Académique Documents
Professionnel Documents
Culture Documents
Cancer
Significance
• 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
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?
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
Edema!!
Recurrent Glioblastoma
What is Operable?
Operable
• Anterior R temporal lobe w mass effect
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
– 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
• 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
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%
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
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)
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
week 1 2 3 4 5 6
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
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)
1 3
4
2
Combined Chemoradiotherapy for Non-
Brainstem High-Grade Glioma (ACNS0423)
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)
< 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
40%
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)
CTEP ))
SPECIMEN
Survival vs. P8633/9233 SUBMISSION
Endpoints:
• Age
• Performance status
• Neurologic functional status
Treatment
• Surgery
• Radiation
• Chemotherapy
Treatment - Surgery
• 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
• 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
• 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
• Pl-3 kinase system small molecules targeting Pl-3 kinase and Akt
• mTOR inhibitors rapamycin
• p53 gene therapy
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.