newer management techniques for glioblastoma
DESCRIPTION
Neurosurgery presentation on glioblastomaTRANSCRIPT
![Page 1: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/1.jpg)
Local Therapies for Brain Tumors
Zvi Ram
Department of Neurosurgery
Tel Aviv Medical Center, ISRAEL
![Page 2: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/2.jpg)
What is a Local Therapy?
Direct administration of a therapeutic measure into the brain tumor, or its surroundings, to produce an anti-tumor response
![Page 3: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/3.jpg)
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
![Page 4: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/4.jpg)
Malignant Gliomas
![Page 5: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/5.jpg)
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)
![Page 6: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/6.jpg)
![Page 7: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/7.jpg)
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?)
![Page 8: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/8.jpg)
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
![Page 9: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/9.jpg)
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
![Page 10: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/10.jpg)
![Page 11: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/11.jpg)
INTRACAVITARY CHEMOTHERAPY - AGENTS-
• Gliadel, Prolifeprosan 20,
(3,85%, 7.7mg BCNU)
![Page 12: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/12.jpg)
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.
![Page 13: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/13.jpg)
![Page 14: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/14.jpg)
![Page 15: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/15.jpg)
![Page 16: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/16.jpg)
![Page 17: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/17.jpg)
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
![Page 18: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/18.jpg)
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
![Page 19: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/19.jpg)
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
![Page 20: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/20.jpg)
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
![Page 21: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/21.jpg)
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
![Page 22: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/22.jpg)
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
![Page 23: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/23.jpg)
31% of patients are alive
versus
6% of patients with placebo polymers are alive
Two Years After Implantation
![Page 24: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/24.jpg)
March 2003
![Page 25: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/25.jpg)
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
![Page 26: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/26.jpg)
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
![Page 27: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/27.jpg)
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).
![Page 28: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/28.jpg)
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
![Page 29: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/29.jpg)
Gliadel® demonstrates proof of principle that controlled
release with polymers directly to the brain is safe and
improves outcome
![Page 30: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/30.jpg)
![Page 31: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/31.jpg)
![Page 32: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/32.jpg)
Adverse Events of Concern
• Seizures
• Cerebral edema
• Healing abnormalities
• Intracranial infections
![Page 33: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/33.jpg)
Late non-specific inflammatory changes
No tumor found on histology
![Page 34: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/34.jpg)
Edema and Cyst Formation
![Page 35: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/35.jpg)
Transient edema and “abscess-like”Appearance.
Resolution with steroids over time
![Page 36: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/36.jpg)
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
![Page 37: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/37.jpg)
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
![Page 38: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/38.jpg)
Intracranial Infections
• Recurrent Trial
– GLIADEL® Wafer group 3.6%
– Placebo group 1.0%
• Primary Trial
– GLIADEL® Wafer group 6.0%
– Placebo group 5.0%
![Page 39: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/39.jpg)
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
![Page 40: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/40.jpg)
Conclusion
The benefit to risk ratio in patients undergoing either initial or
recurrent surgery for malignant glioma favors GLIADEL® Wafer
![Page 41: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/41.jpg)
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
![Page 42: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/42.jpg)
![Page 43: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/43.jpg)
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
![Page 44: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/44.jpg)
![Page 45: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/45.jpg)
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.
![Page 46: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/46.jpg)
• 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
![Page 47: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/47.jpg)
![Page 48: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/48.jpg)
Hazard Ratio = 0.75
Stupp, R. et al. N Engl J Med 2005;352:987-996
TMZ Overall Survival
![Page 49: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/49.jpg)
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
![Page 50: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/50.jpg)
![Page 51: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/51.jpg)
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
![Page 52: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/52.jpg)
![Page 53: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/53.jpg)
![Page 54: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/54.jpg)
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.
![Page 55: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/55.jpg)
Is there a way to overcome the resistance
to BCNU?
![Page 56: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/56.jpg)
![Page 57: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/57.jpg)
![Page 58: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/58.jpg)
Chemo-Resistance: Clinical
![Page 59: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/59.jpg)
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
![Page 60: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/60.jpg)
CEDThe Concept of Convection-Enhanced Delivery
for Brain Tumor Therapy
![Page 61: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/61.jpg)
Bypassing the BBB:Intra-Tissue Drug Delivery
![Page 62: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/62.jpg)
Convection
Gd-saline infusion, 100 min
Moseley, Stanford University, 2000Moseley, Stanford University, 2000
![Page 63: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/63.jpg)
![Page 64: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/64.jpg)
![Page 65: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/65.jpg)
![Page 66: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/66.jpg)
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
![Page 67: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/67.jpg)
![Page 68: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/68.jpg)
Drugs
• Choosing the right drugs for CED– Efficacy
– Toxicity to normal brain
– Stability in situ
– Individual DISTRIBUTION characteristics (Infusate!)
![Page 69: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/69.jpg)
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)
![Page 70: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/70.jpg)
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
![Page 71: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/71.jpg)
Deformation due to edema
Sampson, Duke University, 2003Sampson, Duke University, 2003
Intra-TumoralTransmid Infusion
![Page 72: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/72.jpg)
![Page 73: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/73.jpg)
![Page 74: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/74.jpg)
Convection-Enhanced Delivery of Taxol in Recurrent Malignant Gliomas
CED of Cytotoxic Drugs
![Page 75: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/75.jpg)
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.
![Page 76: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/76.jpg)
Pre Taxol
2 wks post Taxol SP
![Page 77: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/77.jpg)
DW MRI as an indicatorOf tumor response
![Page 78: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/78.jpg)
baseline (left), d 4 Taxol (middle), d 60 (right)
![Page 79: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/79.jpg)
T1-Gd (before)
T1-Gd (immed after)
T1-Gd (1 mo after)
![Page 80: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/80.jpg)
Immed Post Taxol
6 Months Post Taxol
![Page 81: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/81.jpg)
Post TaxolPre Taxol
![Page 82: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/82.jpg)
Baseline MRI
2 Weeks post taxol
Large Tumors
Effect
![Page 83: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/83.jpg)
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)
![Page 84: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/84.jpg)
Penetration into the Ventricular System
Multifocal GBMNecrotic Tumor
![Page 85: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/85.jpg)
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
![Page 86: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/86.jpg)
Convection EffectDiffusion Effect
Effect of Diffusion on Covective Volume
![Page 87: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/87.jpg)
1 day post Taxol
7 days post Taxol
Diffusion Effect
![Page 88: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/88.jpg)
Histology
• Tissue obtained from treated tumors by Biopsy (1 patient) or resection (3 patients)
![Page 89: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/89.jpg)
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)
![Page 90: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/90.jpg)
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
![Page 91: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/91.jpg)
CED of Pseudomonas Exotoxin(NeoPharm)
IL13 receptor expressed only on tumor cells
Post resection – Peri-tumoral CED
![Page 92: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/92.jpg)
CED of Intra-Tumoral TransMid (Diphtheria Toxin/Transferrin)
(KS Biomedix, Xenova)
Tf Receptor expressed only on tumor cellsIntra-Tumoral CED
![Page 93: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/93.jpg)
Research Goals to Improve CED
• Optimizing convection:
Better distribution = Better response
(Optimal infusate)• Imaging the convective process• Simulation of convection (Pre-treatment)
![Page 94: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/94.jpg)
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
![Page 95: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/95.jpg)
Viscosity• Linear correlation found between viscosity,
volume of convection, and the incidence of backflow.
Low Intermediate High
![Page 96: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/96.jpg)
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.)
![Page 97: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/97.jpg)
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
![Page 98: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/98.jpg)
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
![Page 99: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/99.jpg)
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
![Page 100: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/100.jpg)
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)
![Page 101: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/101.jpg)
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.
![Page 102: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/102.jpg)
![Page 103: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/103.jpg)
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
![Page 104: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/104.jpg)
Possible Applications of CED
• Neoplastic diseases
• Degenerative brain diseases– Parkinson’s disease– Alzheimer
• Metabolic and genetic disorders
• Extracranial indications
![Page 105: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/105.jpg)
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
![Page 106: Newer management techniques for glioblastoma](https://reader037.vdocuments.mx/reader037/viewer/2022102721/54c230414a7959635f8b456d/html5/thumbnails/106.jpg)