newer management techniques for glioblastoma
DESCRIPTION
Neurosurgery presentation on glioblastomaTRANSCRIPT
Local Therapies for Brain Tumors
Zvi Ram
Department of Neurosurgery
Tel Aviv Medical Center, ISRAEL
What is a Local Therapy?
Direct administration of a therapeutic measure into the brain tumor, or its surroundings, to produce an anti-tumor response
Prerequisites for Local Therapies
• Specificity (No collateral damage)• Efficacy• Mode of delivery – How to get your therapy to
the target• Predictability of effect and toxicity
Malignant Gliomas
Does Local Therapy for Brain Tumors Make Sense?
• NO• Malignant brain tumors are in fact a “systemic
infiltrative disease”• Always recur• Hemispherectomy fails (contralateral tumor
progression will cause death)
Does Local Therapy for Brain Tumors Make Sense?
• Yes• 90% of GBM recur within 2 cm from the original
resection site.• Gross total resection of tumors prolongs life.• May replace more aggressive measures (surgery)• May enable treatment of surgically- inaccessible
tumors. • Local interaction may produce additional effects
(Immune enhancement?)
Examples of Local Therapies
• In Situ Cytotoxic drugs• In Situ Toxins• Gene transfer into tissue• Ablative procedures (Brachytherapy,
radiofrequency ablation, Focused ultrasound, laser ablation, etc.)
• Local Immune enhancers• Stereotaxic Radiosurgery
Bypassing the BBB
• Direct Intra-Tumoral Injections - Failed
• Intra-Thecal Injections - Failed
• Intra-arterial injections - Failed
• Blood Brain Barrier Disruption - Failed
• Diffusion-based delivery (Gliadel)
• Convection-Enhanced Delivery
INTRACAVITARY CHEMOTHERAPY - AGENTS-
• Gliadel, Prolifeprosan 20,
(3,85%, 7.7mg BCNU)
GLIADEL® WaferMechanism of BCNU Release
• Released via surface erosion
• Hydrophobic monomers permit surface erosion for slow release & protect active agent from hydrolysis
• 70% release of BCNU by 3-4 weeks
TimeSurface Erosion
Brem H, Langer R: Polymer-Based Drug Delivery to the Brain. Science & Medicine. 1996;3(4):2-11.
THE LANCETPlacebo-controlled Trial of Safety and Efficacy of Intraoperative
Controlled Delivery by Biodegradable Polymers of Chemotherapy for Recurrent Gliomas
Henry Brem, Steven Piantadosi, Peter C Burger, Michael Walker, Robert Selker, Nicholas A Vick, Keith Black, Michael Sisti, Steven Brem, Gerard Mohr, Paul Muller, Richard Morawetz, S Clifford Schold, for the Polymer-Brain Tumor Treatment Group
Lancet 345:1008-12, 1995
Recurrent GlioblastomaRecurrent Glioblastomasurvival at 6 monthssurvival at 6 months
GliadelGliadel® ® Polymer 56%Polymer 56%
Placebo Polymer 36%Placebo Polymer 36%
p=0.0020p=0.0020
Survival from Polymer ImplantationAll Patients (ITT)
GLIADEL® WaferPlacebo
*Hazard ratio adjusted for prognostic factors
Hazard ratio 0.67*
Risk Reduction = 33%
p=0.006
0.00
0.25
0.50
0.75
1.00
0 20 40 60 80 100 120 140
Time (weeks)
Pro
bab
ilit
y of
Su
rviv
al
Median survivalGLIADEL 31 wksPlacebo 23 wks
6-Month SurvivalGBM Subgroup
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6
Months From Implant Surgery
Su
rviv
al R
ate
(%)
GLIADEL® WaferPlacebo
56%
36%
p-value = 0.02
Simo Valtonen , M.D., Ulla Timonen, M.D., Petri Toivanen, M.SC., Hannu Kalimo, M.D., Leena Kivipelto, M.D., Olli
Heiskanen, M.D. Prof., Geirmund Unsgaard, M.D.Prof., Timo Kuurne, M.D.
Interstitial Chemotherapy with Carmustine-loaded Polymers for High-grade Gliomas: a Randomized
Double-blind Study
Department of Neurosurgery (SV) and Pathology (HK), Turku University Central Hospital, Turku, Finland; Department of Neurosurgery (LK, OH), Helsinki University Central Hospital, Helsinki,
Finland; Department of Neurosurgery (TK), Tampere University Hospital, Tampere, Finland; Department of Neurosurgery (GU), University Hospital of Trondheim, Trondheim, Norway; and Orion
Pharma (UT, PT), Espoo, Finland
Neurosurgery 41:44-8; 1997
European Study of BCNU- Polyanhydride Polymer as the Initial Treatment of Malignant Glioma
100%
75%
50%
25%
0%0 25 50 75 100
Weeks
Su
rviv
al
Placebo (n = 16)
GLIADEL (n = 16)
Placebo-Polymer
BCNU-Polymer
S. Valtonen et al. 1997
31% of patients are alive
versus
6% of patients with placebo polymers are alive
Two Years After Implantation
March 2003
Overall Survival ITT Group
GLIADEL® Wafer Package Insert.
100
90
80
70
60
50
40
30
20
10
00 4 8 12 16 20 24 28 32 36 40 44 48 52
Months From Implant Surgery
Surv
ival
%
HR = 0.73Median Survival G: 13.9 mosP: 11.6 mos(p<0.05 log-rank)
GLIADEL
Placebo
Long term
Long-Term Survival
GLIADEL® (N=120)
N (%)
Placebo (N=120)
N (%)
Survival>1 year
71 (59.2) 59 (49.2)
Survival>2 years
19 (15.8) 10 (8.3)
Survival>3 years
11 (9.2) 2 (1.7)
Data on file, Guilford Pharmaceuticals
Karnofsky Performance Score Decline All Patients (ITT)
0 642 8 141210 16 222018 24 26
Months from Date of Randomization
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
port
ion
with
out
Dec
line
GLIADEL®
Placebo
Hazard Ratio = 0.74
Risk Reduction = 26%p = 0.05
Median Time to DeclineGLIADEL® 11.9 monthsPlacebo 10.4 months
Westphal M, Hilt DC, Bortey E, et al. NeuroOncology. 2003;5(2).
Gliadel as the Initial Treatment of Malignant Brain Tumors
Gliadel : 60 weeks
Placebo: 50 weeks
n = 240p = 0.03
European Association of Neurological Surgeons,
November, 2000
Gliadel® demonstrates proof of principle that controlled
release with polymers directly to the brain is safe and
improves outcome
Adverse Events of Concern
• Seizures
• Cerebral edema
• Healing abnormalities
• Intracranial infections
Late non-specific inflammatory changes
No tumor found on histology
Edema and Cyst Formation
Transient edema and “abscess-like”Appearance.
Resolution with steroids over time
Healing Abnormalities
• Recurrent Trial
– 14% of GLIADEL® Wafer and 5% of placebo patients
– Classified as:
• CSF leaks
• Subdural collections
• Wound dehiscence or poor healing
• Subgaleal or wound effusions
Healing AbnormalitiesPrimary Setting
Placebo
(N=120)
6 (5.0)
GLIADEL® Wafer (N=120)
5 (4.2)Fluid, CSF, or subdural collections
N (%)N (%)
CSF leaks 6 (5.0) 1 (0.8)
Wound dehiscence or poor healing 6 (5.0) 6 (5.0)
Subgaleal or wound effusion 4 (3.3) 5 (4.2)
No difference in overall healing abnormalities among the two groups
Intracranial Infections
• Recurrent Trial
– GLIADEL® Wafer group 3.6%
– Placebo group 1.0%
• Primary Trial
– GLIADEL® Wafer group 6.0%
– Placebo group 5.0%
Summary of Safety Results from Randomized Controlled Trials
• Seizures– No difference in frequency of seizures – Earlier onset of seizures in recurrent setting
• Healing Abnormalities– Greater frequency in recurrent setting NOT
seen in initial surgery setting– Slightly greater risk of CSF leak in GLIADEL®
group in initial surgery setting but NO increased risk of infection
Conclusion
The benefit to risk ratio in patients undergoing either initial or
recurrent surgery for malignant glioma favors GLIADEL® Wafer
NEW TREATMENTSHIGHER DOSE GLIADEL
RX FOR METASTASIS
TAXOL
5FU, EPIRUBICIN
TEMODAR
DRUG RESISTANCE MODIFIERS
ANTI-ANGIOGENSIS
FUTURE:VACCINES
MICROCHIPS
MOLECULAR TARGETS
STEM CELLS
INDIVIDUALIZED THERAPY
TAXOL CLINICAL TRIALS
Oncogel = 6.0mg paclitaxel/ml of ReGel, Protherics, Inc
Phase I: lymphoma, melanoma, lung, head and neck, laryngeal, thyroid and breast carcinoma (16 pts)
Phase I: Recurrent Gliomas:PI: MACIEJ LESNIAK
University of Chicago, University of North Carolina, Vanderbilt, Hopkins
Menei P, Capelle L, Guyotat J, Fuentes S, Assaker R, Bataille B, Francois P, Dorwling-Carter D, Paquis P, Bauchet L, Parker F, Sabatier J, Faisant N, Benoit JP.
• In patients with complete resection, overall survival was – 15.2 months for those receiving 5-FU microspheres followed by radiotherapy– 12.3 months for those receiving radiotherapy alone
• These differences were not significant. Safety was acceptable with prophylactic high doses of corticosteroids
• The implantation of 5-fluorouracil microspheres in the wall of the cavity resection did increase overall survival, however, this study was not designed and sufficiently powered to demonstrate statistical significance
Randomized, Multicenter Phase II Trial in Patients with Gross Total Resection of High-Grade Glioma
Hazard Ratio = 0.75
Stupp, R. et al. N Engl J Med 2005;352:987-996
TMZ Overall Survival
GLIADEL Overall Survival
Gliadel Implantable BCNU Wafers:Similar Survival to Temozolomide
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 28 32 36 40 44
Su
rviv
al R
ate
(%)
Months from Implant SurgeryHazard Ratio = 0.75
Median OS, mo: 10.9 13.1 p=0.0312-yr survival: 6% 33%HR [95% C.I.]: 0.75 [0.58-0.98]
p=0.034
GLIADELPlacebo
Meldorf M et al. AANS, 2003 (Abstract 1492).Stupp et al, ASCO, 2004 (www.asco.org).
TMZ Overall Survival
Placebo GLIADEL
PHASE II: SURGERY, RT, GLIADEL AND TMZ
La Roca RV, Hodes J, Villaneuva TW, Vitaz TW, Morassutti, Doyle MJ, Glisson S, Cervera A, Stribinskiene L, New P, Litofsky, NS
Median Survival 18.6 months
SNO 2007
Stupp et al: 14.6 without Gliadel
Conclusions:Survival rates for newly diagnosed patients were better than those reported in previous phase III trials. The combination of Gliadel and radiochemotherapy with TMZ was well tolerated and appeared to increase survival without increasing adverse events.
Ann Surg Oncol. 2010.
Is there a way to overcome the resistance
to BCNU?
Chemo-Resistance: Clinical
Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme
Quinn JA, Jiang SX, Carter J, Reardon DA, Desjardins A, Vredenburgh
JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE, Threatt S, Friedman HS
52 patients6 month OS = 82%
Median OS = 50.3 weeks1 and 2 yr survival: 47% and 10%
Toxicities: Hydrocephalus (9.6%), CSF leak (19.2%), Infection (13.4%)
Clin Cancer Res. 15, 1064-8, 2009
CEDThe Concept of Convection-Enhanced Delivery
for Brain Tumor Therapy
Bypassing the BBB:Intra-Tissue Drug Delivery
Convection
Gd-saline infusion, 100 min
Moseley, Stanford University, 2000Moseley, Stanford University, 2000
Variables Acting in Convection
• Anatomy• Physical barriers (scar tissue, gliosis,
sulci, etc.)• Drugs• Toxicity• Chemical and physical characteristics• Local degradation by enzymes• Clearance from the brain parenchyma
Drugs
• Choosing the right drugs for CED– Efficacy
– Toxicity to normal brain
– Stability in situ
– Individual DISTRIBUTION characteristics (Infusate!)
The Concept of Backflow
•Backflow reduces efficacy of distribution
•Backflow increases toxicity (spillage of the drug into the subarachnoid space and CSF
where it can affect the entire brain surface)
Infusion-induced edema is significant
Under infusion- or tumor-induced edema, dramatic increases in conductivity in white matter occurUnder infusion- or tumor-induced edema, dramatic increases in conductivity in white matter occur
Sampson, Duke University, 2004Sampson, Duke University, 2004
IL13PE peri-Tumoral infusion
Deformation due to edema
Sampson, Duke University, 2003Sampson, Duke University, 2003
Intra-TumoralTransmid Infusion
Convection-Enhanced Delivery of Taxol in Recurrent Malignant Gliomas
CED of Cytotoxic Drugs
Paclitaxel (Taxol©)
• Paclitaxel (Taxol©) is an antineoplastic agent with proven antimitotic and antitumoral activity and acts by promoting microtubule assembly into meta-stable structure that the cell cannot disassemble.
• Taxol does not efficiently cross the BBB.
• Based on In Vitro studies Taxol is a good candidate for CED into brain tumors.
Pre Taxol
2 wks post Taxol SP
DW MRI as an indicatorOf tumor response
baseline (left), d 4 Taxol (middle), d 60 (right)
T1-Gd (before)
T1-Gd (immed after)
T1-Gd (1 mo after)
Immed Post Taxol
6 Months Post Taxol
Post TaxolPre Taxol
Baseline MRI
2 Weeks post taxol
Large Tumors
Effect
Failures
• Mechanical/Physical issues– Placement in cystic/necrotic cavities– Penetration into ventricles/cysts/necrosis
• Backflow (Associated with CSF distribution and toxicity)
• Anatomical/structural boundaries (glial scars, tissue conductivity, etc)
Penetration into the Ventricular System
Multifocal GBMNecrotic Tumor
Diffusion
19 hours post infusion
Diffusion allows slow spread Diffusion allows slow spread of drug molecules not of drug molecules not metabolized or degradedmetabolized or degraded
Moseley, Stanford University, 2000Moseley, Stanford University, 2000
Convection EffectDiffusion Effect
Effect of Diffusion on Covective Volume
1 day post Taxol
7 days post Taxol
Diffusion Effect
Histology
• Tissue obtained from treated tumors by Biopsy (1 patient) or resection (3 patients)
ImagingImaging
T1 +CM
Baseline Day 28during CED
T1 +CM
FET-PET
Diffusion weighted MRI
FET-PET
Time points: MRI baseline, d3, d6, d28, w6, w12, w18, w24, w30 … PET baseline d28 w12 w24 …
Mardor (2001)
Convection Studies• Taxol• Toxins
– Pseudomonas toxin linked to IL-13– Diphtheria toxin linked to transferrin– Pseudomonas toxin linked to IL4– Chemotherapeutic drugs (Temozolomide)
• Other Studies– Antisense Pharma– Oncolytic viruses (Crusade)– CED for Parkinson’s disease
CED of Pseudomonas Exotoxin(NeoPharm)
IL13 receptor expressed only on tumor cells
Post resection – Peri-tumoral CED
CED of Intra-Tumoral TransMid (Diphtheria Toxin/Transferrin)
(KS Biomedix, Xenova)
Tf Receptor expressed only on tumor cellsIntra-Tumoral CED
Research Goals to Improve CED
• Optimizing convection:
Better distribution = Better response
(Optimal infusate)• Imaging the convective process• Simulation of convection (Pre-treatment)
How Can We Enhance Drug Convectibility?
• Several parameters were evaluated:– Capillarity– Polarity (considered by some)– Density– Molecular Wt (considered to have a limit)– Viscosity– Membrane interaction (?)– LogP/LogD (partitioning coefficient, distribution
coefficient)– Diffusibility
Viscosity• Linear correlation found between viscosity,
volume of convection, and the incidence of backflow.
Low Intermediate High
y = 0.10x - 0.06
R2 = 0.79p< 0.003
0
0.05
0.1
0.9 1.1 1.3 1.5 1.7
Viscosity
CE
D v
olu
me
Volume of convection for various drugs as a function of their viscosity
•Viscosity can be readily increased by simple measures (added sugars, albumin, etc.)
Imaging Convection
• Efficacy and safety guidelines• Convection volume can be reliably predicted by mixture
of Gd (1:70 concentration) in the infusate
Infusate mixed with Evans Blue/Blue bovine serum Albumin (40Kd)
R2=0.95, p<0.0001
CED of Nano Particles(Iron Oxide)
• Use of particles that can be imaged by MRI (i.e., Ferromagnetic particles coated with drugs).
Collaboration – S. Margol Bar Ilan University
Prediction of cytotoxicity• Cytotoxic drugs – correlation between early
DWMRI changes and later observed changes (anti-tumor, local toxicity) on T1 MRI
• Toxic complications – early prediction
T1 DWMRI T1
2 Weeks post treatment 6 Weeks post treatment
Simulation of CED
• Measurement of multiple imaging variables before treatment.
• Simulate the convective process for individual patients as a function of location of catheters, flow rates, etc.
• Simulate and predict potential toxicity (mostly from backflow)
Simulation result displayed as green overlay over an anatomical T1 scan.Simulation result displayed as green overlay over an anatomical T1 scan.
Simulation result overlaid over segmented gadolinium infusion.Simulation result overlaid over segmented gadolinium infusion.
Future Studies
• Mandatory to use tracers mixed with the convected infusate
• Verfication of the simulation models
• Enhancing predictive value
• Integrating advanced imaging modalities
• Upcoming CED study of Temozolomide
Possible Applications of CED
• Neoplastic diseases
• Degenerative brain diseases– Parkinson’s disease– Alzheimer
• Metabolic and genetic disorders
• Extracranial indications
Acknowledgements
• Collaborative work of Neurosurgery (Tel Aviv Medical Center) and Advanced Technology Center, Sheba Medical Center (Yael Mardor).
• BrainLAB• Therataxis (Raghu Raghavan)• Clinical Collaborators (Munich)• Pharma Companies