Brain

Cancer
 Significance

• The brain is the center of

thoughts, emotions,
memory and speech.
• Brain also control muscle
movements and
interpretation of sensory
information (sight, sound,
touch, taste, pain etc)
 Significance

• Tumors can effect any part of the brain and

depending on what part(s) of the brain it
affects can have a number of symptoms.
– Seizures
– Difficulty with language
– Mood changes
– Change of personality
– Changes in vision, hearing, and sensation.
– Difficulty with muscle movement
– Difficulty with coordination control
 Background

• Estimated 18,400 primary

malignant brain tumors will be
diagnosed in 2004 —10,540 in
men & 7,860 in women.
• Approximately 12,690 people will
die from these tumors in 2004.
• Accounts for 1.4% of all cancers
• Accounts for 2.4% of all cancer
related deaths
 Background

• In adults over 45
years of age 90%
of all brain tumors
are Gliomas
– Gliomas: A general
category of cancer that
includes astrocytomas,
oligodendrogliomas, and
ependymomas
 Astrocytoma

• Astrocytes brain cells abnormally dividing causing

tumors called astrocytomas.
• Astrocytes are glial cells that help nourish neurons–
they help repair damage
• How the astroytomas are classified
– How close the cells are together within the tumor
– How abnormal the cells are
– How many of the cells are proliferating
– Whether or not there are blood vessels growing near the tumor
– Whether or not some of the cancer cells have degenerated or
not
 Astrocytomas--Treatments
• If tumors have not infiltrated normal
brain tissue then surgery can be a cure
• Low-grade Astrocytomas are not curable
by surgery. However through surgery as
much of the tumor as possible is removed
and then the patient usually goes through
radiation treatment.
 Astrocytomas--Treatment
• High-grade Astrocytomas are not curable
by surgery. After surgery has removed
as much of the tumor as possible the
patient can go through radiation
treatment and chemotherapy.
• Most common drug given to these
patients after chemotherapy is BCNU
 Oligodendrogliomas

• These tumors start in mutated

oligodendrocyte brain cells
• Oligodendrocytes make myelin which
help neurons transmit signals
through the axons
• These tumors may spread through
cerebrospinal fluid pathways but
typically do not usually spread to
locations outside of the brain or
spinal cord.
 Oligodendrogliomas--
Treatments
• Because these tumors infiltrate normal
brain tissue these tumors are not cured
through surgery. However removal of
part of the tumors can relieve some
symptoms and prolong life.
• If the tumor is causing disabilities to the
patient after surgery the patient may go
through chemotherapy, perhaps followed
by radiation treatments.
 Ependymomas

• Mutated ependymal cells

• Ependymal cells line the
ventricles in the central area of
the brain and they line part of
the pathway through which the
cerebrospinal fluid travels
• Theses mutated cells may
block the cerebrospinal fluid
from exiting the ventricles
causing the ventricles to
enlarge (hydrocephalus)
Ependymomas--Treatments
• These tumors do not usually infiltrate
normal brain tissue and are therefore
curable through surgery.
• If surgery is unable to completely remove
the tumors the patient may try radiation
therapy.
 Diagnosis
• These tumors can be detected through a
MRI, CT scan or a PET scan.
• Once detected, depending on where the
tumor is located, a biopsy officially is
used to diagnosis cancer.
 Risk Factors
• Most brain cancers happen for reasons
unknown, however some small risk
factors are
– Radiation exposure
– Exposure to vinyl chloride
– Immune system disorders
 Prognosis
• For people ages 15-44 five year survival
rate is 55%
• For people ages 45-64 five year survival
rate is 16%
• For people over 65 five year survival rate
is 5%
What Causes Brain Tumors??

– What is a Brain Tumor??

Basic Principles of
Tumor Growth
What is the Cause of a Brain
Tumor?
“Where facts are few,
speculation flourishes”
• Most common cause of a brain tumor,
is metastatic lung cancer, so stop
smoking
• Metastatic melanoma to the brain is
the third most common metastases,
and is linked to environment (sun
exposure), and is, in part, preventable
• The cause of gliomas is unknown
– 4% are clearly hereditary, 96% are
“sporadic”
What is the Cause of a Brain
Tumor?
“Where facts are few,
speculation flourishes”
1.Genetic – Altered genome – cancer genome-
Microarray Glioma Microarray NIH Study (Dr. H.
Fine) – REMBRANDT Data Base
– Personalized medicine
– Pharmacogenomics
– Total Cancer Care

1.Dietary
– 30% of cancers, in general, linked to diet
– Obesity promotes tumor growth
– Little is known about brain tumors
– Carcinogens or additives in diet???
What is the Cause of a Brain Tumor?

3.VIRUS
– HPV linked to cervical cancer and Vaccine effective
– Epstein-Barr Virus linked to PCNS Lymphoma
– Viral particles found in human b.t. specimens, but also found in
“normal” brain and many tumors without viral particles
3. HORMONES
– Meningiomas – 3: 1 in females
– Incidence higher with Hormone Replacement Therapy
– Tumors increase with pregnancy
– Estrogen receptors targets for RU 486
– But other tumors, male slightly higher preponderance
– Overall, brain tumors are equal opportunity employers.
What is the Cause of a Brain
Tumor?
5.Pesticides - Petrochemicals
– Cluster of cases near factories, chemical waste dumps, and
in petroleum factory workers
– Carcinogenic in animals
5.Ionizing Radiation
Israeli immigrant children treated with scalp RT for
fungus developed gliomas, meningiomas
Gliomas have developed years later at radiation-sites for
other tumors
Laboratory models support ionizing radiation which
causes misrepair of DNA, and damage to DNA
?? CT Scans – 2% of cancer incidence??????
What is the Cause of a Brain
Tumor?
7.Cell Phones
– Electromagnetic fields can induce mutations
and DNA damage in cell cultures
– Reports of higher incidence of brain tumors and
leukemia in children living near high energy
towers and lines
– Epidemiological data to support this hypothesis
is not conclusive and the preponderance of
data currently is that cell phones do not
contribute to brain cancer burden
What is a Brain Tumor?- 3
Definitions
• Large collection of abnormal cells residing in or near the brain
that has potential for proliferation, invasion, angiogenesis,
cerebral edema, and by mass effect can cause neurological
morbidity or even, at times, death, with growth determined
by a series of mutations in the genes controlling cancer
(oncogenes), modulated by local microenvironment, growth,
molecular signature, and therapeutic options, such as
surgery, chemotherapy, radiation therapy
• A mass of abnormal cells located in the head – on the
surface, in the brain, or a tumor migrating to the brain.
• Nothing – if asymptomatic, benign, small, stable, cystic-
Harvey Cushing story
 What is a Brain Tumor?

• The World Health Organization (WHO) recognizes

120+ different types of brain tumors
• 3 Basic types (N. Vick):
– Tumors of the Brain – Gliomas –
– Tumors to the Brain – Metastases
– Tumors on the Brain – Meningiomas,
Pituitary Tumors, Acoustic Neuromas, etc.
 What is the Cause of a Brain
Tumor?
• At a molecular - biological level, either
– Overdrive - Overamplification of Genes, RNA,
Proteins that promote cell growth (EGFR,
VEGF, cyclins, pAKT, ras, src, myc) or
– Loss of “brakes” (natural inhibitors) such as
p53, p21, p16, thrombospondin,
– Probably not one single event, but a series of
abnormal gene mutations
 What is the Cause of a Brain
Tumor?
• At a cellular level, either
– Cells of origin (Glial, Meningeal, Cancer)
receive signal to proliferate
– Coordinated cellular “orchestra” with
numerous cell types interacting – stem
cells, blood vessel cells, immune cells, as
well as astrocytes and nerve cells
 What is the Cause (of
Confusion) Regarding a
Brain Tumor?
• Prognosis depends on many factors – Hard to
predict the individual course – as biology of tumors
is not “linear”
– Kaplan-Meier “survival” curves are for large
group of patients with a similar histological
diagnosis
– Survival and Quality of Life are related to
Many Factors
 Barriers to Successful
Therapy
• Complete Surgical Removal (or surgical cure) limited
by infiltration of tumor along blood vessels and white
matter fiber tracts, crossing the midline with many
gliomas, even 99% tumor removal leaves 10 X 107
• Infiltration of gliomas leads to very high local
recurrence rate, yet local therapies are limited because
of the isolated tumor cells at a distance from the center
• Blood-brain barrier limits penetration of large
molecules to the tumor cell
• Stem Cells may hide in “vascular niche” and are
relatively radioresistant and chemoresistant
 Barriers to Successful
Therapy
• Sensitivity of surrounding vessels and
neurons to chemotherapy and radiation
therapy – “chemo-brain”
• Heterogeneity of the tumors at the
immunological, histological, genomic level –
‘moving target’
• Ability of the tumor to spread into different
compartments, e.g. from the brain to the
cerebrospinal fluid and spread via the CSF,
“seeding”
 Barriers to Successful
Therapy
• Biochemical “redundancy” of molecular
pathways so that combinations may be
required as with treatment of HIV,
tuberculosis, hypertension – “triple
therapy”
• Hypoxia leads to chemoresistance and
radioresistance
• Poor animal models – Can cure in mice,
but not in humans
 Factors that
Determine Outcome
• Growth rate of the Tumor – Ki-67
• Size
• Benign vs. Anaplastic vs. Malignant
• Location, Location, Location
• Operability – Solid vs. Diffuse, Focal vs. Multifocal, Deep
vs. Surface
• Access to Sophisticated Care – Team Approach
• Experience/ Expertise of the Center
• Compliance of the Patient, and Adherence of the Team to
Best Practices – Guidelines
• Clinical Trials
Parasaggital Meningioma
Case Presentation
 Parasaggital Meningioma
Case Presentation

• 74 y.o. male, father of cardiologist

• 4 year hx of R foot drop, worse after spinal
surgery
• New weakness of R arm
• Seizures
• MRI shows a L parasagittal mass
Parasaggital Meningioma
Case Presentation
Parasaggital Meningioma
Case Presentation
 Recurrent Glioblastoma

Case Presentation
• 8 months PTA, craniotomy per ____
• Completed 2 of 4 cycles of CI-980
• Completed EBRT
• Progressed through procarbazine
(Sugen 101 protocol)

Surgery
Radiation Therapy
Chemotherapy
 Recurrent Glioblastoma

Daumas-Dupport / Kelly Type II Growth Pattern

(Solid +Infiltrative)
 Recurrent Glioblastoma

The invasive radiations of a tumor prevent

surgical cure
Recurrent Glioblastoma

Tumors are wrapped around blood vessels

Recurrent Glioblastoma

Oh, Those Vessels!!

Recurrent Glioblastoma

Edema!!
 Recurrent Glioblastoma

What is Operable?
Operable
• Anterior R temporal lobe w mass effect

• “Bulky” central part of tumor-

not prominent in this case
 Recurrent
Glioblastoma
What is Inoperable?
Inoperable

• Infiltrative Tumor into Insula,

Sylvian Vessels, Pia-Arachnoid
• Vascular Network
• “Edema” with Microscopic
Disease
RADIOTHERAPY AND
CHEMOTHERAPY
 OBJECTIVES
• Explain what combined modality therapy is
• List the exploitable mechanism in combined
therapy
• Define and explain therapeutic gain
• Explain the use of molecular targeting to
enhance radiation response
• Discuss problems in the efficiency of combined
modality trials
• List statistics involving combined modality
treatment for head and neck cancer, lung
cancer, gastrointestinal cancer and breast
cancer
• Illustrate how a Gammaknife system works
• Describe how the cyberknife system works
• Compare the gammaknife and cyberknife
systems
 CHEMOTHERAPY
Chemotherapy, refers to treatment of disease
by chemicals that kill cells, specifically those of
micro-organisms or cancer.
 RADIOTHERAPY
Radiotherapy is the use of exact, carefully
measured doses of radiation to treat disease
 COMBINED THERAPY

All classes of chemotherapeutic agents

have been used in combined modality
involving one or more drugs plus
radiotherapy
The main aim is an improvement in local
control and/or eradication of metastases
Illustration showing herceptin antibody,
which inhibits DNA repair
 THERAPEUTIC GAIN
In order to evaluate the benefit of combined modality
treatments, therapeutic gain is essential

A therapeutic gain is achieved if the combined modality

results in improved tumour response, with respect to
either agent alone

Any increase in toxicity from the combination should be

taken into account
EXPLOITABLE MECHANISMS IN
COMBINED RADIOTHERAPY AND
CHEMOTHERAPY
Interactive: one modalities modifying the
response of the other.
Non-interactive: each modality exerting its own
independent effect
Enhancement of response: When the radiation
dose-response curve is increase by the addition of
chemotherapy
Inhibition: When the radiation dose-response
curve is decrease by the addition of
chemotherapy
Protection: Where the combination give less
effect than radiation alone
SPATIAL CO-
OPERATION
The use of radiotherapy and chemotherapy
to target disease in different anatomical
sites.

The commonest situation is where

radiation is used to treat the primary
tumor and chemotherapy is added to deal
with systematic spread
 INDEPENDENT CELL KILL

If two modalities can both be given at full dose, then

the tumor response (total cell kill) should be greater
than that achieve with either agent alone

The radiotherapy and chemotherapy should have no-

overlapping toxicities

The chemotherapy should not enhance normal-

tissue damage within the radiation field
 DEBULKING
This concept involves the use of
several cycles of chemotherapy

Smaller tumour will be easy to cure

by radiotherapy

The disadvantage of debulking

schedules is that they involve a
delay in starting radiotherapy
ENHANCED TUMOR RESPONSE
There are several mechanisms, by which
radiotherapy and chemotherapy may interact
either:
Directly: to give an alteration in the shape of the
cell survival curve
Indirectly: by killing subpopulations resistant to
the other modality
Several commonly used chemotherapy agents
have been shown to inhibit the repair of radiation
damage. cisplatin, bleomycin, adriamycin, and
hydroxyurea. these drugs, like radiation, produce
DNA damage which is manifest as DNA breaks
SEQUENSING OF CHEMOTHERAPY AND
RADIOTHERAPY IN RELATION TO
NORMAL-TISSUE TOXICITY
Normal tissue damage after combined
modality treatment is strongly influenced by
the sequence and timing of the modalities

Many commonly used drugs cause substantial

increase in normal tissue radiation injury
when the modalities are given in close
sequence but not when they are separated in
time
Words to be Familiar with
• Angiogenesis--the growth of new blood vessels from pre-
existing blood vessels
• Adjuvant therapy - refers to additional treatment, usually
given after surgery where all detectable disease has been
removed
• Neoadjuvant therapy - given before the main treatment to
reduce the size of the tumor so as to facilitate more effective
surgery.
• ErbB-1 – (epidermal growth factor receptor) protein found on
the surface of some cells and to which epidermal growth
factor binds, causing the cells to divide.
• COX: Cyclo-oxygenase, protein that acts as an enzyme to
speed up the production of certain chemical messengers,
called prostaglandins, within the stomach.
• Chemotherapy drugs used to treat various types of cancers:
– 5-FU (Fluorouracil)
– Cisplatin
– MMC (Mitomycin C)
– Carboplatin
– Etoposide
Molecular Targeting for Enhanced
Radiation Response

• A new development in cancer therapy is the

increased understanding of cellular growth factors
and signaling pathways for control of cell
proliferation, differentiation, and angiogenesis

• The above mentioned pathways are activated in

tumors or in inflammatory tissues but not in
healthy or normal tissues – this offers potential
for drug targeting
Epidermal Growth Factor Receptor

• Over-expression of ErbB correlates with

an aggressive and radioresistant
phenotype
• EGRF blocking antibodies have been
developed that inhibit tumor proliferation
and angiogenesis, which promotes
apoptosis in cells over-expressing the
receptor
• Antibodies blocking this receptor leads to
growth arrest and radiosensitization in
over-expressing cells
 Molecular Targeting
• COX enzymes are needed for synthesis of
prostaglandins, which are implicated in the
initiation and growth of tumors:
– COX-1 enzyme is expressed in all tissues.
– COX-2 is inducible and expressed in inflammatory
and tumor tissue

• Inhibitors of COX-2 have been developed that are

effective in preventing the growth of colonic
polyps in patients

• COX-2 inhibitors also cause a marked increased

in radiosensitivity of murine tumors, without any
changes in radiosensitivity in healthy intestine
Perspecta Dome
Consists of a 20-inch
dome that easily
plugs into a PC to
display full color and
full motion MRI, x-
ray, CT and nuclear
medicine images in
true 3D space
Problems In Efficiency of Combined
Modality Trials

• There have been comparisons made between

the outcome of combined modality treatments
with retrospective trials where patients were
treated with radiotherapy or surgery alone

• However, it is difficult to evaluate the

therapeutic benefits between the comparisons

• There have been certain factors in the

comparison of treatments that can be identified
as bias
 Factors Identified as Bias:

• Patient selection – only those patients who are fit to

receive the relatively toxic combined modality
schedules will be entered in the trial.

• Stage migration – improved diagnostic and detection

methods such as CT or NMR scanning help to detect
smaller amounts of metastatic disease and have the
effect of shifting patients into higher stage categories

• The duration of follow-up – usually shorter in the new

studies

• Small numbers of patients – In order to detect an

improvement in survival of 15% with 90% confidence,
about 300-400
 Head and Neck Cancer

• Chemotherapy with radiotherapy gave a larger

increase in survival of 12.1% compared to the
3.7% survival benefit from just chemotherapy.

• An analysis of over 10,000 patients demonstrated

a significant 5-year overall survival benefit of 4%
in favor of combined modality

• The combination of concurrent chemotherapy and

radiotherapy was more effective than a 10%
increase in radiation dose
 Lung Cancer
• In one trial where hyperfractionated radiotheraphy
was given with concurrent carboplatin and etoposide
there was a 42% improvement in 4-year recurrence-
free survival versus 19% with just the
hyperfractionated radiotherapy

• Alternating chemotherapy-radiotherapy schedules

have produced some of the best results ever reported
for this disease, with a 3-year survival of 26% -- some
high incidents of severe toxicity have been reported in
more recent studies
 Gastrointestinal Cancer
• Results of locally advanced oesophageal cancer, which
demonstrated a large benefit for treatment with 5-FU,
cisplatin and radiotheraphy versus a higher dose of
radiotheraphy alone (27% versus 0% 5-year survival)

• Two trials for anal cancer demonstrated significant

improvement in local control and colostomy-free
survival for concurrent chemotherapy and radiotherapy
versus radiotherapy alone
Breast Cancer
• Post-mastectomy radiotherapy reduces the risk of local
recurrence from about 30% to 10%

• A study of over 1,700 patients demonstrated that

radiotherapy combined with postoperative chemotherapy
further reduces loco-regional recurrence, which indicates
an improved 10-year survival by 54%
Breast Cancer
• Adjuvant hormone therapy gives a significant
increase in long-term survival, with a 25% reduction
in the death hazard ratio

• The best results were women who received both

adjuvant chemotherapy and hormone therapy, with
a 35% reduction in the death hazard ratio
 Cancer of the Cervix

• Study in 1999 shows significant survival advantage

for concurrent chemo and radiotherapy with 30-50%
reduction in risk of death compared to radiotherapy
alone

• Concomitant chemo and radiotherapy is now

standard for bulky cervical cancer
 Bladder Cancer

• Survival rates for locally advanced bladder

cancer are poor

• Standard treatment is cystectomy with or

without radiotherapy

• Newer studies done in 1999

In Testing
• Photodynamic therapy (PDT) is a cancer treatment
that uses a drug and a certain type of laser light to kill
cancer cells.
 Future Perspectives

• There are currently over 6000 clinical studies

being done on the use of chemotherapy and
radiotherapy on different areas of the body
• Conjugation of cytotoxic drugs to tumor
seeking carriers
• Antibodies are being developed which can
block the signaling pathways involved in
tumor cell proliferation, differentiation, and
angiogenesis
• Cytostatic chemotherapy is also being
researched in conjunction with radiotherapy
Radiotherapy the “old way”
Gamma Knife
head only
 Gamma Knife
• Able to focus radiation directly,
and very precisely, on the target in
the brain without affecting
surrounding healthy tissue
• No incision or blood, and minimal
risk of complications
• Use of 3D computer-aided
planning guide the dose to the
target
 Gamma Knife
• Up to 201 sources of cobalt-60
loaded within the unit
• Thousands of radiation beams can
be generated from these sources
with a level of accuracy of more
than 0.3mm
• So accurate, the full dose of
radiation can be delivered during a
single session
Leksell Gamma Knife
 Procedure
• 4 stages of gamma knife surgery
– Attaching the frame

– Imaging

– Treatment planning

– Treatment
Cyber knife system
 Components of the Cyber Knife
System
• RoboCouch Patient Positioning System–Robotically aligns patients precisely with 6
degrees of freedom, reducing patient setup times and enabling faster treatments

• X-ray Sources–The low-energy X-ray sources generate orthogonal diagnostic X-

ray images to determine the location of bony landmarks, implanted fiducials or
soft tissue targets throughout the entire treatment.

• Image Detectors–The flush mounted detectors capture high-resolution anatomical

images throughout the treatment. These live images are continually compared to
previously captured DRR’s to determine real-time patient positioning and target
location

• Robotic Manipulator–The high precision robotic manipulator capable of delivering

repeatable sub-millimeter accuracy, positions the linear accelerator in almost any
direction

• Linear Accelerator–This compact, light weight 6MV X-band linear accelerator

precisely delivers highly collimated beams of radiation

• MultiPlan Treatment Planning System–intuitive workflow-based workstation

designed for radiosurgery, enables the creation of plans that have excellent
conformality and coverage with steep dose gradients.
Capabilities
• Synchrony® Respiratory Tracking System–Continuously
synchronizes beam delivery to the motion of the tumor, allowing
clinicians to significantly reduce margins while eliminating the need
for gating or breath-holding techniques.

• Xsight™ Spine Tracking System–Eliminates the need for surgical

implantation of fiducials by using the bony anatomy of the spine to
automatically locate and track tumors, making radiosurgery less
invasive along the spinal column.

• Xsight™ Lung Tracking System–Tracks the movement of lung

tumors directly, without fiducials, with precision, reliability and self-
adjusting repeatability.

• Xchange™ Robotic Collimator Changer–Automatically exchanges

collimators robotically, maintaining highly conformal treatments
delivered more efficiently.

• 4D Treatment Optimization and Planning System–Takes into account

not only the movement of the target but also the movement and
deformation of the surrounding tissue.
 Cyber knife advantages
• Treats tumors anywhere in the body
• Continuously tracks, detects and corrects for tumor and patient
movement throughout the treatment
• Delivers treatments with sub-millimeter accuracy, minimizing damage
to surrounding healthy tissue
• Utilizes the skeletal structure of the body as a reference, eliminating
the need for bone fiducials or invasive frames typically used with
traditional radiosurgery systems
• An option for inoperable or surgically complex tumors
• Successfully treats patients in single or multiple fractions
• Provides linac maneuverability and access and coverage for any tumor
volume
• Boasts a patient-centric design providing a relaxed treatment
experience
• Enables superior flexibility in treatment planning:
– forward or inverse treatment planning
– isocentric or non-isocentric treatment plans
– simultaneous treatment of multiple tumors
• Allows for the flexible scheduling of treatments
• Attracts a new patient population to a physician's practice
 Ultimate Showdown
Gamma Knife
• 201 source cobalt unit designed
exclusively for non-invasive brain
surgery
• Radiologic accuracy better than
0.3mm
• Rigid immobilization to prevent head
movement using a lightweight
stereotactic head frame fixed to the
outer skull.
• Provides exact MR and CT
correlation from planning to
treatment delivery in 3D.
Treatment delivered during one
•
session
• Target position is confirmed 10
times per second
CyberKnife
• Single source linear accelerator with
robotic arm to compensate for patient
movement during treatment
• 1 mm accuracy; dose outside the target
area is 2-6x greater than with GK
• Non-rigid immobilization reduces head
movement by using a face mask that is
shrink-wrapped to the table
• The CK is inherently less accurate since
the positioning is optically guided, not
head-frame based.
• Provides relative MR and CT correlation
from planning to treatment delivery in
3D.
• Single or multiple treatments, possibly
over a period of days
• Target position confirmed once every
10 seconds
 Proton therapy
• Due to their relatively enormous mass, protons scatter less easily in
the tissue and there is very little lateral dispersion
• All protons of a given energy have a certain range; no proton
penetrates beyond that distance
• The dosage to tissue is maximum just over the last few millimeters of
the particle’s range; this maximum is called the Bragg Peak.
• This depth depends on the energy to which the particles were
accelerated by the proton accelerator, which can be adjusted to the
maximum rating of the accelerator
• It is therefore possible to focus the cell damage due to the proton
beam at the very depth in the tissues where the tumor is situated:
– tissues situated before the Bragg peak receive some reduced dose
– tissues situated after the peak receive none
 Proton therapy
• Interesting for its ability to accurately
target and kill tumors, both near the
surface and deep seated within the body,
while minimizing damage to the
surrounding tissue
• Favored for treating certain kinds of
tumors where conventional X-ray
radiotherapy would damage surrounding
radio-sensitive tissues to an unacceptable
level(pediatric patients, choroidal
malignant melanomas)
• Proton therapy, however, needs heavy
equipment - weighing into the hundreds
of tons(cyclotron)
 Summary
• Combined modality therapy uses all classes of chemotherapeutic agents
combined involving one or more drugs plus radiotherapy
• The main aim is an improvement in local control and/or eradication of
metastases
• In order to evaluate the benefit of combined modality treatments, therapeutic
gain is essential
• A therapeutic gain is achieved if the combined modality results in improved
tumour response, with respect to either agent alone
• In order to evaluate the benefit of combined modality treatments, therapeutic
gain is essential
• A therapeutic gain is achieved if the combined modality results in improved
tumour response, with respect to either agent alone
• The first step in identifying exploitable mechanisms for combined modality
therapy is to define whether the modalities are:
• Interactive: one modalities modifying the response of the other.
• Non-interactive: each modality exerting its own independent effect
 Summary
• The increased understanding of cellular growth factors and signaling
pathways for control of cell proliferation, differentiation, and
angiogenesis offers potential for drug targeting
• It is difficult to evaluate the therapeutic benefits between the
comparisons, because there are certain factors in the comparison of
treatments that can be identified as bias
• The use of chemotherapy along with radiotherapy improves the survival
rate for those who suffer from head and neck caner, lung cancer,
gastrointestinal cancer, and breast cancer.
• The old style of therapy works, but it isn’t the best
• The Gamma Knife is only for radiotherapy to the head and has cobalt
sources
• The Cyber Knife is for anywhere on the body and uses a linear
accelerator
• The Gamma Knife is more accurate than the Cyber Knife
• Proton therapy is even less damaging than the Cyber Knife or the
Gamma Knife
 REFERENCES
• Bartelink, Harry. "The Combination of radiotherapy and chemotherapy."
Basic Clinical Radiobiology. Edited. G. Gordon Steel. London: Arnold,
2002.

• McKay, Judith, and Nancee Hirano. The Chemotherapy and Radiation Therapy
Survivor's Guide, 2nd ed. Oakland, CA: New Harbinger Publications, 1998.

• Radiation Combined With EGFR Signal Inhibitors: Head and Neck Cancer
Focus . Seminars in Radiation Oncology , Volume 16 , Issue 1
Pages 38 - 44 P . Harari , S . Huang

• "Understanding Cancer." National Cancer Institute. 2008. U.S. National

Institutes of Health. 17 Oct 2008 <http://www.cancer.gov/
cancertopics/understandingcancer>.
COG CNS Committee
2003-2007
 Scientific Goals
• Identify biological characteristics of
childhood CNS tumors that influence
treatment response, and initiate risk-
adapted stratification.
• Develop comprehensive treatment
approaches to improve survival and quality
of life for children with primary CNS
tumors.
• Identify effective therapies for CNS tumors
resistant to prior treatments.
• Define and validate strategies for reducing
treatment-related long-term sequelae.
CNS Committee Cross-Study
Therapeutic Hypotheses

Medullo I
PNET T
Optimize
Chemo to A
A99996611
Reduce ACNS0331 9
Cooperative Group Scientific
Accomplishments
• Observation that the use of adjuvant
chemotherapy permits CSRT dose reduction to
2340 cGy with >75% survival for M0
medulloblastoma.
• Demonstration that extent of resection is
associated with outcome for children with
medulloblastoma, ependymoma, low- and high-
grade glioma.
• Initiation of the largest biological study to date
of high-grade gliomas of childhood, and
preliminary delineation of prognostic factors.
Reduced Dose Radiotherapy Is Feasible in
Standard-Risk Medulloblastomas If
Combined with Adjuvant Chemotherapy

102
 Amount of Residual Disease Is
Associated with Outcome in
Children with High-Grade Glioma
100%
Event-Free Survival

80%

60%

40% >90%Resection (N=66)

20% <90%Resection (N=101)

p=0.002
0%
0 2 4 6 8 10 12
Years Post Onstudy

CCG-945
Wisoff et al., J Neurosurg 89: 52, 1998
103
 Scientific Accomplishments
• Determination that moderately intensive chemo
improves survival for poor-risk medullo/PNET.
• Identification of molecular factors correlated with
outcome of infant tumors.
• Documentation that building upon induction chemo
in infant tumors with high-dose consolidation or
focal irradiation improves outcome.
• However, despite improvements in the prognosis of
some tumor types, others remain resistant and late
effects remain a concern.
 Management of Average-Risk
Medulloblastomas
1)
1)Post
Postfossa
fossalocation
location
2)
2)M0
M0
3)
3)<<1.5
1.5cm
cm2Residual
2
Residual

A9961
A9961

2340
2340cGy
cGyCSRT
CSRT
5580
5580cGy
cGyLocal
LocalRT
RT

CCNU
CCNU CPM
CPM
CPDD
CPDD CPDD
CPDD
VCR VCR N > 400
VCR VCR
Has provided a platform for additional study development
Goals: 1) Further CSRT dose reduction by modifying chemo
2) Target volume reduction (boost site) using conformal RT
 A9961 Progression-Free Survival from Study Entry
RegA RegB

100%
Percent Progression-Free

86% +/- 2.5%

90%

80%
84% +/- 3%
70%

60%
p=0.49
50%
0 1 2 3 4 5 6 7
Time (Years)

106
Accuracy of Staging Strongly Influences
Effectiveness of Reduced Dose Therapy

107
Figures 5 and 6 were based on all patients on A9961 with anaplasia information (including those
ineligible by central review due to dissemination or excess residual).
108
RT Dose Reduction for Average-Risk
Medulloblastoma (<8 yrs)

1800 cGy CSRT 2340 cGy CSRT

with VCR with VCR

Conformal tumor Conformal post fossa

bed boost (5400 cGy) boost (5400 cGy)

ACNS0331
Activation 4/04 CCNU, CPDD, VCR
135 pts accrued alt. with CPM, VCR
 RT Dose Reduction for
Average-Risk
Medulloblastoma (>8
yrs)
Both strata include prospective
Trk C and2340 erbB2/4
cGy CSRT
w/ VCR
analysis,
expression profiling, and
histological review to identify ~
20% of tumors
Conformal tumor thatpost
Conformal are not
fossa
bed boost (5400 cGy) boost (5400 cGy)
biologically “average risk” –
SPECIMEN SUBMISSION
ACNS0331
Activation 4/04 CCNU, CPDD, VCR
STRONGLY ENCOURAGED.
alt. with CPM, VCR
 High-Risk PNET
Radiosensitization Study

Carbo Carbo Carbo (Carbo) (Carbo) (Carbo)

VCR VCR VCR VCR VCR VCR

Craniospinal (36 Gy) XRT Boost (18 Gy) XRT

week 1 2 3 4 5 6

CPM ACNS0332 CDDP

VCR Protocol approved by CPM
(CCG-99701) CTEP/PCIRB VCR
Phase I MTD established
Phase II completed 12/04
 99701 Overall Survival for Metastatic MB
1.00

n=58
0.75
Probability

3 yr OS: 81 + 5%

0.50

2 3 yr OS: 81 ± 5%
0.25

0.00
0 1 2 3 4 5 6 7

Years from study entry

 Overall Survival by Anaplasia
1.00
No Anaplasia (n=39)
3 yr OS is 89 ± 5%
3 yr OS: 89 ± 5%
0.75
Probability

Anaplasia (n=19)
0.50
3 yr OS is 64 ±12%
3 yr OS: 64 ± 12%

0.25
p=0.008
0.00
0 1 2 3 4 5 6 7
Years from study entry
Management of Low-Grade Glioma

Progressive
ProgressiveDisease
Disease
High-risk,
High-risk,Unresectable
Unresectable
<<10
10years
years

New Studies
A9952
A9952 • Carbo/VCR/TMZ pilot
– ACNS0223 (protocol
NF1 opened 7/04;
Non-NF1
Non-NF1 recently opened
groupwide - 32 pts)

• Conformal RT pilot
6-thioguanine
6-thioguanine
Carboplatin
Carboplatin Procarbazine
Procarbazine – ACNS0221
VCR
VCR CCNU
CCNU
VCR (recently open)
N=250 randomized, 350 VCR
total
 Intensive Chemotherapy Followed by
Irradiation Fails to Alter Prognosis in Newly
Diagnosed Brainstem Glioma
100%

90%

80%

70%
Event-Free Survival

60%
Uniformly poor results of all
50%

40%
recent studies provide for reliable
30% natural history control data.
Regimen A (N=32)
Regimen B (N=31)

20%

10%

0%
0 1 2 3 4
YEARS

A
A

CCG-9941
Jennings et al. JCO, 2002 115
Phase I/II Studies of
Radiosensitization and Chemo-
Radiotherapy for Brainstem
Gliomas
• Temozolomide (ACNS0126) – closed 8/05
– accrued at twice rate projected (60/yr)
– standardized BSG stats (SPRT), imaging, response
analysis in collaboration with PBTC
• Topotecan (ACNS 0224) – protocol
opened 10/10/05
• Gadolinium texaphyrin
– Phase I completed (CCG-09712)
– Phase II protocol approved by CTEP/PCIRB - in queue to open
(ACNS0222)
Combined Chemoradiotherapy for
Non-Brainstem High-Grade
Glioma (ACNS0126)
• Sequential study design
– Temozolomide qd w/RT, 5d schedule p-RT - done
– Temozolomide + anti-angiogenic/signaling
• inhibitor/other
Natural chemotherapeutic
history control agent
(CCG-945 centrally reviewed cohort)
• 100 pts each, 12-18 months accrual
– EFS endpoint
– Accrued at twice rate projected
– Preliminary results available
One year (GBM)

945 126 p-value Stupp

(53) (51) (287)
EFS 32% 33% .47 27%

OS 60% 64% .33 61%

 Differences in MGMT Expression are
Noted Among Childhood Malignant
Gliomas and Correlate with Promoter
Methylation

1 3

4
2
Combined Chemoradiotherapy for Non-
Brainstem High-Grade Glioma (ACNS0423)

• Builds upon ADVL0011

(CCNU/temozolomide) (1CR, 1 near CR, 2
PR, 3 MR among 27 pts during induction
• MTD 90 mg/m2 CCNU and 160 mg/m2 x 5
TMD q6wk
• ACNS0423, opened 3/21/05 – has accrued
58 pts
• A third study (ACNS0622) is under
development (TMZ/irinotecan)
Management of Germinomas (ACNS
0232) – Approved by CTEP/CIRB
Biopsy Confirmation
- Markers

Std RT (45Gy)
21Gy Whole ventricular
Chemotherapy
(Carbo/etoposide)
24 Gy boost to 1o site
(30Gy CSR/15Gy 1o for disseminated)

CR < CR
30 Gy to 1o site 40.5 Gy to 1o site
(21Gy CSR/9 Gy 1o for disseminated) (24 Gy CSR/16.5 Gy 1o for disseminated)

Endpoints: EFS, QOL, Neuropsych

Management Paradigm for NGGCTs
(ACNS0122)
Tissue Diagnosis Induction Chemo
(Open/Stereo Bx) Carbo/VP alt with
+ Markers Ifos/VP x 3

< CR CR
(40%) (60%)

Second Look
PBSC Harvest Surgery RT
High Dose 36 Gy CS Axis
Chemo 54 Gy Tumor Bed
Thiotepa/VP16 Activation 1/04
46 pts accrued
Ependymoma Management
Schema
ACNS0121 (Opened 8/25/03)
E p e n d y m o m a
C e n t r a l P a t h o l o g y R e v i e w

E x t e n t o f R e s e Ec t x i ot e n n : t G o T f R R e1 s E e x c t t e i o n n t : o S f TR R e s e c E t ix o t ne :n tN o T f R R / G e sT e R c t2 i o
D i f f e r e n t i a t e d H i As t n o y l o H g i ys t o l o g y A n y H i s t o l oA gn ya p l a s t i c H i s t o l o g
S u p r a t e n t o r i a l A n y L o c a t i o n A n y L o c a t i o An n y H i s t o l o g y I n f r

O b s e r v a t i o n C h e m o t h e r a p y
C o n f o r m a l R a d i a t i o n T h e
C a r b o p l a t i n / V i n c r i s t i n e
T o t a l D o s e : 5 9 . 4 G y
C y c l o p h o s p h a m i d e / E t o p o s i d e
C l i n i c a l T a r g e t V o l u m e : 1 .
D u r a t i o n : 7 w e e k s
Novel Features
R e s p o n s e E v a l u a t i o n
( P D / S D / P R / C R )
1) Observation arm
U n r e s e c t a b l e R e s e c t a b l e
2) Histo-based stratification
C o n f o r m a l R a d i a S t ei o c n o nT d h e S r u a r p g y e r y
T o t a l D o s e :S 5u 9 r g. 4 e Gr y y E n d p o i n t 1 : R e s e c t a b i l i t y 3) Chemo to increase rate of
C l i n i c a l T a r g e St Vu ro g l ue mr y e E : n 1 d . 0 p oc mi n t 2 : M o r b i d i t y
GTR via 2nd-look surgery
C o n f o r m a l R a d i a t i o n T h e r a p y
T o t a l D o s e : 5 9 . 4 G y 4) Group-wide conformal RT
C l i n i c a l T a r g e t V o l u m e : 1 . 0 c m
(270 pts accrued, twice
projected rate – 5/62/76/127)
CCG-99703: Phase I/II Study of Intensive
Consolidation Chemo with PBSC Support
Infant Brain Tumors
Completed: Results Pending

Surgery

Induction Chemotherapy
(9921 Regimen A)
PBSC harvesting

Consolidation
CBDCA/Thio/VCR x 3 courses
 Event-Free Survival 99703 v 9921
Event-Free Survival

1.00

0.75
CCG-99703 (n=92)
Probability

0.50

CCG-9921 (n=284)
0.25
Logrank p=0.025

0.00
0 1 2 3 4 5 6 7 8
Years from study entry

01/16/06
 BIOLOGICAL STRATIFICATION OF INFANT
TUMORS: AT/RTs are prognostically distinct
from PNETs and warrant distinct therapy
100%

80%
Survival

60% Non-Rhabdoid PNET (N=94)

40%

20% Rhabdoid (N=16)

p=0.02
0%
0 1 2 3 4 5 6

CCG-9921 Years Post Onstudy

127
Molecular Evaluation (FISH and
Mutation Analysis) Will Be Included
for Stratification on All Infant
Malignant Tumor Studies
Histologic INI1 mutation analysis:
FISH:
diagnosis: Single base pair change
Deletion 22
PNET

Biegel et al. Cancer Res 59: 74, 1999; Cancer Res 62: 328, 2002
Management of M0 Infant
Medulloblastomas (P9934)

Separate studies for M+

Resection
Staging
Induction
Chemotherapy
Second
Surgery
medullo (ACNS0334 (in queue
8-36 months 4 4-wk cycles

to open)) and AT/RT

Maintenance Focal conformal RT
(ACNS0333 (Protocol
Chemotherapy to
(Age & response-adjusted)

CTEP ))
SPECIMEN
Survival vs. P8633/9233 SUBMISSION
Endpoints:

Neuropsych and endocrine outcome

MANDATORY
Safety of 2nd-look surgery
Biologically based concepts for
high-risk/refractory malignant
brain tumors
• Examples:
– Disruption of growth factor-mediated signal
transduction
• R115777 (ACNS0226) - 97
• Tarceva (ADVL0214) - 46
• Cilengitide (ACNS0621) – in development
• Tarceva/Avastin (ADVL0526) – in development
– Induction of maturation (e.g., 13-cis-RA) –
medullo (ACNS0332) – in queue to open
Glioblastoma
Multiforme Treatment
Options
Patient History
• 47 y/o female presented with focal motor
seizures involving the face and slurred
speech
• MRI showed a 1.5 x 2.6 x 2.2cm tumor in
the left frontal lobe
• Subtotal excision of the mass with
pathology positive for glioblastoma
multiforme
 Primary Intracranial CNS
Tumors
• Gliomas (46%)
– Astrocytomas (40%)
– Oligodendrogliomas (5%)
– Mixed Oligoastrocytomas (1%)
• Meningiomas (27%)
• Pituitary (9.7%)
• Nerve sheath (7.3%)
• CNS lymphoma (3.5%)
• Craniopharyngiomas (1.0%)
• Other (5%)
 Gliomas
• Astrocytomas
– Pilocytic Astrocytomas (grade 1)
– Diffuse Astrocytomas (grade 2)
– Anaplastic Astrocytomas (grade 3)
– Glioblastoma Multiforme (grade 4 – 50%)
• Oligodendrogliomas
– Low Grade Oligodendroglioma (grade 2)
– Anaplastic Oligodendroglioma (grade 3)
• Mixed Oligoastrocytomas
– Low Grade Oligoastrocytoma (grade 2)
– Anaplastic Oligodendroglioma (grade 3)
 Clinical Presentation
• Symptoms caused by mass effect or destruction of normal
tissue
• Symptoms
– Headache
– Seizures
– Neurological Deficits
• Personality Changes
• Slowing of Motor Function/Hemiplegia
• Hallucinations
• Memory Impairment
• Vision Impairment
 Prognosis for GBM

• Mean survival 12-14 months from diagnosis

• Mean survival 4-5 months from recurrence
• 2 year survival 10%
• Recurrence occurs within 2-3 cm of the margins of the
original tumor in 80% of patients
 Prognostic Factors in GBM

• Age
• Performance status
• Neurologic functional status
 Treatment

• Surgery
• Radiation
• Chemotherapy
 Treatment - Surgery

• Surgery done for diagnosis and to relieve symptoms when

possible
• Median survival after surgery alone is 3-4 months
• Resections are suboptimal secondary to preservation of
normal brain tissue
• Re-excision at recurrence an option in patients with good
performance status
 Treatment - Radiation

• Radiation after surgery extends median survival to 9-11

months
• CNS tumors infiltrate into surrounding normal brain tissue up
to 3 cm or more
• Radiation delivered on a focal field including the tumor bed
with a 2-3 cm margin with total dose of 58-60 Gy
Treatment - Chemotherapy

• Nitrosoureas (BCNU/CCNU)
– Best known chemotherapy agents
– Metaanalysis showed increase in median
survival of 2 months over surgery and
radiation alone
– BCNU impregnated wafers show similar
results to systemic therapy

• PVC (Procarbazine, CCNU,

Vincristine)
• Temozolomide
– Oral alkylating agent
– Randomized Controlled Trial in patients (225) with relapse
GBM +/- prior chemotherapy
Procarbazine Temozolomide
6 month PFS 8% 21%
Median PFS 8.3 weeks 12.4 weeks

Temozolomide group had a 6 week median survival

advantage (not statistically significant)

(Yung, WK, et al., British J. Cancer 83, (2000), 588-593)

• Thalidomide
– GBM overexpress VEGF
– Thalidomide blocks VEGF induced angiogenesis
– Phase 2 uncontrolled trials in patients with recurrent
GBM or High Grade Gliomas

– Patients (42) treated with 100-500mg/day

• 5% partial response
• 42% had stable disease for >/= 4 weeks
• 1 year survival from start of Thalidomide was 35%
(Marx, GM. et al, J. of Neuro-Oncology, 54, (2001), 31-38)
• Thalidomide (cont.)
– Patients (39) treated with 800-
1200mg/day
• 6% partial response
• 6% minor response
• 33% had stable disease for >/= 8
weeks
• 1 year survival from start of
Thalidomide was 21%
(Fine, HA. et al, J. of Clinical Oncology, 18 (4),
(2000), 708-715)
• Tamoxifen
– GBM expresses high levels of PKC activity
– In vitro glioma cells are sensitive to inhibitors of
PKC
– Tamoxifen inhibits PKC in glioma cell lines in
micromolar concentrations
– Postulated Tamoxifen acts to inhibit PKC
activity
• Tamoxifen (cont.)
– Patients (35) treated with high dose tamoxifen(100mg
BID – males, 80mg BID – females)
• 25% partial response
• 19% with stable disease
• Median survival from the start of tamoxifen was 7.2 months
– 2 Patients with DVT
(Couldwell, WT., et al, Clinical Cancer Research, 2, (1996), 619-622)
• BCNU + O6-Benzylguanine
– Nitrosoureas cause damage by alkylating DNA,
particularly at O6 position of deoxyguanine
– O6-alkyl-guanine DNA transferase activity is
responsible for resistance to nitrosoureas
– O6-Benzylguanine inactivates the enzyme
– Trials ongoing looking at combination BCNU +
O6-Benzylguaine
• Phase 1 trial of BCNU + O6-Benzylguanine
– Identified the MTD of BCNU combined with
100mg/M2 of O6-Benzylguanine
• Reported 7 of 23 patients had stable disease for >/=
to 1 treatment cycle
– Phase 2 and 3 trials ongoing
(Friedman, HS., et al, J. of Clinical Oncology, 18, (2000), 3522-
3528)
• Gleevec ??
– Overexpression of PDGFR
seen in GBM

– Gleevec activity seen in animal

studies

– Not studied in humans

Conclusions
• Glioblastoma multiforme continues to
have a dismal prognosis
• Significant work has been done to identify
genetic pathways in glioma progression
• Genetic information being used to identify
targets for therapies and has potential to
identify chemotherapy responsive tumors
Glioblastoma
Multiforme
Case Presentation

• 49 y/o presents to ED with 2

episodes of loss of consciousness
over the preceeding month.
• Symptoms associated with
lightheadedness, nausea, generalized
weakness, and confusion upon
arousal. Episodes not witnessed.
• Dull frontal headache for a month.
• 30 pound weight loss over past 3
months.
Case cont.
• PMHx: Two prior “brain tumor
resections,” and patient
describes similar symptoms prior
to these resections.
• Social: lives with his mother,
past hx of etoh abuse and ivda
• Meds: none
• NKDA
• FHX: n/c
• ROS: no nightsweats,
fevers/chills, rest ros (-)
Case cont.

• PE: AF VSS
• Thin, NAD
• Oriented x 4, no papilledema, perrl
• CN grossly intact, strength 5/5,
sensation intact, reflexes symmetric,
finger to nose intact, unsteady gait
• Rest of exam unremarkable
• Labs: chemistries and blood counts
unremarkable
Case cont.-Head CT
• evidence of prior left frontal craniotomy
• suggestion of large mass in the frontal
region near the midline
• left temporal vasogenic edema
• mass effect on the intrahemispheric
fissure and the frontal horns of the lateral
ventricles.
Case cont.-MRI
• 5 x 4 x 4 cm homogeneously enhancing
left frontal mass with midline shift to the
right of 1 cm
• 2 x 2 x 2 cm enhancing lesion in left
temporal lobe
• 1.2 cm lesion in right cerebellar
medullary angle
Old records obtained

• 1994 left frontal lobe mass resection

with pathology “low grade
astrocytoma.”
• 1999 recurrent resection of left frontal
lobe mass with pathology “malignant
astrocytic cells with enlarged
pleomorphic hyperchromatic nuclei and
focal areas of necrosis c/w glioblastoma
multiforme.”
• Underwent adjuvant tx with EBRT
(6300Gy) and BCNU in 1999
Epidemiology of Primary
Brain Tumors
• ACS 2005: estimated 18,500 new cases
estimated 12,760 deaths
• CBTRUS : 14.1/100,000/yr
7.3/100,000/yr are
malignant
• Worldwide: 3.6/100,000 males/yr
2.5/100,000 females/yr
• Overall the incidence is higher in
developed countries
Histologic Subtypes of
Primary Brain Cancer
• Glioblastoma Multiforme 21.7%
• Malignant Astrocytomas 16.6%
• All oligodendroglioma 3.1%
• All ependymomas 2.3%
• Low grade astrocytomas 1.8%
• Meningiomas 26.7%
• Pituitary 9.7%
• Nerve Sheath tumors 7.3%
• CNS Lymphoma 3.5%
• Neuron and neuron/glial tumors 1.0%
• Craniopharyngiomas 1.0%
• Germ Cell Tumors 0.5%
• Choroid plexus 0.3%
• Other tumors 2.7%
Histologic Classification
of Glial Tumors
(World Health Organization 2000)
Astrocytic Tumors
Pilocytic (grade 1)
Diffuse/Fibrillary (Grade 2)
Anaplastic (grade 3)
Glioblastoma Multiforme (grade 4)
Oligodendroglial tumors and mixed variants
Oligodendroglioma, well differentiated (grade 2)
Anaplastic oligodendroglioma (grade 3)
Mixed oligodendroglioma/astrocytoma (grade 2)
Mixed anaplastic oligodendroglioma/astrocytoma
(grade 2)
Ependymal Tumors
Myxopapillary ependymoma (grade 1)
Ependymoma (grade 2)
Anaplastic (grade 3)
Histology
More Histology

• Necrosis surrounded
by pallisading cells
• Hypercellular
• Hyperchromatism
• Pleomorphism
Clinical Presentation
(Varies depending upon size and
location of tumor)
Most common symptoms:
Headache (80%)
Seizure (30%)
Focal neurologic deficits
Change in mental status
Time from initial symptoms to diagnosis
usually < 6 months (70% of patients)
Imaging
Prognosis
• Median Survival at time of diagnosis is
4-12 months depending upon degree of
tx
• 5 year survival rate <5%
• Good prognostic indicators:
Young age
Good performance status
Treatment
• Surgery
• Radiation
• Chemotherapy
Surgical Resection
• Incurable secondary to the infiltrative
nature
• Rationale behind resection:
-to obtain definitive histologic diagnosis
-to palliate symptoms from local tumor
effect
-to potentially provide better tumor
control
with radiation/chemotherapy
-to provide tissue for molecular/genetic
analysis for
prognostication and research
-to provide improved survival
Surgery cont.
• Controversy exists behind the correlation
between the extend of resection and
survival
• Goal is to remove as much tumor without
causing neurologic dysfunction
• Those that cannot be removed will need a
stereotactic/open needle bx
Radiation Therapy
• Most effective therapy postoperatively
• Improves local control and survival
• 80-90% of recurrence are within 2 cm of
original tumor, thus EBRT is directed at
the
T2 weighted tumor with an additional 1.5-
2.0 cm margin (total dose 60Gy)
Radiation Therapy cont.
• Alternative strategies:
-Hyperfractionated/Accelerated therapy
-Conformational radiotherapy
-Interstitial brachytherapy
-Stereotactic radiosurgery
-Heavy particle therapy
-Radiosensitizers
have been investigated alone and in conjuction
with EBRT
without any additional improvement in survival
Chemotherapy
• Two meta-analyses showed survival
benefit with adjuvant chemoradiation vs.
radiation alone.
• Traditional Choices:
Nitrosoureas
(BCNU/CCNU) vs.
PCV (procarbazine, CCNU,
vincristine)
**Neitherregimen has been proven
to be more effective.
Chemotherapy cont.
• Temozolomide
-oral alkylating agent
-FDA approval in 1999 for
recurrent/progressive anaplastic
astrocytoma that had failed
nitrosoureas/procarbazine
-Phase II study, 2002, by Stupp et. al
showed potential survival advantage by
adding TMZ concomitantly and
adjuvantly to RT.
Phase III of concomitant
and adjuvant TMZ with RT in
newly dx GBM
• 573
Stupp patients;
et al, 85 centers
JCO 2004 (22)14S: 2

• Histology proven to be grade 4 at a central

location
• Randomized to
1. Standard RT (60 Gy in 30 daily
fractions)
VS.
2. Standard RT (60 Gy in 30 daily
fractions)
+ concomitant (TMZ 75 mg/m2/d daily
x 42 days;
followed by 6 cycles of adjuvant TMZ
(150-200
mg/m2, daily x 5 days, q28d).
 Results
RT/TMZ
RT (n=286) (n=287) p-value

Median age 56.6 55.7 NS

Tumor resection 70% 68% NS

WHO PS: 39% / 49% / 39% / 48% / NS

0 / 1 /2 12% 13%

Baseline steroids 75% 67% p=0.041

PFS 5 months 7.2 months p<0.0001

Median survival 12 months 15 months p<0.0001

2 yr survival 8% 26% p<0.0001

Results cont.
• Toxicities
Grade 3/4 myelosuppression in:
7% during concomitant
TMZ/RT
16% of adjuvant TMZ
• Overall showed improved PFS/OS in GBM
•BCNU embedded in a biocompatible,
biodegradable wafer which is deposited within the
resected cavity
•FDA approved in 1996 as an adjunct to surgery
for recurrent GBM
•2003 approval extended to include the use as
adjunct to surgery and RT for newly dx GBM
Phase III study
comparing adjuvant
BCNUwafer vs placebo
• international,
Westphal multicenter,
et al. Neuro-oncol 2003 (2): 79 double-blind,
placebo-controlled trial of 240 patients
with primary high grade gliomas
• randomized to resection and RT +/- Gliadel
wafer vs. placebo
BCNU Placebo
Median survival 13.9 months
11.6 months (p=0.3)
Median Survival GBM subset 13.5 months
11.4 months (p=0.1)

• Adverse events: CSF leak (5% bcnu vs 0.8%

placebo)

Intracranial HTN (9.1%

bcnu vs 1.7% placebo)
Molecular Pathways
in Gliomas
(UpToDate 2005)
Targets and Potential Novel
Therapeutic Agents
• EGFR antibodies (including tagged to
toxins/radioactive isotopes)

tyrosine kinase inhibitors of EGFR (ie.

gefitinib, erlotinib)

• PDGF inhibitors of tyrosine kinase activity of PDGFR

(imatinib)

• Pl-3 kinase system small molecules targeting Pl-3 kinase and Akt
• mTOR inhibitors rapamycin
• p53 gene therapy

• Ras pathway antisense oligonucleotides, farnesyl

transferase inhibitors

• Angiogenesis antibodies to VEGF, VEGF receptors, tyrosine

kinase

inhibitors of VEGF
Recurrent
Astrocytoma-
Treatment
• Surgical Resection if possible
• Further EBRT usually not feasible, but
possible role for brachytherapy or
stereotactic radiosurgery
• Chemotherapy-
Gliadel wafer
Temezolemide
Nitrosoureas (but limited by previous use
secondary to resistance and cumulative toxicities
ie. myelosuppresion/pulmonary fibrosis)
• Clinical trial
Phase II study of 225 patients
with first relapse GBM
randomized to temozolomide or
procarbazine
TMZ 150-200mg/m2/day x 5 days repeated q28 days
•
Yung et al., BJC 2000 (5): 588
vs.
PCB 125-150mg/m2/day x 5 days repeated q28 days
• Primary objectives: PFS, Safety; Secondary objectives:
OS, HRQL

TMZ PCB
6 month PFS 21% 8%
(p=0.0008)
Median PFS 12.4 wks 8.32 wks
(p=0.0063)
6 month OS 60% 44%
(p=0.019)
***QOL favored TMZ over PCB
Systemic review of the
effectiveness of temozolomide
for the tx of recurrent malignant
glioma
Dinnes, BJC 2002 (86): 501
• Temozolomide may increase PFS, but has
no significant impact on overall length of
survival.
• Appears to have few serious side effects
• Positive impact upon quality of life
• Overall, evidence is not strong and more
controlled randomized studies are
needed.
Conclusions
• Most common primary brain malignancy
in adults with very poor prognosis
• Incurable, but current therapy can
prolong survival: surgery + RT +
chemotherapy
• Novel agents targeting molecule
mechanisms may provide improvements
in therapy or may eventual be used for
prognostic implications.