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