High Grade Glioma;What Else?

El-Ghoneimy E (M.D.) – Moustafa M (M.D.)Abdulla M (M.D.)

Department of Clinical OncologyKasr El-Aini School of Medicine

Cairo UniversityBarcelona – March, 2002

Neurological Deficits Already

Present at Time of

Diagnosis

Lack of Tissue Repair

Following Surgical Trauma

Current Therapeutic

Modalities are Lacking The Appropriate

Effectiveness

*2% of all malignant Diseases

*Disproportionate Morbidity & Mortality

* 3rd cause of cancer related mortality

Why Poor Prognosis?

• Incompatible with life even at a relatively small burden.

• Symptomatic at a size between 30-60 gms (3-6 X 1010 cells).

• Fatal when reaching about 100 gms (10 11 cells).

• Lack of draining lymphatics; impedes removal of necrotic debris; life-threatening ++ ICT; death of patient.

Survival Issues of Malignant Glioma

14

20

36

50

0 20 40 60 80 100

ConservativeManagement

Surgery

Surgery + Rth

Surgery + Rth + Cth

(Huncharek & Muscat, 1998)

Biological Associations:Biological Associations:

P-53 mutationsRB mutationmdm-2 overexpressionbcl-2 mutationPDGFR,PDGF-A overexpressionEGFR overexpression

Mitotic ActivityInvasion.Vascularization.Chemoresistance Radioresistance.

Complete Surgical Removal is Impossible Due to Surrounding Vital Regions.

Infiltrative Nature of The Lesion.

Limitations of Radiation Dose Delivery Because of Tolerance.

Chemo-resistance & Lack of Drug Concentration within The Lesion

Dose Escalation & Altered Fractionation Schedules

Conformal Radiation, Radiosurgery with the advent of Mutlileaf Collimators and IMRT.

The Use of Radiation Therapy

Nitrosureas: Marginal Benefit.

PCV Regimen: Minimal Improvement in TTP only in Anaplastic Astrocytoma not in G.M.

Investigational: CPT-11, Platinum Compounds, Taxanes….etc

The Use of Chemotherapeutics:

Basic Requirements for Investigational Therapies of

Malignant Gliomas:

Non Invasive. Least Morbidity. No further affection of Neurological

Insult. Not associated with further

deterioration of performance status.

Single Institution Experience

NEMROCK EXPERIENCE; 1988-2003:1988-1990

1991-1995

1997-1999

1999-2002

1999-2002

2001 - Ongoing

Whole Brain + Boost RTh vs Localized Rth in GM & AA.

Hypofractionated Rth in GM.

Lomustine/Platinum X 2 + Radical Rth Vs Radical Rth in GM & AA.

SRS Single Fraction vs Lomustine+VCR X3-6 in Recurrent or Residual GM & AA.

The Use of TEMOZOLOMIDE in High Grade Gliomas at Relapse.

Adjuvant P.O. SRT vs Conventional Rth in Low Grade Glioma

NEMROCK 1997-199860 patients with high grade glioma

Arm A29 Pts

Arm B31 Patients

CCNU/Platinum No Cth

Radical Irradiation

RadicalIrradiation

The Role of Neoadjuvant Cth

24 m. OAS Among Both Groups

0%

50%

100%

Duration (Months)

%

Surv

ival

G AG B

The Role of Neoadjuvant Cth

24 months Progression Free Survival Among Both Groups

0%

50%

100%

Duration (Months)

%

Surv

ival

G AG B

The Role of Neoadjuvant Cth

Drug Related Toxicity Profile Among 30 Patients with High Grade Glioma Treated by

TEMOZOLOMIDE at Relapse (NEMROCK 2000-2002)

73%

7% 3% 13% 3%0%

50%

100%

Nau

sea

-

Vom

itin

g G

I

- II

Neu

tropen

ia

Thro

mbocy

top

enia

Dep

ress

ion

Cuta

neo

us

Ras

h

Toxicity

%Temozolomide at Relapse:

Post-Treatment Changes in KPS Among 30 Patients with Hiogh Grade Gliomas Treated by

TEMOZOLOMIDE at Relapse (NEMROCK 2000-2002)

10%

30%

60%

0%

50%

100%

Improved Deteriorated Stationary

KPS

%Temozolomide at Relapse:

Post-Treatment Chganges in Manifestations of ++ ICT and Steroid Dependance Among 30 Patients with High Grade

Glioma Treated by TEMOZOLOMIDE at Relapse (NEMROCK 2000-2002)

7%

50%43%

0%

50%

100%

Improved Stationary DeterioratedICT Status

%

Temozolomide at Relapse:

Radiological Response Among 30 Patients with High Grade Glioma Treated by TEMOZOLOMIDE at Relapse (NEMROCK

2000-2002)

33%

22%

45%

0%

50%

100%

Regression Progression Stationary

Radiological Response

%Temozolomide at Relapse:

TEMOZOLOMIDE

X

6 Courses

Survival & Response Parameters:Median Time to Progression = 32.6 Weeks.

Survival Range: 10-36 Months

Median Survival: 17.3 months

Actuarial 12-month OAS = 63.7%

Temozolomide at Relapse:

Th

e U

se o

f TEM

OZ

OLO

MID

EADEQUATE SAFETY PROFILE

NO G III-IV MORBID EVENTS

+ VE SUBJECTIVE EFFECT IN THE MAJORITY OF PATIENTS

+ VE OBJECTIVE RESPONSE

Future Directions

Adjuvant Basis

Metaststic Disease

Concurrent Use with Rth

Temozolomide at Relapse:

Rational For High Rational For High Precision External Beam Precision External Beam RT:RT:

Dose Reduction

To Normal Tissue

Dose Escalation

To CTV

Biological Considerations:Biological Considerations:

Significant Improvement in Tumor Coverage

+ Significant Reduction to Normal Tissue Dose

Dose Escalation to

CTV

Maximum Locoregional

Tumor Control

? Improved Survival

Palliat ive Combinat ion

Chemotherapy

CCN U/ VCR

S tereotact ic Radiosurgery

"S ingle S ession"

15- 17 Gy

40 Pat ients with

H igh Grade Glioma

at Relapse

Radiosurgery at Relapse:

• Headring and Mask Headring and Mask SystemSystem

• Localizer boxLocalizer box

• CouchmountCouchmount

• QA HardwareQA Hardware

• Target Positioner boxTarget Positioner box

• Conical Collimator SetConical Collimator Set

• Conformal blocksConformal blocks

• Headring and Mask Headring and Mask SystemSystem

• Localizer boxLocalizer box

• CouchmountCouchmount

• QA HardwareQA Hardware

• Target Positioner boxTarget Positioner box

• Conical Collimator SetConical Collimator Set

• Conformal blocksConformal blocks

NEMROCK NEMROCK BrainSCAN BrainSCAN Hardware consists Hardware consists of:of:

NEMROCK NEMROCK BrainSCAN BrainSCAN Hardware consists Hardware consists of:of:

Head ring Head ring

For flexible patient fixation and referencing

For single fraction & consists of:

For flexible patient fixation and referencing

For single fraction & consists of:

• Carbon fiber post - variable angle and position - maximum vertical length for

Deep seated lesions.

• Carbon fiber post - variable angle and position - maximum vertical length for

Deep seated lesions.

• Robust and lightweight frame ( Positioned at least 2 cm below lesion)• Robust and lightweight frame ( Positioned at least 2 cm below lesion)

• Two torque wrenches for pressure adjustment of pins• Two torque wrenches for pressure adjustment of pins

• Artifact-free fixation pins for CAT scan with ceramic tips (S.C local anesthesia is applied at fixation site)

• Artifact-free fixation pins for CAT scan with ceramic tips (S.C local anesthesia is applied at fixation site)

• CT Localization• CT Localization

Treatment Planning StepsTreatment Planning Steps

• Automatic Image Fusion (if required)• Automatic Image Fusion (if required)• Outlining of lesion and critical organs• Outlining of lesion and critical organs• Treatment planning• Treatment planning

• Dose Verification - Isodose Lines and Dose-Wash - DVH - 3D Dose representations

• Dose Verification - Isodose Lines and Dose-Wash - DVH - 3D Dose representations

• First radiological assessment among 40 First radiological assessment among 40 patients with residual or recurrent brain patients with residual or recurrent brain tumorstumors

• (Most of the patient in both groups (Most of the patient in both groups experienced PR followed by SD and CR) experienced PR followed by SD and CR)

• (NEMROCK, April 1999-April 2001)(NEMROCK, April 1999-April 2001) • (P-value: 0.603)(P-value: 0.603)

01020304050607080

Group A Group B%

• First clinical and neurological assessment among 40 patients First clinical and neurological assessment among 40 patients with residual or recurrent brain tumorswith residual or recurrent brain tumors

• (Most of the patient in both groups experienced improvement (Most of the patient in both groups experienced improvement followed by persistence) followed by persistence)

• (NEMROCK, April 1999-April 2001)(NEMROCK, April 1999-April 2001)• (P-value: 0.41)(P-value: 0.41)

75

20

5

60

30

10

0

20

40

60

80

100

Group A Group B

PFS dating end of Chemotherapy & date of SRS showed insignificant survival benefit in the Chemotherapy arm (P- value: 0.1)

Overall survival dating initial diagnosis showed insignificant survival benefit in favor of the SRS arm. (P- value: 0.19)

0

5

10

15

20

25

%

Headache Convulsive Fits Nausea & Vomiting Worsening of

Pretreatment

Manifestations

Manifestations

Immediate Post-SRS & SRT Side Effects

• Establishment of SRS & SRT.• > 300 Cases “Cranial & Extra-

Cranial” Targets are Treated.• Ongoing Research.• Committee Decision• Upgrading.

Current Situation:

Why to Irradiate More if we can Irradiate Less?