may improve prognosis Disadvantages of imri suite vs. Standard Neurosurgical OR Scan time increases the duration of surgery; use preoperative MRI and frameless stereotaxy for centering incisions and locating the tumor eliminates initial imri scans immediately before surgery; prefer linear incisions to scalp flaps Head holders are less adjustable; positioning is less variable Table is more firm; need to place additional cushions Special safety considerations are required MR compatible instruments Avoid contact of coil to body and looping of wires Surgical navigation system in the intraoperative MRI suite eliminates the need for an initial imri scan and is useful in orienting anatomic relationships displayed on the radiographic images to the surgical exposure. Interventional MRI Advantages Intraoperative evaluation of completeness of resection of tumors Recognize residual tumor Resect residual tumor Improved resections may improve prognosis Evaluates for surgical complications that can be treated early Intracerebral hemorrhage Intraoperative confirmation of correct position of biopsy needles and intraventricular catheters. Well-suited for monitoring of intracerebral infusions Disadvantages Scan time increases the duration of surgery Higher costs Display of 3D image sets is not as straightforward as with frameless stereotactic systems Special safety considerations are required MR compatible instruments Avoid contact of coil to body Avoid looping of wires 5-Aminolevulinic acid (5-ALA) to highlight tumor Adjunct measure to identify more high-grade glioma tissue during the operative procedure Results in protoporphyrin accumulation in tumor Peak uptake 6 hours after oral administration Glioma visualized using filter on microscope Violet light visualize protoporphyrin IX Does not identify low-grade glioma Assessment improves removal of tumor from non-eloquent brain Phase III clinical trial of malignant glioma 322 patients* Microsurgery 5-ALA guided Gross total resection 36% 65% 6 m PFS 21% 41% No apparent affect on neurological funcron Preserves survival quality No difference in SAEs and AE between 2 groups *Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Aznella F, Reulen JH, ALA-Glioma Study Group: Fluorescenceguided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomized controlled multicenter phase III trial. Lancet Oncol 2006 May; 7(5): Fig. 3 Representative photographs showing cortical motor mapping (white circles), and 5-ALA fluorescence in glioblastoma showing tumor tissue under a white-light conditions and b illuminated with a blue filter. Orange fluorescence (Asterisk) is seen at the base of the resection cavity, indicatingresidual glioblastoma. 12

13 Immunotherapy Trials for GBM Activated lymphocytes freely enter and exit the CNS through the blood brain barrier. Immune checkpoint inhibitors, including 1) CTLA-4 (cytotoxic T-lymphocyte antigen 4) and 2) PD-1 (Programmed Death 1), suppress immune activation in tumors. Ipilimumab, a monoclonal antibody against CTLA4, received FDA approval in 2011 for treatment of metastatic melanoma Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH: Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol 11:504-14, 2015 Nivolumab and pembrolizumab, monoclonal antibodies inhibiting the PD1 receptor received FDA approval in 2014 for the treatment of malignant melanoma Ongoing clinical trials evaluating immune checkpoint inhibitors in glioblastoma include the Phase III trial NCT : Nivolumab (anti-pd1), Nivolumab + ipilimumab (anti- CTLA4), Bevacizumab (control group) for recurrent glioblastoma, n = 372 Laser Interstitial Thermal Therapy (LITT) Assessment: Surgical procedure (LITT) destroys tumor Rssue from non-eloquent brain areas Preserving neurological funcron 12% perm. neurologic deficit 3% vascular injury Preserving survival quality Temporary and permanent neurologic deficits? Removing maximal tumor from non-eloquent areas Limited to 1-2 cm radius? Complete excision with Grade I Tumors? Maximal cytoreduction with Grade II-IV (infiltrative) tumors Palliation?: Tumor tissue coagulated, not removed Perioperatively, LITT increases perilesional edema Long-term, similar or less mass effect after treatment Less invasive than craniotomy FIGURE 1. Laser ablation of 68-year-old man with recurrent glioblastoma pre-ablation (A) and post-ablation (B). Note that the ablation zone stops at the ambient cistern, sparing the adjacent brainstem. FIGURE 2. Laser ablation of a 45-year-old man with recurrent anaplastic oligodendroglioma pre-ablation (A) and post- ablation (B). The ablation zone conforms posteriorly to the precentral sulcus, avoiding injury to the primary motor cortex. Lee I, Kalkanis S, Hadjipanayis CG: Stereotactic laser interstitial thermal therapy for recurrent high-grade gliomas. Neurosurgery 79: , 2016 FIGURE 3. A 51-year-old man with distant right thalamic recurrence of a right temporal glioblastoma, pre-ablation (A) and post-ablation (B). Tumor Treating Electric Fields Randomized trial in GBM patients previously treated with chemoradiotherapy (median time from diagnosis to randomization of 3.8 months) Temozolamide vs. temozolomide + tumor treating fields (TTF): No placebo TTF delivered over 18 h/d to shaved scalp Planned interim analysis 105 patients with temozolomide 210 patients with temozolomide + TTF TMZ TMX + TTF Median PFS 4.0 m 7.1 m p= Median Survival 15.6 m 20.5 m p= % incidence of mild to moderate and 2% incidence of severe skin reaction (medical device site reaction beneath the transducer arrays) in patients treated with TTFields plus temozolomide. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al.: Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA 314: , 2015 Electric fields disrupt cancer cell division Figures from: consultqd.clevelandclinic.org 13

14 Methods to Enhance Drug Delivery to the Tumor Drug delivery into brain tissue or lesion Convection- BBB Opening Enhanced Delivery During tissue infusion During opening of the BBB Systemic Chemotherapy Limited by the intact BBB MW of therapeutic agent Brain: Blood Concentration Hydrophilic compounds Hydrophobic compounds Large or small Large or small Small > 100 x systemic concentration 1 x systemic concentration < 1 x systemic concentration Enters CNS Enters CNS <<< 1 X systemic concentration Enters CNS Enters CNS < 1 x systemic concentration Distribution of Compound within CNS Volume of brain that can be treated Volume spreads radially from infusion site Volume of distribution in the arterial distributions injected with mannitol Entire CNS Large (4-8 cm3) Large (4-8 cm3) Large (entire brain) Speed of drug delivery into brain tissue or lesion Means of spread of drug Intracerebral Drug Delivery Techniques Convectionenhanced delivery Bolus intralesional therapy Slow-release polymer Hours to Days Seconds Days to Weeks Drug moves by bulk flow through the interstitial space Drug moves by diffusion along concentration gradients Drug moves by diffusion along concentration gradients Spread by MW Small=Large MW Small > Large MW Small > Large MW Variability of drug concentration Depth of Penetration of Drug Volume of brain that can be treated Homogeneous drug levels (1-100% of infused) within a brain volume High concentration at infusion point with steep fall off in concentration throughout the surrounding brain mm 1-4 mm 1-4 mm Large (4-8 cm3) Small (mm3) Small (mm3) High concentration around polymer with steep fall off in concentration throughout the surrounding brain Summary 1. Describe standard treatment for glioblastoma Maximal safe resection, concurrent TMZ and radiotherapy 2. Describe the impact of surgical neurological deficit and extent of resection on patient survival in glioblastoma Surgically-induced neurology deficit: Reduced survival quality and length Extent of resection: Improved survival quality and duration results from removal of maximal amount of tumor from non-eloquent areas 3. Describe the impact of functional brain mapping on surgical outcome and long-term prognosis in different types and grades of glioma Removing more tumor from non-eloquent brain areas should extend survival, especially in lower grade glioma Tumor in eloquent brain is not amenable to safe resection 4. Name a few agents and methods that are being tested in glioma clinical trials Laser Interstitial thermal therapy Intraoperative MRI guided glioma resection 5-ALA guided high-grade glioma resection Immune checkpoint modulators: Phase III Trial of Nivolumab, a mab inhibiting PD-1 receptor Tumor-treating electrical fields Methods to target chemotherapy to tumor tissue and reduce off-target effects Blood-brain barrier opening/convection-enhanced delivery/slow-release polymers 14

15 References 1. Duffau H: The reliability of asleep-awake-asleep protocol for intraoperative functional mapping and cognitive monitoring in glioma surgery. Acta Neurochir (Wien) 155:1803-4, Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH: Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol 11:504-14, Rodriguez A, Tatter SB, Debinski W: Neurosurgical Techniques for Disruption of the Blood- Brain Barrier for Glioblastoma Treatment. Pharmaceutics 7:175-87, Sanai N, Mirzadeh Z, Berger MS: Functional outcome after language mapping for glioma resection. N Engl J Med 358:18-27, Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-96, Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al.: Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA 314: , Vogelbaum MA, Aghi MK: Convection-enhanced delivery for the treatment of glioblastoma. Neuro Oncol 17 Suppl 2:ii3-ii8, Weingarten DM, Asthagiri AR, Butman JA, Sato S, Wiggs EA, Damaska B, Heiss JD: Cortical mapping and frameless stereotactic navigation in the high-field intraoperative magnetic resonance imaging suite. J Neurosurg 111: ,