GBM Fellow Talk 2009

7/30/2019 GBM Fellow Talk 2009

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Glioblastoma Multiforme:The Multidisciplinary Approach

to Treatment (2009)

H. Ian Robins MD, PhDUniversity of Wisconsin

School of medicine and Public HealthProfessor, Departments of Medicine,

Human Oncology, and Neurology


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Background

Primary Brain Neoplasia: Incidence

16,500 new cases predicted1

13,000 deaths/year1

1.4% of all cancers and 2.4% of all cancer deaths2

21% of childhood cancers2,3

60% are malignant glioma3

1Greenlee RT, et al. CA Cancer J Clin. 2000;50:733.2http://www.cancer.org. Accessed May 2005.3Chamberlain MC, et al. West J Med. 1998;168:114120.


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Background

Primary Brain Neoplasia: Frequency*

*Total is >100 due to rounding.

GBM = glioblastoma multiforme.

Levin VA, et al. In: Cancer Principles and Practice of Oncology. 1997;2022-2082.


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Background

Glioma: Grading

Grade Tumor Type Glioma %

I/II Well-differentiated(low-grade) astrocytoma

15 to 20

III Anaplastic astrocytoma 30 to 35

IV Glioblastoma multiforme 40 to 50

Chamberlain MC, et al. West J Med. 1998;168:114-120.


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Background

Genetic Risk Factors

A small percentage of CNS tumors attributable to inherited cancersyndromes or neurologic disorders1,2

von Hippel-Lindau

Li-Fraumeni

tuberous sclerosis neurofibromatosis

Heritable factors may account for 5% to 12% of all CNS cancers and 2%of CNS tumors in children1,2

Risk of brain cancer reported to be elevated in people with first-degreerelatives with Hodgkins disease or stomach, colon, or prostate cancer1

Familial clusters may be due to genetic and/or environmental factors3,4

1Hill DA, et al. CancerEpidemiol Biomarkers Prev. 2003;12:14431448.2Hemminki K, Li X. Cancer Epidemiol Biomarkers Prev. 2003;12:11371142.3Malmer B, et al. Int J Cancer. 2003;106:260263.4Grossman SA, et al. CancerInvest. 1999;17:299308.


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Background

Median Survival:

Importance of Histologic Grading Pathologic diagnosis is crucial in determining treatment

and prognosis1

Tumor Type

Median

Survival,years

Low-grade oligodendroglioma 4-102

Low-grade astrocytoma 53

Anaplastic oligodendroglioma 3-42

Anaplastic astrocytoma 33

Glioblastoma multiforme


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Background

Glioblastoma Multiforme (GBM):

Overall Characteristics

Grade IV malignant glioma

Most malignant, invasive, difficult-to-treat primary brain tumor

Frequency: most common in older adults (peak age, 55 to 65 years)

Recurrence: rapid growth; size may double every 10 days

Median survival: ~1 year


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Background

Features of Glioblastoma Multiforme

Rapid progression

Enhancing tumor

Surrounding edema

Contains tumor


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Background

Glioblastoma Multiforme

Classic Pseudopallisading


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Background

Anaplastic Astrocytoma:Overall Characteristics

Grade III malignant glioma

Less aggressive than GBM; malignant but somewhat better prognosis

Frequency: highest in young adults (30 to 40 years)

Recurrence: often as a higher grade glioma

Challenge: difficult to remove completely with surgery

Median survival: approximately 3 to 4 years

GBM = glioblastoma multiforme.


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Background

Anaplastic Astrocytoma

Ill-defined Borders High Cellularity

Nuclear Atypia

High Proliferation Index

Ki 67

Diffusely Infiltrating


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Tumor Type WHO Grade Chromosomal Abnormality

Astrocytoma Grade II p53 gene; chromosome 22q

Anaplastic astrocytoma Grade III Chromosome 9p, 13q, 19q

Glioblastoma multiforme Grade IV Chromosome 10

Louis DN, et al. Available at: http://brain.mgh.harvard.edu/MolecularGenetics.htm.

Background

Molecular Biology of Grade II-IVAstrocytic Tumors


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Gliomagenesis: Mol Targets

Glial Cell

LGG

AA

AO

GBM

1p/19q loss

p53 mut

22q loss

Rb mut

19q loss

p15/p16 loss

MDM2 amp

CDK4 amp

Chr 10 loss

Chr 10 loss

EGFR amp

PTEN mut: PI3kChr 10 loss

Angiogenesis: VEGF, VEGFR, PDGF, FGF


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Surgical Management

Surgery: Objectives in Malignant Glioma

Bulk reduction

Resection and potential for cure

Palliation

Biopsy for tissue diagnosis

Overall, the objectives of surgery in the treatment of CNSmalignancies include:


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Surgical Management

Therapeutic Impact of Radical Surgery inGlioblastoma Multiforme

0

2

4

6

8

10

12

14

98%

All patients

(n=416)

No prior treatment

(n=233)

P


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Surgical Management

Surgical Implantation of ChemotherapyWafers: Gliadel

Gliadelis a trademark of Guilford Pharmaceuticals.


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Surgical Management

GliadelTrial Protocol

Randomized, double-blind, placebo-controlled trial1

240 patients with newly diagnosed malignant glioma1

Glioblastoma multiforme: 207

Anaplastic oligoastrocytoma: 10

Anaplastic oligodendroglioma: 9

Anaplastic astrocytoma: 2

Wafers implanted at the time of surgery 120 active/120 placebo1

Most patients received 6-8 wafers2

Mean tumor resection was 89.9% in the Gliadel group and88.3% in the placebo group

77.5% of Gliadel patients and 81.7% of controls received 55-60 Gy

of irradiation beginning 3 weeks after surgery2

14% of Gliadel patients and 10% of controls also received systemicchemotherapy during the study2

Participants followed for up to 30 months1

1Westphal M, et al. Neuro-oncol. 2003;5:79-88.2Gliadel product information. Baltimore, MD: Guilford Pharmaceuticals, Inc.


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Surgical Management

Overall Survival Intent-to-Treat Group

Note:GBM patients (n=207) did not achieve survival

benefit; survival at 22months ~10%; no improvement in PFS

Westphal M, etal , Neuro-Oncol, 20035:79-88


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Radiation Therapy


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Radiation Therapy

Objectives of Radiationin Malignant Glioma

Potential for cure Prolong survival times

Control local infiltration of cancer cells

Palliation

Overall, the objectives of radiation in the treatment of CNSmalignancies include:


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Radiation Therapy

Adverse Effects of Radiation Therapyon Brain Tissue

Acute reaction due to radiation-induced edema; symptoms include:

Headache

Nausea/vomiting

Somnolence

Late effect: fatigue

Levin VA, et al. In: Cancer Principles and Practice of Oncology. 1997;2022-2082.


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Radiation Therapy

Radiation Treatment for AnaplasticAstrocytoma and Glioblastoma Multiforme

Efficacy confirmed in early randomized trials1-3

Significantly improved survival over supportive care alone orwith chemotherapy

Addition of chemotherapy did not improve survival compared withradiotherapy alone

External beam radiotherapy

Cornerstone of therapy4

Fractionation improves therapeutic ratios5

Anaplastic astrocytoma and glioblastoma treated with larger fields4

Radiosensitizers6

1Walker MD, et al. J Neurosurg. 1978;49:333-343.2Walker MD, et al. N Engl J Med. 1980;303:1323-1329.3Kristiansen K, et al. Cancer. 1981;47:649-652.4Soo EW, et al. Available at: http://www.cancernetwork.com. Accessed March 31, 2005.5Levin VA, Leibel SA, Gutin PH. Neoplasms of the central nervous system. In: DeVita VT, et al, eds. Cancer Principles and Practice of

Oncology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:21002160.

6Knisely JP, et al. Neuroimaging Clin N Am. 2002;12:525-536.


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Radiation Therapy

Stereotactic Radiosurgery

A focal, single-fraction radiation delivery method1

Linear accelerator

Gamma knife

Delivers a high dose of radiation to a small, discrete,

well-defined target1

Rapid dose fall-off

External beam method to deliver brachytherapy boost

Focal therapy for infiltrative disease

Functional neuroimaging2

No selection bias in clinical trials3

1Levin VA, Leibel SA, Gutin PH. Neoplasms of the central nervous system. In: DeVita VT, et al, eds.

Cancer Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:21002160.2McDermott MW, et al. J Neuro-oncol. 2004;69:83-100.

3Lustig RA, et al.Am J Clin Oncol. 2004;27:516-521.


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Radiation Therapy

Stereotactic Radiosurgery


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Radiation Therapy

RTOG 9305: Newly Diagnosed GBMStereotactic Radiosurgery Phase III Trial

Souhami L, et al. Int J Radiat Oncol Biol Phys. 2004;60:853-860.


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Chemotherapy


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Conventional Chemotherapy for Malignant Gliomas

Other alkylating agents (e.g., procarbazine, temozolomide)

Response rate in GBM 20% - 35% in newly diagnosed 5% - 15% in recurrent cases

Nitrosoureas (e.g., BCNU, CCNU)

Effect on survival modest

Salvage agents used include platinoids, CPT-11, and others

1Rieger J, et al. Neurol Psychiatr Brain Res. 1999;7:37-46.

2Levin VA, Leibel SA, Gutin PH. Neoplasms of the central nervous system.

In: DeVita VT, et al, eds. Cancer Principles and Practice of Oncology. 6th ed.

Philadelphia, PA: Lippincott Williams and Wilkins


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Limitations of Chemotherapy:Perfusion

Rieger J, et al. Neurol Psychiatr Brain Res. 1999;7:37-46.


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Chemotherapy

Limitations of Chemotherapy in TreatingBrain Tumors: Drug Interactions

Enzyme inducers1

Anticonvulsants (paclitaxel and CPT-11 clearance)1

Carbamazepine

Oxycarbazepine

Phenobarbital

Phenytoin

Enzyme inhibitors1

Valproic acid

Cytoprotective effect Corticosteroids2

1Vecht CJ, et al. Semin Oncol. 2003;30:49-52.

2Weller M, et al. Neurology. 1997;48:1704-1709.


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Chemotherapy

Meta-analysis of Chemotherapy inHigh-Grade Glioma

Stewart LA. Lancet. 2002;359:10111018.


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0

5

10

15

20

25

30

35

40

45

50

1-year survival 2-year survival

%o

fpatients

No chemotherapy

Chemotherapy

Chemotherapy

Meta-analysis of Chemotherapy inHigh-Grade Glioma

Stewart LA. Lancet. 2002;359:10111018.


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Chemotherapy

Limited Role for Chemotherapyin the Treatment of GBM

Randomized trials

with adjuvant PCV

chemotherapyhave failed to

demonstrate any

survival benefit

Medical Research Council Brain Tumor Working Party. J Clin Oncol. 2001;19:509-518.


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Temozolomide:

Mechanism of Action

and Pharmacokinetics


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Temozolomide

Temozolomide: Second-GenerationAlkylating Agent

TMZ spontaneously converts to MTIC at physiologic pH: no hepaticor renal metabolism required: therefore, drug levels not altered byanticonvulsant use

NN

O

NN

CNH2

NO CH3

pH > 7.0

Spontaneous

hydrolysis NN

O

NN

CNH2

N

HCH3

O

NN

CNH2

NH2

Temozolomide MTIC AIC Methyldiazoniumion

+ N NCH3

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

Denny BJ, et al. Biochemistry. 1994;33:90459051.


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*High cytotoxicity.

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

N3 adenine

9%

Other sites

16%

O6

guanine5%*

N7 guanine

70%

Position/base total adducts (%)

Temozolomide

Temozolomide Exerts Cytotoxic Effectsvia Methylation of DNA


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Temozolomide

Temozolomide PharmacokineticCharacteristics

Key characteristics of temozolomide include1,2: Excellent bioavailability

Rapid, complete absorption Peak plasma concentrations in 1 h

Rapid elimination: mean t1/2 = 1.8 h

Newlands ES, et al. Br J Cancer. 1992;65:287-291.

TEMODAR Prescribing Information.


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Temozolomide

Temozolomide Drug Interactions

In a multiple-dose study, administration of temozolomide withranitidine did not change the Cmax or AUC values for temozolomideor MTIC

Coadministration of valproic acid decreases the clearance oftemozolomide by 5%

Coadministration of the following drugs had no influence ontemozolomide clearance: Dexamethasone

Carbamazepine

Prochlorperazine

Ondansetron

Phenytoin H2-receptor antagonists

Phenobarbital


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Temozolomide

Primary Mechanisms of Resistance

High levels of O6-alkylguanine DNA alkyltransferase (AGT)

Applies to methylating and chloroethylating agents

A Principal cytotoxic mechanism is DNA damage caused by failureof DNA mismatch repair (MMR): cells with deficiency in MMR do not

recognize O6

-MG adducts allowing replication without apoptosis.Applies to methylating agents only

Poly(ADP- ribose) polymerase (PARP)

Friedman HS, et al. Clin Cancer Res. 2000;6:2585-2597.


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Poly(ADP-ribose) polymerase

Can we exploit the other DNA alkylation events associated withtemozolomide?

Only about 7% of the alkylation caused by temozolomide involves the O-6position of Guanine

Far more common is alkylation of the N-7 position of Guanine and the N-

3 position of Adenine

These are repaired by base exicision pathway enzymes,which can beinhibited by PARP inhibitors


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Temozolomide in Newly DiagnosedGlioblastoma Multiforme


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Temo zolom ide in GBM

Phase II Study in Newly DiagnosedGlioblastoma Multiforme

Study design and objectives

Two center, open-label pilot study

Evaluate safety, tolerability, and overall survival

Inclusion criteria

Adults with newly diagnosed GBM ECOG performance status 2

Adequate hematologic, renal, and hepatic function

Stupp R, et al. J Clin Oncol. 2002;20:1375-1382.


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Patients (n=64)

Median age = 52

Performance status 0 or 1 in 86%

Complete resection in 42%

Treatment Temozolomide discontinued in 4 patients in concomitant phase due to infection

or thrombocytopenia

Maintenance therapy administered in 49 patients for median 5.5 cycles

Thirty-nine percent received all planned temozolomide


Phase II Study: Patients andTreatment Delivery


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Hematologic toxicity

Concomitant phase: Grade 3/4 neutropenia and thrombocytopenia in 6% ofpatients each

Maintenance phase: Grade 3/4 neutropenia or thrombocytopenia in 2% and 6%of cycles, respectively

Pneumocystis cariniipneumonia in 2 patients

Non-hematologic toxicity

Most mild-to-moderate severity

Nausea, vomiting, and fatigue most common


Phase II Study: Adverse Events



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Phase II Study: Adverse Events

Hematologic toxicity

Concomitant phase: Grade 3/4 neutropenia and thrombocytopenia in 6% ofpatients each

Maintenance phase: Grade 3/4 neutropenia or thrombocytopenia in 2% and 6%of cycles, respectively

Pneumocystis cariniipneumonia in 2 patients*

Non-hematologic toxicity

Most mild-to-moderate severity

Nausea, vomiting, and fatigue most common



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Phase II Study: Survival


Median survival = 16 months

n=64


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Radiotherapy plus Concomitant andAdjuvant Temozolomide for Glioblastoma

R Stupp, WP Mason, MJ van den Bent, et al.

N Engl J Med. 2005;352:987-996.


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Phase III EORTC/NCIC Trial:Study Design

Phase III, randomized, open-label, multicenter study

Patients randomly assigned to receive either radiotherapy (RT) 5days/week for 6 weeks or radiotherapy plus concomitant temozolomide(TMZ) followed by maintenance TMZ for 6 cycles

StuppR, et al. N Engl J Med. 2005;352:987996.


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Inclusion Criteria

Newly diagnosed, histologically proven GBM

Age 18 70 years

WHO performance status 2

6 weeks since biopsy or resection

Adequate bone marrow, hepatic, and renal function

No other severe underlying disease

Stratification factors:

Age

Resection vs. biopsy Performance status 0 to 1 vs. 2

Institution


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Temozolomide 75 mg/m2 po qd for 6 weeks,

then 150200 mg/m2 po qd d15 every 28 days for 6 cycles

Focal RT daily 30 x 200 cGy

Total dose 60 Gy

Concomitant

TMZ/RT*Adjuvant TMZ

Weeks6 10 14 18 22 26 30

RT Alone

R

EORTC 26981-22981 and NCIC CE.3: Schema

0

*PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.

Stupp, NEJM,2005


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Patient Characteristics

Characteristic Radiotherapy

n=286

TEMODAR plus Radiotherapyn=287

Age, yrsMedianRange

5723-71

5619-70

WHO performance status, n (%)012

110 (38)141 (49)35 (12)

113 (39)136 (47)38 (13)

Sex, n (%)MaleFemale

175 (61)11 (39)

185 (64)102 (36)

Extent of surgery, n (%)

BiopsyDebulking 45 (16)241 (84) 48 (17)239 (83)

Corticosteroid therapy, n (%)YesNoMissing data

215 (75)70 (24)12 (4)

193 (67)94 (33)10 (3)


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Treatment delivered, n (%) Radiotherapyn=286

Radiotherapy plustemozolomide

n=287

Radiotherapy

Received >90% of doseEarly discontinuation

264 (92%)19 (7%)

273 (95%)14 (5%)

Completed both radiotherapy andtemozolomide

N/A 243 (85%)

Discontinued temozolomide due totoxicity

N/A 14 (5%)


Treatment Delivery: Concomitant Phase


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Treatment Delivery: Maintenance Phase

Treatment delivered Patients

n=287

Started maintenance therapy, n (%) 223 (78%)

Cycles completed, median (range) 3 (0-7)

Completed 6 cycles, n (%) 105 (47%)

Dose escalated at cycle 2, n (%) 149 (67%)

Reasons for discontinuation, n (%)Disease progressionToxicityOther

86 (39%)17 (8%)15 (7%)


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Treatment Delivery: Salvage Therapy

Radiotherapy

n=286

Radiotherapy plusTemozolomide

n=287

Progressive disease, n (%) 268 (94) 244 (85)

Second surgery, % 23 23

Chemotherapy, % 72 58

Temozolomide, % 60 25

Stupp R, et al. N Engl J Med. 2005;352:987-996.


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EORTC Phase III Trial Overall Survival

months

0 6 12 18 24 30 36 420

1020

30

40

50

6070

80

90

100RT TMZ/RT

Median OS, mo: 12.1 14.6 p


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Temozolom ide Safety

Adverse Events in Newly DiagnosedGlioblastoma Multiforme

ConcomitantPhase

Radiotherapy +Temozolomide

(n=288)

MaintenancePhase

Temozolomide(n=224)

Adverse Event Number (%) of patients

All Grade >3 All Grade >3

Alopecia 199 (69) 0 124 (55) 0

Fatigue 156 (54) 19 (7) 137 (61) 20 (9)

Nausea 105 (36) 2 (1) 110 (49) 3 (1)

Vomiting 57 (20) 1 (


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Conclusions

Temozolomide given concomitantly with radiotherapy and asmaintenance therapy significantly improves survival in patients withnewly diagnosed glioblastoma multiforme compared with radiotherapyalone.

Temozolomide provides a measurable response in patients withtreatment-tolerability profile.

Non-cumulative myelosuppression is the dose-limiting adverse effect.


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Phase II German Trial

Used 50 mg/m2 TMZ during XRT Used no post-XRT TMZ

Results:

53 pts with GBM; 60 Gy/6 wks

Resection: complete 14, subtotal 22, Bx 17

Median PFS: 8 mos; Median survival: 19 mos

1-yr survival: 72%; 2-yr survival: 29%

No adjuvant TMZ; used lower daily dose

Combs, ASCO 2004.


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Wedge SR, et al. Ant icancer Drugs1997;8:92-97.

TMZ & XRT: Increased Inhibition of Cell Growth*

* In-vitro studies of U373MG

glioblastoma cell line

Radiation (Gray)

35

30

25

20

15

10

5

00 1 2

InhibitionofCellG

rowth(%) RT only

RT + 5 M TMZ

RT + 10 M TMZ


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Overall & Progression-Free Survival by

Treatment

Variable RT (n=286) RT+TMZ (n=287)

Value (95% Confidence Interval)

Median Overall Survival (mos) 12.1 (11.2-13.0) 14.6 (13.2-16.8)

Overall Survival (%)

at 12 months 50.6 (44.7-56.4) 61.1 (55.4-66.7)

at 24 months 10.4 (6.8-14.1) 26.5 (21.2-31.7)

Median PFS (mos) 5.0 (4.2-5.5) 6.9 (5.8-8.2)

Progression-Free Survival (%)

at 12 months 9.1 (5.8-12.4) 26.9 (21.8-32.1)

at 24 months 1.5 (0.1-3.0) 10.7 (7.0-14.3)

Adapted from Stupp R, et al. N Engl J Med. 352:10:987-996.

Overall Survival by MGMTPromoter


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yMethylation Status

Hegi ME, et al. N Engl J Med. 352:10:997-1003.


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Survival with Methylated MGMTPromoter(44.7% had methylated MGMT)

Promoter Status & Outcome RT (n=100) RT+TMZ (n=106)

Number of Patients 46 46

Progression-Free Survival

Median (months) 5.9 (5.3-7.7) 10.3 (6.5-14.0)

at 6 months 47.8 (33.4-62.3) 68.9 (55.4-82.4)

Hazard Ratio for Death 1.00 0.48 (0.31-0.75)

Overall Survival

Median (months) 15.3 (13.0-20.9) 21.7 (17.4-30.4)

at 2 years (%) 22.7 (10.3-35.1) 46.0 (31.2-60.8)


Adapted from Hegi ME, et al. N Engl J Med. 352:10:997-1003.

Note: Numbers in parentheses are 95% con f idence intervals.


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Survival with Unmethylated MGMTPromoter

Promoter Status & Outcome RT (n=100) RT+TMZ (n=106)

Number of Patients 54 60

Progression-Free Survival

Median (months) 4.4 (3.1-6.0) 5.3 (5.0-7.6)

at 6 months 35.2 (22.5-47.9) 40.0 (27.6-52.4)


Overall Survival

Median (months) 11.8 (9.7-14.1) 12.7 (11.6-14.4)

at 2 years (%)


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Months0 4 8 12 16 20 24 28 32 36 40

0

10

20

30

40

50

60

70

80

90

100

O N Patients at risk, n

54 54 28 9 0 0 0 0 0 0 0

53 60 44 18 8 8 8 7 5 3 1

45 46 33 15 7 3 2 1 0 0 0

40 46 35 28 18 14 10 6 3 1 0

Unmeth, RTaloneUnmeth, TMZ/ RTMeth, RT aloneMeth, TMZ/ RT

Overall Wald test: P< .0001 (df = 3)

Progression-free

survival

Meth, TMZ/RT

Meth, RT

Unmeth,TMZ/RTUnmethRT

Progression-Free Survival by MGMT and +/- TMZ

Survival by EGFR and MGMT Status


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Survival by EGFRand MGMTStatus

Months

Survi

val

Low EGFR,Meth

Low EGFR, Unmeth

High EGFR,

Unmeth

High EGFR,Meth

EGFRexpression data based on GeneChip U133 Plus 2.0

Wald test, p= 0.0031

Hegi, SNO 2004

MGMT I hibiti /D L l


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-100

-80

-60

-40

-20

0

0 7 15 22

Days

75mg/m2 100 125 150 175

%C

hange

50-150 mg/m2/d 21 d with 1 wk rest

Tolcher AW, et al. Br J Cancer, 2003;88:10041011.

MGMT Inhibition/Dose Level


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TMZ Inactivates DNA Repair

Schedule A

50 - 175 mg/m2/day x 7 days repeated q 2weeks

Schedule B

50 - 150 mg/m2/day x 21 days repeated q 4weeks

Serial serum samples collected for 52 of the 72 patients

Inactivation of AGAT noted after 7 days of TMZ treatment

(P


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R

E

G

I

ST

E

R

RT ( 60 Gy) plus

TMZ 75 mg/m2

/d

R

A

N

D

O

M

I

Z

E*

Arm 1: Standard

TMZ days 1 - 5 q 28days

Maximum 12 cycles

Arm 2: Experimental

TMZ days 1 - 21 q 28days

Maximum 12 cycles

RTOG/EORTC 0525 Phase III GBM Trial

*Strat ify b y RTOG RPA class and AGAT statu s

N = 834 to detect 25% relative improvement in median survival

corresponding to hazard ratio = 0.80.

PIs: Gilbert and Mehta

BackgroundMellinghoff et al 11/05


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Grade IV astrocytomas express EGFRvIII

which is constituatively active, strongly

activating PI3K

PTEN inhibits this pathway and is commonly

lost in these tumors

TK inhibitors target the cytoplasmic domain

for blockage-depriving cell from proliferation

(ras) and apoptosis (Akt)

Mellinghoff et al 11/05

KrishnanetalFrontiersinBioscience1/03


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Before I came here I was confused

about this subject.

Now having listened to your lecture, Iam still confused, but at a higher

level.

Enrico Fermi, 1938 Nobel Laureate in

Physics

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GBM Fellow Talk 2009