Updates on Treatment of Childhood Brain Tumors

Atualizações no tratamento de
tumores neurológicos em crianças
francisco helder cavalcante felix
Foco em Gliomas
domingo, 29 de setembro de 13

• Astrocitoma (OMS II)
◦ Protoplásmico, gemistocítico, fibrilar, misto
• Astrocitoma pilocítico (OMS I)
◦ Hemisférico, diencefálico, óptico, tronco, cerebelo
• Astrocitoma pilomixóide (OMS II)
• Astrocitoma subependimário (OMS I)
• Xantoastrocitoma pleomórfico (OMS I)
• Oligodendroglioma (OMS II)
• Oligoastrocitoma (OMS II)
Gliomas de Baixo Grau

• Cirurgia
• Observação (e talvez reoperar)
• Quimioterapia
• Radioterapia deve ser adiada o
máximo possível
Paradigma de tratamento - crianças

• Tumores cerebrais mais frequentes em crianças – 30 a
45% (19,3% no HIAS – 2000 a 2010)
• História natural: sobrevida longa (>15 anos)
◦ SG 87% em 5 anos no HIAS
◦ Ressecção completa (Sanai, 2008)
◦ SLP 36 a 48% sem ressecção total (Fischer, 2008) - HIAS 27 -
58%
• Efeitos tardios e recorrências a longo prazo comuns –
pouco conhecido (Bhat, JCO, 2005)
• Ensaios: sobrevida livre de progressão
Tratamento de GBG

Qaddoumi, Cancer, 2009 – 6212 pctes

Fisher, 2008 – 278 pctes – SLP 55% /48%

Autor Número pctes Ressecção Total Recidiva/progressão
Abdollazadeh , 1994 66 61 5
Pollack, 1995 71 21 13
Campbell, 1996 72 57 13
Pencalet, 1999 168 149 16
Qual o papel da cirurgia?
• Fatores prognósticos:
◦ Ressecção completa
◦ Localização: cerebelar > cérebro > vias ópticas >
tálamo
◦ Recidiva ou progressão em 10-20% dos casos

Qual o papel da cirurgia?
Stokland, 2010 – 639 pctes

• Indicada para crianças com mais de 8-10 anos (sem
evidência estabelecida)
◦ SIOP-LGG-2004 e COG-ACNS0221
• Contra-indicada em pacientes com NF-1 (risco de
vasculopatia)
◦ Guillamo, 2003
• Efeitos tardios: Chadderton, 1995; Kortmann, 2003
• Eficácia contestada: Mishra, 2006
• Merchant, 2009: elevada SLP (87 e 74%)
Qual o papel da radioterapia?

Event-free survival (EFS; gold line) and overall survival (OS; blue line) for pediatric patients
with low-grade glioma.
Merchant T E et al. JCO 2009;27:3598-3604
©2009 by American Society of Clinical Oncology

CI of hormone replacement therapy and therapy for precocious puberty after conformal
radiation therapy (CRT) for pediatric low-grade glioma.

Modeled intelligence quotient (IQ) scores after conformal radiation therapy (CRT) by age and
supratentorial brain dose-volume intervals for pediatric low-grade glioma.

• Inicialmente para estabilizar visão em pacientes com tumores
de VOH (Mitchell, 2001)
• Desfecho primário: doença estável prolongada (Packer, 1997)
• Efeitos a curto prazo da QT negligenciáveis
◦ Efeitos tardios?
• GBG irressecável ou recidivado sintomático
Qual o papel da quimioterapia?
ESQUEMA N RC (%) RP(%) RM(%) DE(%) SLP(%)
CCGS 78 5 28 23 37 68
SIOP-LGG1 204 4 46 - 34 48
TPDCV 42 363636 59 <50
VCR-ACT/D 29 - 7 59 31 30
BB-SFOP 85 - 56 - 31 48

• TPCV: tioguanina, procarbazina, lomustina, vincristina (Prados,
1997)
• Carboplatina + vincristina (Packer, 1997)
• COG A9952: comparou os dois tratamentos (Ater, 2008)
◦ SLP de 48% com TPCV e 35% com Carboplatina e vincristina
◦ Mediana de tempo para progressão 4,9 anos com TPCV e 3,2
com o outro
◦ Alergia à carboplatina em até 42% dos pacientes
• Recorrência após tratamento:
◦ Vimblastina semanal (Bouffet, 2008): 42% resposta, SLP 65% 3a
◦ Cisplatina + etoposido (Massimino, 2002): SLP 78% em 3 anos
Ensaios Clínicos

• Glioma óptico-hipotalâmico (Mishra, 2010): SG 71, SLP 23% 15 a
• Alergia à carboplatina: vimblastina (Lafay-Cousin, Cancer, 2003)
• Recorrência múltipla:
◦ Temozolomida (Khaw, 2007): SLP 57% em 3 anos
◦ Bevacizumab (Packer, 2009): resposta em 7 de 10 (seguimento 22
meses)
• Maior novidade recente: primeira terapia alvo para um glioma de baixo
grau
◦ Astrocitoma subependimário de células gigantes (SEGA)
◦ Associado com Esclerose Tuberosa
◦ Everolimo: inibidor da via mTOR (Krueger, NEJM, 2010)
Ensaios Clínicos

mTOR Pathway
RTK
Rictor
4EBP
GβL
TSC2
Raptor
AMPK
DGKξ
PI3K
Redd1
eIF4B
eIF3
PIP2
PIP3
PKC
p70S6K
mTOR
AMP
eIF4G
eIF4A
eIF4E
Rheb
eIF3
eIF4B
eIF4G
eIF4A
eIF4E
eIF4B
GβL
mTOR
eIF4E 4EBP
VEGF
eIF4G
eIF4A
eIF4E
Growth
Insulin
Energy
StressSerum Nutrient
Hypoxia
Actin
Organization
P
PDK-1
mTORC1
mTORC2
Translation off
40SRPS6
40S
Scanning
Akt/PKB
Translation On
Secondary
Structure
Unwinding
TSC1
PP2A
FKBP12
Rho
HIF1α
VEGF
Pathway
Akt Signaling
PKC
Rac
PMA
PLD
PKCα
PC
LKB1
Akt
PA
DAG
AUG
Ras
RSK
AUG
MAPK
IRS1
Insulin
2009C

• Astrocitoma Anaplásico (OMS III)
◦ Hemisférico, diencefálico, óptico, tronco, cerebelo
• Glioblastoma multiforme (OMS IV)
◦ Variantes: glioblastoma de células gigantes, gliossarcoma
• Oligodendroglioma anaplásico (OMS III)
• Oligoastrocitoma anaplásico (OMS III)
• Incidência menor em crianças: 7-11%
◦ 6% no HIAS – 2000 a 2010
◦ Geralmente supratentoriais
Gliomas de Alto Grau

• Sobrevida livre de doença baixa
◦ CCG-945 – GBM – 15%, AA – 22% (3 anos)
◦ ACNS0126 – GBM – 7%, AA – 13% (3 anos)
• Ressecção completa:
◦ Finlay, JCO, 1995
◦ Cohen, 2011
• Radioterapia: Sposto, 1989 (CCG-943)
◦ SLP 46% vs. 18% (3 anos)
• Quimioterapia:
◦ 8-in-1 vs. pCV: CCG-945
◦ Temozolomida vs. pCV: ACNS0126
◦ HIT-GBM-C: Wolff, 2010 – SG 63% e SLP 48% 5 anos
Tratamento

Finlay, 1995
AA
GBM

Pollack, 2003

.
Pollack I F et al. JCO 2006;24:3431-3437

EFS and OS rates of HGG patients enrolled in ACNS0126.
Cohen K J et al. Neuro Oncol 2011;13:317-323
© The Author(s) 2011. Published by Oxford University Press on behalf of the Society for Neuro-
Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

EFS comparison of ACNS0126 and CCG-945.
Cohen K J et al. Neuro Oncol 2011;13:317-323
© The Author(s) 2011. Published by Oxford University Press on behalf of the Society for Neuro-
Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Intensive chemotherapy improves survival in pediatric high‐grade glioma after gross total
resection: results of the HIT‐GBM‐C protocol
Cancer, Volume 116, Issue 3, pages 705-712, 2 DEC 2009 DOI: 10.1002/cncr.
24730 http://onlinelibrary.wiley.com/doi/10.1002/cncr.24730/full#fig2

• Parsons, Science, 2008: IDH1
• Yan, NEJM, 2009: prognóstico
• Houillier, Neurology, 2010: gliomas de baixo
grau – deleção 1p19
• Christensen, 2011: hipermetilação e MGMT
• Laffaire, 2011: grupos de metilação e deleção
1p19
Diagnóstico Molecular

Point mutations*
Point mutations*
Amplifications†Amplifications† Homozygous deletions†Homozygous deletions†
Gene No. of tumors Fraction of
tumors (%)
No. of tumors Fraction of
tumors (%)
No. of tumors Fraction of
tumors (%)
Fraction of
tumors with
any alteration
(%)
Passenger
probability‡
CDKN2A 0/22 0 0/22 0 11/22 50 50 <0.01
TP53 37/105 35 0/22 0 1/22 5 40 <0.01
EGFR 15/105 14 5/22 23 0/22 0 37 <0.01
PTEN 27/105 26 0/22 0 1/22 5 30 <0.01
NF1 16/105 15 0/22 0 0/22 0 15 0.04
CDK4 0/22 0 3/22 14 0/22 0 14 <0.01
RB1 8/105 8 0/22 0 1/22 5 12 0.02
IDH1 12/105 11 0/22 0 0/22 0 11 <0.01
PIK3CA 10/105 10 0/22 0 0/22 0 10 0.10
PIK3R1 8/105 8 0/22 0 0/22 0 8 0.10
Most frequently altered GBM CAN-genes
* Fraction of tumors with point mutations indicates the fraction of mutated GBMs out of the 105 samples in the Discovery and Prevalence Screens.
CDKN2A and CDK4 were not analyzed for point mutations in the Prevalence Screen because no sequence alterations were detected in these genes in
the Discovery Screen.
† Fraction of tumors with amplifications and deletions indicates the number of tumors with these types of alterations in the 22 Discovery Screen samples.
‡ Passenger probability indicates the probability obtained using the average of the lower and upper bound background mutation rates (12).
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Originally published in Science Express on 4 September 2008, doi: 10.1126/science.1164382 Science 26 September 2008: vol. 321 no. 5897 1807-1812
Table 2.

Fig. 1. Structure of the active site of IDH1.
D W Parsons et al. Science 2008;321:1807-1812
Published by AAAS

Ohgaki, 2009

Fig. 2. Overall survival according to IDH1 mutation status.
D W Parsons et al. Science 2008;321:1807-1812
Published by AAAS

Copyright
©
2009
Massachusetts
Medical
Society.
All
rights
reserved.

Published
by
Massachusetts
Medical
Society.
3
Figure
1
IDH1
and
IDH2
Mutations
in
Gliomas.
Yan,
Hai;
Parsons,
D;
Jin,
Genglin;
McLendon,
Roger;

Rasheed,
B;
Yuan,
Weishi;
Kos,
Ivan;
Batinic-‐Haberle,
Ines;

Jones,
Sian;
Riggins,
Gregory;
Friedman,
Henry;
Friedman,

Allan;
Reardon,
David;
Herndon,
James;
Kinzler,
Kenneth;

Velculescu,
Victor;
Vogelstein,
Bert;
Bigner,
Darell
New
England
Journal
of
Medicine.
360(8):765-‐773,
February

19,
2009.
Figure
1
.
IDH1
and
IDH2
Mutations
in
Human
Gliomas.Panel
A
shows

mutations
at
codon
R132
in
IDH1
and
R172
in
IDH2
that
were
identified
in

human
gliomas,
along
with
the
number
of
patients
who
carried
each

mutation.
Codons
130
to
134
of
IDH1
and
170
to
174
of
IDH2
are
shown.

Panel
B
shows
the
number
and
frequency
of
IDH1
and
IDH2
mutations
in

gliomas
and
other
types
of
tumors.
The
roman
numerals
in
parentheses
are

the
tumor
grades,
according
to
histopathological
and
clinical
criteria

established
by
the
World
Health
Organization.
CNS
denotes
central
nervous

system.

Copyright
©
2009
Massachusetts
Medical
Society.
All
rights
reserved.

Published
by
Massachusetts
Medical
Society.
6
Figure
3
IDH1
and
IDH2
Mutations
in
Gliomas.
Yan,
Hai;
Parsons,
D;
Jin,
Genglin;
McLendon,
Roger;

Rasheed,
B;
Yuan,
Weishi;
Kos,
Ivan;
Batinic-‐Haberle,
Ines;

Jones,
Sian;
Riggins,
Gregory;
Friedman,
Henry;
Friedman,

Allan;
Reardon,
David;
Herndon,
James;
Kinzler,
Kenneth;

Velculescu,
Victor;
Vogelstein,
Bert;
Bigner,
Darell
New
England
Journal
of
Medicine.
360(8):765-‐773,

February
19,
2009.
Figure
3
.
Survival
of
Adult
Patients
with
Malignant

Gliomas
with
or
without
IDH
Gene
Mutations.For
patients

with
glioblastomas,
the
median
survival
was
31
months

for
the
14
patients
with
mutated
IDH1
or
IDH2,
as

compared
with
15
months
for
the
115
patients
with
wild-‐
type
IDH1
or
IDH2
(Panel
A).
For
patients
with
anaplastic

astrocytomas,
the
median
survival
was
65
months
for
the

38
patients
with
mutated
IDH1
or
IDH2,
as
compared

with
20
months
for
the
14
patients
with
wild-‐type
IDH1

or
IDH2
(Panel
B).
Patients
with
both
primary
and

secondary
tumors
were
included
in
the
analysis.
For

patients
with
secondary
glioblastomas,
survival
was

calculated
from
the
date
of
the
secondary
diagnosis.

Survival
distributions
were
compared
with
the
use
of
the

log-‐rank
test.

Association between IDH mutation and methylation phenotype in gliomas.
Christensen B C et al. JNCI J Natl Cancer Inst 2011;103:143-153
© The Author 2010. Published by Oxford University Press.

©2010AAN
Enterprises,
Inc.

Published
by
Lippincott
Williams
&
Wilkins,
Inc. 2
Figure
1
IDH1
or
IDH2
mutations
predict
longer

survival
and
response
to
temozolomide

in
low-‐grade
gliomas.
Houillier,
C;
Wang,
X;
Kaloshi,
G;

Mokhtari,
K;
Guillevin,
R;
MD,
PhD;

Laffaire,
J;
Paris,
S;
Boisselier,
B;
Idbaih,

A;
MD,
PhD;
Laigle-‐Donadey,
F;
Hoang-‐
Xuan,
K;
MD,
PhD;
Sanson,
M;
MD,
PhD;

Delattre,
J-‐Y
Neurology.
75(17):1560-‐1566,
October

26,
2010.
DOI:
10.1212/WNL.0b013e3181f96282
Figure
1

Overall
survival
(OS)
according
to
the

1p19q
and
IDH
status

• Gliomas de baixo grau:
◦ Ressecção macroscópica completa: curativa
◦ RT em crianças maiores de 12 anos
◦ QT em crianças com recorrência antes de 12 anos e em casos
selecionados
◦ Melhor esquema indefinido: TPCV vs. carbo+vincr
• Gliomas de alto grau:
◦ Prognóstico ruim, pior do que se pensava antes
◦ Ressecção completa e RT pós-op sempre que possível; QT com
papel indefinido
• Nova estratificação molecular: prognóstico
Conclusões

A apresentação intitulada “Atualizações no
tratamento de tumores neurológicos em crianças”,
de Francisco Helder C. Felix, contém material
protegido por direitos autorais, obtido sob licença
através de subscrição de periódicos científicos,
apenas para uso educacional. A cópia ou utilização
deste material, mesmo que para outra apresentação
educativa, não é permitida e infringe os direitos
dos autores dos trabalhos, das editoras e do autor
da presente aula. O material aqui mostrado está
disponível para utilização mediante contato com
cada editora.
Esta aula estará disponível apenas para visualização
no site http://pharmak.blogspot.com

Updates on Treatment of Childhood Brain Tumors

Recomendados

Recomendados

Mais conteúdo relacionado

Mais procurados

Mais procurados (20)

Semelhante a Updates on Treatment of Childhood Brain Tumors

Semelhante a Updates on Treatment of Childhood Brain Tumors (20)

Mais de Francisco H C Felix

Mais de Francisco H C Felix (16)

Updates on Treatment of Childhood Brain Tumors