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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)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

Giovanni Andrea Della Croce, Chirurgiae 1573

Primary Brain Tumors

• Incidence on the rise

• 41,130 new cases annually in US (both benign and malignant; CBTRUS data for 2004);

Malignant glioma (22,070primary malignant tumors to be diagnosed in 2010):

1. Glioblastoma (GBM)2 Anaplastic tumorsCBTRUS data for 2004);

62,940 expected to be diagnosed in 2010

• >180,000 new cases annually worldwide

• Risk factors still poorly understood

2. Anaplastic tumors

Low grade gliomas:1. Astrocytoma2. Oligodendroglioma3. Mixed tumors

Types of Primary Brain Tumors

35

40

45

50

1. High grade glioma (HGG)

2. Low grade glioma (LGG)

3 M i i

0

5

10

15

20

25

30

HGG LGG MENING VSCH PIT MIS

HGG

LGG

MENING

VSCH

PIT

MIS

3. Meningioma (MENING)

4. Vestibular schwannoma (VSCH)

5. Pituitary tumors (PIT)

6. Miscelanneous (MIS)

Incidence Rates of Primary Brain Tumors

CBTRUS 1992-1997, Wrensh et al., 2002

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Do Cell Phones Cause Cancer or Not? The Latest Answer Is NoBy Bryan Walsh

Cell phones and brain tumors (glioma)

Swedish cell phone study

Pooled data from two case-controlled studies (1997-2003) Association between use of mobile and cordless phones and

malignant brain tumors only (GLIOMAS) Replies obtained from 85% of cases and 84% controls

1. Increased risk with latency period and with cumulative use in hours2. Highest risk for astrocytoma (OR=2.7) in > 10 year latency group3. 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. 2011

First classification of brain tumors

Immense surgical database of Harvey Cushing and pathological expertise of Percival Bailey -publication in 1926

WHO Classification

•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)

Tumor TypeMedian

Survival, years

Lo grade oligodendroglioma 4 102

Prognostic Implications of Tumor Grade

Low-grade oligodendroglioma 4-102

Low-grade astrocytoma 53

Anaplastic oligodendroglioma 3-42

Anaplastic astrocytoma 33

Glioblastoma multiforme <11

1Bruce J, et al. Available at: http://www.emedicine.com.2Hariharan S. Available at: http://www.emedicine.com.3DeAngelis LM. N Engl J Med. 2001;344:114-123.

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Before we were able to see the tumor Identification: imaging (CT scan)

Identification: imaging (MRI)

T1 no contrast T1 with contrast FLAIR

Identification: imaging (MR Spectroscopy)

Low grade glioma

High grade glioma

Pathologic Diagnosis

• Stereotactic Biopsy– CT or MRI guided biopsy– 2% risk, sampling error g

• Open Biopsy: Craniotomy– Mortality <5% in major centers– Mini tumor excision

H&ET1 + gad

Low Grade Astrocytoma

Non-enhancing mass Cellular pleomorphic infiltrates

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T1 + gad H&E

Anaplastic Astrocytoma (WHO III)

May enhance, 30% don’t enhance ! Cellular, mitoses w/o vessels

H&E

Glioblastoma (WHO IV)

T1 + gad

Enhancing cystic w. necrosis Cellular, vessels, necrosis, MIB-1

Beginnings of brain tumor surgery

• Goals:– Accurate diagnosis– Maximum tumor debulking: >98% advantage– Preservation of neurologic function: mapping

• Reduces mass effect - palliation

Surgery

p• 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

P<0.0001 P=0.028.8 mo

13 mo

Extent of surgery is an important prognostic factor

Lacroix M, et al. J Neurosurg. 2001;95:190-198Data from Stummer et al, Neurosurgery 2008, confirmed benefit of more extensive resection.

>98% >98%All patients

(n=416)No prior treatment

(n=233)

Surgical Implantation of Chemotherapy Wafers: Gliadel®

Gliadel is a trademark of Guilford Pharmaceuticals.

N=240 (new GMB)6-8 wafersMedian Survival 13.9 vs. 11.6

Westphal et al, Neuro-Oncology 2003

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Polish contribution to neuro-oncologyand the beginning of radiation-oncology

Improved survival for anaplastic gliomas and GBM

Prolonged time to progression for low grade gliomas

Radiation Therapy

XRT to the tumor and 1-2 cm margin

Dose 54-60 Gy = 5-6 weeks of therapy

First chemotherapy trials

• Chemotherapy prolongs survival • At 1 year:

• 15% decrease in risk of death• Increased survival of 6% (40% to 46%)

Chemotherapy

Meta-analysis of 12 Trials

• 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

Limitations of Chemotherapy in Treating Brain Tumors: Perfusion and Hypoxia

Rieger J, et al. 1999

Temozolomide: Second-Generation Alkylating Agent

TMZ spontaneously converts to MTIC at physiologic pH

NN

OC

NH2 pH > 7.0Spontaneous

NN

OC

NH2O

CNH2

MTIC, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide.

Denny BJ, et al. Biochemistry. 1994;33:9045-9051.

NN

NN N

O CH3

phydrolysis N

NN

N NH

CH3 NN

CNH2

Temozolomide MTIC AIC

+ N N–CH3

Methyldiazoniumion

•100% oral bioavailability•Crosses blood-brain barrier•20% of serum AUC found in CSF•Minimal cytochrome P450 effect

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Adjuvant Temozolomide Improves Survival in Glioblastoma Adjuvant Temozolomide Improves Survival in Glioblastoma

Adjuvant Temozolomide Improves Survival in Glioblastoma

(n=287)

(n=286)

Stupp et all., 2005

Glioblastoma – Current Standard of Care

• Maximal surgical resection

• Radiotherapy with concomitant and adjuvant chemotherapy (temozolomide)

• Median OS = 11-17 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

Gene Gene Function Chromosome Comment

TP53 Tumor suppressor 17p13.1 33% 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 cell lif i

12q13-14 & 7q21-22

Amplified in 15% of cases without p15 or p16 iproliferation 22 mutations

PTEN Tumor suppressor 10q23 25-40% of glioblastomas

MGMT DNA repair gene 10 Promoter methylation in 24-40% of gliomas

Retinoblastoma Tumor suppressor 13q14 33% of high grade astrocytoma

- - 19 Frequent in high grade astrocytomas

- - 22q 20-30% of all grades of astrocytomas

EGFR Oncogene 7 33-50% of high grade astrocytomas, always associated with 10 loss

PDGFR Oncogene - Expressed in all grades of astrocytomas

1p - Nearly all oligodendrogliomas, usually expressed with 19q loss

Novel Therapies_____________________________

• Anti-angiogenic approach

• Overcoming resistance to chemotherapy

• Tumor treating fields (TTfields)

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Vascular Endothelial Growth Factor

Normal human cortex

Angiogenesis in gliomaMalignant Gliomas Generate Abnormal Blood Vessels

From S. Stiver, Frontiers in Bioscience 9, 3105-3123, September 1, 2004

Anti-angiogenic Therapy in Malignant Glioma

First generation angiogenesis inhibitors:

1. Thalidomide

2. Lenalidomide

3. Penicillamine

4. Carboxyamidotriazole

Small-molecule inhibitors of VEGRF/PDGFR/

EGFR:

1. Cediranib (AZD 2171)

2. Vatalanib (PTK 787)

3. Pazopanib (GW 786034)

Inhibitors of VEGF

Bevacizumab

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

N = 32

BEV + CPT 11

Anti-angiogenic Therapy in Malignant Glioma

BEV + CPT-11

CR in 3 patients

PR in 16 patients

Overall radiographic response 66%Stark Vance, WFNO, May 2005

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

Vredenburgh et al. Clinical Cancer Research 2007

GBM:

PFS-6 (30%) = 20 weeks (9 weeks hc)

Anaplastic glioma:

PFS-6 (56%) = 30 weeks (13 weeks hc)

Other benefits of anti-angiogenic therapy

July 2009 September 2009

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• Overall survival remains poor despite treatment

• Alkylating agents are used to treat GBM (temozolomide – TMZ and carmustine – BCNU)

Hi h O6 th l i DNA th lt f (MGMT) l l i

Overcoming resistance to chemotherapy

• High O6methylguanine-DNA-methyltransferase (MGMT) levels in tumors confer TMZ and BCNU resistance (poor prognosis)

• MGMT promoter methylation status influences prognosis

• O6benzylguanine (O-6-BG) can inhibit wild type MGMT and enhance TMZ and BCNU activity in tumor cells BUThematopoietic toxicity has been dose limiting

Repairs alkylation DNA damage by removing adducts from the O-6 position on guanine

What is MGMT?

DNA repair mechanism through O6-methylguanine-DNA-

methyltransferase

AGT = O6-Alkylguanine-DNA Alkyltransferase

Chemotherapy Boosters

Direct protein inhibition

O6-benzylguanine (O6-BG)

• in mice tumors resistant to high doses of BCNU

Increasing efficacy of chemotherapy

AGT

gresponded after treatment with O6-BG

• in humans, tumor AGT activity can be completely suppressed by O6-BG

• Friedman et al. found that 100 mg/m2 of O6-BG depletes AGT activity to undetectable levels in gliomas18 hours after administration

• Quinn et al. conducted Phase I trials of temozolomideplus O6-BG and determined the MTD of temozolomide at 472 mg/m2

• Phase II study reported activity of this combination in recurrent malignant glioma

Surgical Resection

Radiation Therapy

MGMT promoter methylation screening

unmethylated = eligible

G-CSF Mobilization

Weeks -7 to -1

Day -7

D 6

Increasing efficacy of chemotherapy

G CSF MobilizationDay -6

Day -5Day -4Day -3

Day -2Day -1Day 0

Apheresis #1 Apheresis #2

BCNU 600 mg/m2

(Conditioning/chemotherapy)

Stem Cell Infusion

28 day cycles of O-6-BG (120 mg/m2 bolus followed by 30mg/m2/day for 48h)+ TMZ (first dose 472 mg/m2)

CD34 Selection

Gene Transfer

Patient% Gene Transfer by

MGMT Stain*Cells/kg Infused

1 51.9 8.9 x 106

Efficient Ex Vivo Gene Transfer to CD34+ cells

2 59 21.9 x 106

3 64.4 7.5 x 106

*MGMT assessed by flow cytometry on day 3 after transduction

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All three patients demonstrated presence ofed

cel

lspy

per

cel

l)

PATIENT # 1

100

0

20

40

60

80

100

0 25 50 75 100 125 150 175 200 225 250 275 300 325

Sustained Presence of P140K in Peripheral White Blood Cells

demonstrated presence of gene-modified

granulocytes in peripheral blood by western blot and

PCR up to 10 months after transplant

Days after cell infusion

Per

cent

gen

e m

odifi

e(a

ssum

ing

one

prov

iral

cop

PATIENT # 3

PATIENT # 2

0

20

40

60

80

0 25 50 75 100 125 150 175 200 225 250 275 300 325

0

20

40

60

80

100

120

0 25 50 75 100 125 150 175 200 225 250 275

Treatment course and response

PATIENT#1

9 SD/SD alive at 34 months

Number oftreatment cycles

Disease status at 6 and 12 mo

Treatment Course and Response

Overall survival

PATIENT#2

3 SD/PD 18

PATIENT#3

4 SD/SD 23

SD – stable diseasePD – progressive disease

PATIENT #1

Treatment Course and Response

#1

Diagnosis 6 months 12 months

#3

Science Translational Medicine, May 9th 2012

Outside the Box

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, y g q ( ) g y,radio frequency tumor ablation

3. Electric fields at medium frequencies (100-300 kHz) have specific inhibitory effects on dividing cells

TTFileds – “tumor treating fields”

Effects of TTFields

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Metaphase Effect

• 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

Tumor Treating Fields (in vitro)

Kirson et al., Cancer Research 2004

TTField is targeted to a specific cancer cell

Intestine – 50kHz

Breast cancer – 120kHz

TTField effect on cells is frequency specific and (inversely) related to cell size

GBM – 200kHz

Cancer Research, 2004

Tumor Treating Fields (in vivo)

Treated Untreated

TTFields in brain tumor therapy

PNAS, 2007

TTFields in brain tumor therapy

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Clinical Trials with TTFields – Recurrent GBM

Surgery/BiopsyRT/TMZ + Maintenance TMZ

Recurrence10% - 1st recurrence

90% - 2-4th recurrence

Randomization 1:1

NovoTTF-100A Monotherapy

Active Chemotherapy

Clinical Trials with TTFields

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/dayFrequency 220 kHz, intensity 1-2 V/cm

Outcome TTF group BSC

OS p=0.23 6.6 months 6.0 months

OS; biopsy only patients; p=0.026

10.7 months 5.2 months

OS; post anti-VEGF therapy; p=0.014

6.3 months 3.2 months

PFS6 p=NS 21.4% 15.2%

viva

l

0 7

0.8

0.9

1.0

TTF Th

Overall Survival

TTF Therapy

BPC chemotherapy0.8

0.9

1.0

Avastin Failures (n=21 vs. 23)All Patients (n=120 vs. 117)

Months

Frac

tion

Ove

rall

Sur

v

0 6 12 18 24 30 36 42 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7 TTF Therapy

BPC chemotherapy

BPC chemotherapy

Wong et al., SNO 2011

Overall Survival (months)

Frac

tion

sur

viva

l

0 6 12 18 24 30 360.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

TTF Therapy

BPC chemotherapy

Ram et al., SNO 2010, 2011

Patient 01042 - Baseline Patient 01042 – 6 months

Response to TTFields

• 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

Gliomas Summary

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

Kiem LabHans-Peter KiemJennifer AdairBrian BeardGrant TrobridgeCh i ti I id

University of WashingtonAlex SpenceMarc ChamberlainJason RockhillDan SilbergeldP B k

CPF/GCTLCathy LindgrenChris BrownDavid SchneiderDeanna Brown

Duke UniversityHenry Friedman

PATIENTS and FAMILIES

The Team

Christina IronsideAllie EvansSum Ying ChiuTera MatsonPast and current members

Pam BeckerCarrie GrahamLaurie LeeNeuro Oncology Tumor Board

CTLShelly Heimfeld

SCCAGold Autologous Team

Henry Friedman

NGVL/IUVPFKenneth CornettaNIH/NCI

5R01CA114218

NCI/CTEPO-6-BG

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The “guilty” trio