RT - Fortbildung USZ

Management von primären
ZNS Tumoren
Silvia Hofer
Onkologie
16.11.2011
i.R. nicht heilbar
 500 Neuerkrankungen
pro Jahr in der CH
(Erwachsene)
WHO Klassifikation: > 100 Arten
kaum Metastasen
ausserhalb des ZNS
Tumorarten & Häufigkeiten
2007
Maligne Gliome


WHO III und IV
anaplastische Gliome und Glioblastom
Stammzellen
Vorstellung der Entstehung …
Vorläuferzellen
Reife Zellen
Akkumulation von genetischen Alterationen
BRAF
IDH 1 Mut
Fusion-Gen
LOH1p19q
A
OA
O
1° Glioblastom
AA
AOA
WHO I
Pilozyt.
Pilozyt. Astro
WHO II
EGFR Amp
PA
AO
2° Glioblastom
WHO III
WHO Klassifikation
beruht auf den Augen des Neuropathologen
Diffuse astrocytoma
WHO grade II
Cellularity:
low/moderate
Pleomorphism:
low/moderate
Nuclear atypia:
moderate
Mitotic activity:
low
Vascular proliferation: absent
Necrosis:
absent
Molecular lesions
TP53 mutations
Anaplastic astrocytoma, OA
WHO grade III (6-10%)
high
moderate/marked
marked
high
absent
absent
Glioblastoma
WHO grade IV
high
marked
marked
high
present
present
EGFR ampl. + mut.
PTEN mutations
Therapie Optionen
2011
But chemo works !
TMZ/RTTMZ phase III trial
100
RT (95% CI)
90
80
70
TMZ/RT (95% CI)
Median OS, mo: 12.1 (11.2, 13.0)
2-yr survival:
10.9% (7.6-14.8)
5-yr survival:
1.9% (0.6-4.4)
14.6 (13.2, 16.8)
27.2% (22.2-32.5)
9.8% (6.4-14.0)
HR [95% C.I.]:
p <0.0001
60
0.63 [0.52-0.75]
50
40
30
20
10
0
(years)
0
O
278
254
N
286
287
1
2
Number of patients at risk :
144
31
175
76
3
4
5
6
7
11
39
6
23
3
14
0
6
Treatment
RT
TMZ/RT
Stupp et al. N Engl J Med 2005, 352:987-996
Stupp et al. Lancet Oncol 2009, 10:459-466
Gründe
before 2004
after 2004

CCNU, BCNU & PCV

Temozolomide (TMZ)

Chemo given sequentially

Concomitant chemoradiotherapy

Toxicity, e.g. PCV(PCV)

Favorable toxicity profile of TMZ



MRC: 50% tx delays
Dose reductions, delays, early
discontinuation
Drugs not reaching the target


More intensive and longer
treatment exposure

Good penetration of TMZ into CNS
blood-brain barrier, e.g. vincristine

Variable histologies

Homogenuous (GBM vs AA)

Recurrent disease:

Improvements


antiepilepitic
Corticosteroids

More salvage therapies
P Glycoprotein
Prognose Score für GBM
Wer profitiert von der CT ?
Prognostische Faktoren
Prädiktive Faktoren
unabhängig von Therapie
Tumorantwort auf Therapie
Bsp
Bsp
• Alter
• Performance Status
• Tumor Grade
• Hormonrezeptoren Mamma
• Kras Status Kolon
• Methylierungs Status des
MGMT Promotors beim
Glioblastom
Resistenz auf alkylierende
Chemotherapie  MGMT Status
O
C
NH2
NH
NH22
G
N
N
N
O
N
N
CH3
S
HS
CO
CO
CH3
Temozolomide
methylation
« gene silencing»
Promotor
CH22
CH
NH
CH
CH
COOH
DNA
MGMT
expression
MGMT gene
MGMT prädiktiv für Temodal
Ansprechen (GBM)
Methylated MGMT
Unmethylated MGMT
RT
TMZ/RT
RT
Median OS:
11.8 mo 12.7mo
2-yr survival: 1.9%
13.8%
100
100
Logrank : p = 0.062
90
TMZ/RT
Median OS:
15.3 mo 21.7mo
2-yr survival: 22.7%
46.0%
90
80
Overall Survival
80
70
70
60
60
50
50
TMZ RT
TMZ/
40
TMZ/
TMZ RT
40
30
30
RT
20
RT
20
10
10
0
0
0
4
8
12
16
20
24
28
months
Hegi et al. N Engl J Med 2005, 352:997-1003
32
36
40
0
5
10
15
20
25
months
30
35
40
gilt nur für GBM !


MGMT ist nur prädiktiv beim GBM
und nur prognostisch bei anaplastischen
(WHO grade III) Gliomen
R
Anaplastic Glioma
(grade III)
ChemoTx
progression
RT
Wick et al
J Clin Oncol 2009
ChemoTx
RT
Time to 1st treatment failure
2nd failure (progression)
NOA-04-Study
PFS (1st progression)

No difference in PFS
Gliome(time to 1st
progression) for
treatment with
chemo- or
radiotherapy

anaplastische WHO III
6
12
18
24
30
36
42
48
54mo
Improved outcome
for methylated
patients
R
NOA-04-Study
Wick et al
J Clin Oncol 2009
Anaplastic Glioma
(grade III)
ChemoTx
ChemoTx
RT
Time to 1st treatment failure
2nd failure (progression)
progression)
RT
PFS (1st progression)
besserer Verlauf
für
methylierte
Patienten
unabhängig von
Chemo oder RT
6
12
18
24
30
36
42
48
54mo
Standartherapie Grad III
Gliome

RT  Rezidiv  Chemo

Chemo  Rezidiv  RT
NOA 04 Trial
JCO 2009
Standard Therapie für GBM
TMZ tägl
¾ Jahre
Rezidivtherapie Gliome

rein supportiv

Re-Operation ?

Re-Bestrahlung ?

Zweitlinien Medikamente ?
Avastin
Tyrosinkinaseinhibitoren
mTOR Inhibitor
typisch für Glioblastome
Gefässneubildung
„ angiogenic switch“
VEGF vascular endothelial growth factor,
factor, proangiogenic cytokine
*Ricci Nature 2010
Wang Nature 2010
-- 
Brain edema ↓↓, interstitial pressure ↓
?
Tumor hypoxia

 endothelial cells
 blood brain barrier
restoration
adapted from Chamberlain M, Cancer 2010
Age
Elderly
Elderly + RT
Prognose bei älteren GBM Patienten im Prinzip schlechter
28 x 1.8 Gy, 50.4 Gy
weeks
Keime-Guibert for ANOCEF: NEJM 2007; 15:1527-35
Und: Equivalent outcome with hypofractionated RT in elderly (>60 yrs)
Probability of survival
Probability of survival
Aber: RT improves survival also in the
elderly (>70 yrs)
30 x 2.0 Gy, 60 Gy (6 wks)
vs
15 x 2.66 Gy, 40 Gy (3 wks)
weeks
Roa et al. J Clin Oncol 2004; 22:1583-8
EORTC 26981/NCIC CE.3
Elderly 60-70 y
Stupp et al. Lancet Oncol 2009
Figures unpublished
60-65 y
65-70 y
HR=0.64 (0.43-0.94)
HR=0.78 (0.50-1.24)
, p=0.02
, p=0.29
TMZ/RT
TMZ/RT
RT
RT
RT (95%CI)
TMZ/RT
Median
11.4
(9.0-13.3)
12.2
(8.6-17.4)
2-yr survival
8.3%
(1.0-15.5)
24.2%
(12.7-35.7)
RT (95%CI)
TMZ/RT
Median
12.0
(9.5-13.3)
10.9
(8.7-18.4)
2-yr survival
4.9%
(0.0-11.2)
17.6%
(5.0-30.2)
Elderly GBM
TMZ oder RT ?
Wick et al: ASCO 2010, abstract # 2001
Malmstrom et al: ASCO 2010, abstract # 2002
NOA-08 (n=373 pts, 65+; med. age 72 yrs )
Nordic (n=342 pts, 60+; med. age 70 yrs)
 TMZ dose-dense 7/7
R
 TMZ 5/28d
 RT 60 Gy (30 fx)
 RT hypofx 34 Gy (10 fx)
R
 RT 54-60 Gy (30 fx)
RT 9.8 mo
/ TMZ 8.6 mo
Hazard ratio 1.28 (0.94-1.63)
Median survival:
RT60 6.0 / RT34 7.5 / TMZ 8.3 mo
Conclusions:
 TMZ alone may be inferior to RT
 TMZ may be an alternative to RT
Elderly> 70, Karnofsky < 60  TMZ
Performance status, MMSE and QoL
KPS improved over time during the treatment period (p<0.001):
• 23 patients (33%) improved their KPS  10 points
• 18 patients (26%) achieved a KPS  70
30 40 50 60
70
80
90
KPS
MMSE improved over time before progression (p<0.001)
QOL evaluation over time before progression :
•  global quality of life scale (p=0.01)
•  physicial (p=0.003), role (p=0.02), cognitive (p=0.006) and social (p<0.001)
functioning scales
TAG Trial, JCO 2011 n=70
Elderly GBM
ARTE
multicenter trial USZ (n=60)
Radiotherapy
R
Radiotherapy plus Bevacizumab
Klinisch relevante
Molekulare Marker
in der Neuro-Oncologie

LOH 1p/19q

 translocation chrs. 1;19
Cairncross & Louis. JNCI 1998 90:1473-9.
Jenkins, Cancer Res 2006; 66:9852-61

MGMT promoter methylation
Esteller & Herman. NEJM 2000; 343:1350-4.
Hegi & Stupp. NEJM 2005; 2005;352:997-1003.

IDH1+IDH2 mutations
Yan& Bigner. NEJM 2009;360:765-73.
Zhao & Xiong . Science 2009.
Oligodendrogliome
Genetik & Chemo
Radiotherapy (33x1.8 Gy)
R
Neo-adj. PCV x4
Adj. PCV (6 cy.)
N=185
R
Radiotherapy (33x1.8 Gy)
N=148
N=143
N=183
Genetic marker and treatment
LOH 1p19q
PCV +
PCV -
PCV +
PCV -
van den Bent et al., J Clin Oncol 2006; 24:2715-22
Cairncross et al., J Clin Oncol 2006; 24:2707-14
Proportion of patients surviving
Zeit bis zum Therapieversagen
abhaengig von der Histologie bei WHO III
AA
AOA
AO
Oligodendroglialer Anteil
Time, months
NOA-04-Study
IDH1 & IDH2 Mutationen
Genome sequencing
within the NCCTA project
identified IDH mutations
in some CNS tumors
939 tumor and matched
blood samples analyzed
from the Duke biobank
•445 CNS tumors
•494 non-CNS tumors
Yan, Parsons … & Bigner. NEJM 2009, 360:765-73
IDH Mutation 
bessere Prognose
Anaplastic Astrocytoma
Genome sequencing
within the NCCTA project
identified IDH mutations
in some CNS tumors
939 tumor and matched
blood samples analyzed
from the Duke biobank
•445 CNS tumors
•494 non-CNS tumors
Glioblastoma
Yan, Parsons … & Bigner. NEJM 2009, 360:765-73
EGFR
EGFR wt
selbstaktivierendes
Onkogen
EGFRvIII
deletion exon 2-7
30-40% der GBM,
Auch NSCLC
nicht in
normalem Gewebe
Zelloberfläche
intrazellulär
Rindopepimut (CDX-110)
Peptide Vakzine gegen EGFRvIII GBM
T Zellen attackieren Tumorzellen
Marker &
Entscheidungen



Diagnostisches Tool
Prognostisch/Prädiktiv
Therapie Target
diagnostisch
prognostisch
prädiktiv
Therapie target
ja
ja
nein
nein
nein
ja
ja GBM
ja
IDH
ja
ja
?
?
EGFRvIII
ja
vielleicht
ja, Impfung
Impfung
LOH 1p 19q
MGMT
Gene
signatures
vielleicht
Validierung !
Imaging
Ausdehung der Läsion 
Metabolismus der Läsion 
Geografie
Inhalt
Postoperative Veränderungen
DD: Resttumor
2 Wochen postop
Aminosäuren PET
Pseudoprogression
a) prä OP
b) post OP
c) nach RT/TMZ d) 3 Zyklen TMZ
e) nach 6 Zyklen TMZ
Pseudoresponse
6 Wo BEV
Radionekrose
Tumorgrösse
Tumorinhalt
Monitorisierung Therapieansprechen
Roelcke et al 2007
Antiepileptics
2011