De Hippocampus
Jose Belderbos radiotherapeut
Emmy Lamers radiotherapeutisch laborant Oncologie in perspectief
5 Juni 2014
Limited disease SC (LD SC):
Aupérin et al. NEJM 1999; 341:476‐484
PCI: Extensive disease SCLC
(Slotman et al. NEJM 2007;357:664‐72)
Prophylactic Cranial Irradiation
Pro’s ‐ significant (2 fold) reduction of BM
 improvement QoL (?)
‐ marginal survival benefit ‐ LD 3 yrs survival 15.3 to 20.7% ‐ ED 5.4 to 6.7 months
Con’s ‐ no 100% prevention of BM
‐ neuro cognitive toxicity
Greene‐Schloesser et al. Frontiers in Oncology, 2012
The key‐role of the hippocampus
First results HA‐WBRT RTOG 0933 in pts with brain mets
• HA was associated with memory and quality of life preservation ‐ Pts with brain mets received HA‐WBRT of 30 Gy in 10 fractions
‐ The dose received by the hippocampus did not exceed 10 Gy
‐ The risk of developing a new metastasis in the hippocampus was 4.5%.
‐ 42 pts at 4 months post‐RT had a 7% decline in HVLT vs 30% decline in an historical control group (WBRT without HA)
Gondi, presented at ASTRO 2013 and WLCC
PCI Hippocampus Avoidance
SCLC (LD and ED)
PCI
R
•Does HA-PCI increase QoL?
• 168 pts will be included •10 fractions up to 25 Gy
full PCI
HA-PCI
• Monitoring cognitive
sequelae : Neuro-cognitive tests
6 times: Baseline and 4/8/12/18/24
• Repeat MRI
Study endpoints: Primary endpoint:
• The total recall score of the Hopkins Verbal Learning Test–Revised assessed at 4 months after PCI. A decline in the total recall score of 5 points or greater will be considered a failure.
Secondary endpoints:
• Neurocognitive functioning and QOL, motor function
• Assessment of structural and functional brain abnormalities • Incidence and location of brain metastases
• Overall survival
• Progression free survival
• Biomarkers (neuro‐inflammation)
The distribution of brain metastases
around the hippocampus
• 3% metas within 5mm of the hippocampus
Gondi V Radiother Oncol 2010;95:327-331.
Ghia A Int J Radiat Oncol Biol Phys 2007;68:971-977.
• Occurrences of metas
appears homogeneous
• PCI effect proportional
to coverage
Relative volume/occurrence metastases
Gondi N=1133
Ghia N=272
100
80
%Volume
Gondi
60
Ghia
40
20
0
<5mm
5 to <10mm
10 to <15mm
≥ 15mm
Distance from Hippocampus
Total
HA-PCI technique
•
•
•
•
Irradiation of the brain (25 Gy), while sparing the hippocampus (as
low as possible)
Challenging! This requires a very steep dose gradient
Definition of PTV??
– There is no GTV/CTV
Then what about margins?
– PTV = Brain – (Hippocampi + 5mm)
Techniques for HA-PCI
PTV
Hippocampus
V95 [%]
Max ph. Dose [Gy]
(α/β = 2 Gy)
Mean BED [Gy]
Helical Tomo
97.6
12.8
4.9
IMRT
96.9
15.3
7.3
Gondi V, et al., Hippocampal-Sparing Whole Brain Radiotherapy: A “How-To” Technique, Utilizing Helical Tomotherapy and LINAC-based Intensity
Modulated Radiotherapy, International Journal of Radiation Oncology, Biology,Physics, doi:10.1016/j.ijrobp.2010.01.039
VMAT isodosen
IMRT
38.0 Gy
33.0
30.0 Gy
30.0
29.0 Gy
29.0
27.0 Gy
27.0
12.0 Gy
12.0 Gy
VMAT
@NKI
38.0 Gy
30.0 Gy
33.0
29.0 Gy
30.0
27.0 Gy
29.0
12.0 Gy
27.0
12.0 Gy
38.0 Gy
30.0 Gy
33.0
29.0 Gy
30.0
27.0 Gy
29.0
12.0 Gy
27.0
12.0 Gy
(Core) neuropsychological battery
PRO:EORTC QLQ C30, QLQ BN20, QLQ‐LC13; EQD5; MOS Scale
Motor function: neurological examination
Characteristics of a neuropsychological test battery
•
•
•
•
•
•
Repeatable (parallel forms, minimal practice effect)
Good psychometric properties (in terms of reliability, validity, norms)
Sensitive to changes in function
Highly standardized, simple administration
Able to be completed by most patients
Measurement of relevant cognitive functions
HVLT‐R Free Recall
Trial 1
LEEUW
SMARAGD
PAARD
TENT
SAFFIER
HOTEL
GROT
OPAAL
TIJGER
PAREL
KOE
HUT
Trial 2
Trial 3
HVLT‐R Delayed recall
LEEUW
SMARAGD
PAARD
TENT
SAFFIER
HOTEL
GROT
OPAAL
TIJGER
PAREL
KOE
HUT
HVLT‐R Recognition
J N
J N
J N
J N
PAARD
robijn
GROT
ballon
koffie
LEEUW
huis
OPAAL
TIJGER
boot
sjaal
PAREL
HUT
SMARAGD
SAFFIER
hond
appartement
cent
TENT
berg
kat
HOTEL
KOE
diamant
TRAILMAKING A and B
Trials A
Trails B
20
Lexical fluency
‘’B”
01 ______________ 02 ______________ 03 ______________ 04 ______________ 05 ______________ 06 ______________ 07 ______________ 08 ______________ 09 ______________ 10 ______________ 11 ______________ 12 ______________ 13 ______________ 14 ______________ 15 ______________ 16 ______________ 17 ______________ 18 ______________ 19 ______________ 20 ______________ “D”
________________ ________________ ________________ ________________ ________________
________________
________________ ________________ ________________ ________________ ________________ ________________ ________________ ________________ ________________ ________________ ________________ ________________ ________________ ________________ “H”
______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ ______________ WAIS III DIGIT SPAN forward & backward
1‐7
6‐3
5‐8‐2
6‐4‐3‐9
……………
7‐1‐3‐9‐4‐2‐5‐6‐8 2‐4
5‐7
6‐2‐9
4‐9‐6‐8
……………
7‐2‐8‐1‐9‐6‐5‐3 WAIS III symbol substitution
Lafayette’s pegboard
Radiological assessment in HA‐PCI trial
MRI brain: at baseline and at 4/12 months after PCI  HA
•
•
•
•
•
3D T1 – volumetry
SD FLAIR – white matter hyperintensities
DTI – microscopic white matter injury
Resting state fMRI – neural activity/functional networks
Susceptibility weighted imaging – cerebral mircobleeds
Hippocampal volume
• preservation of hippocampal
volume measured by
segmentation of the
hippocampus on hi-res 3D
MPRAGE scans
Figure: sagittal slice of MPRAGE
scan with segmentation of
hippocampus in red
Structural connectivity
• preservation of nerve tracts
connecting the hippocampus
with other brain regions as
measured with DTI
tractography
Figure: axial slice of MRI scan with tractography
of uncinate fasciculus (from: Kurki et al.,
Journal of Magnetic Resonance Imaging, 2013
Functional connectivity
• (partial) preservation of functional connectivity of
hippocampus with other brain regions as measured with
resting state fMRI
prefrontal and parietal regions
showing functional connectivity with
the hippocampus during rest as
measured with fMRI (from: Wible et
al., Frontiers in Human
Neuroscience, 2012
Recently started WBRT mice
11 Behavior
18 Sham
7 Immunocytochemistry
36 animals
11 Behavior
18 Radiation
7 Immunohistochemistry
Day
-14
0-4
14
22-29
31
32
35-39
42-44
Activity
Arrival
Irradiation
Transport VU
Automated
home cage
Open
field
NLR/
NOR
Barnes maze
Fear
conditioning
Adult (11 weeks of age) male C57BL/6j mice (Charles River, France)
Xrad 225Cx HA-PCI in mice
Developed by Princess Margaret Hospital (PMH, Toronto) in
collaboration with Precision X-ray Inc (PXI, USA)
conclusions
• Neurocognitive problems after PCI or
WBRT
• Hippocampus plays a key-role
• HA-PCI is feasible with small underdosage
• HA-PCI phase III trial is acruiing
aknowledgement
NKI‐AvL Amsterdam
Sanne Schagen
Michiel de Ruiter
Willem Boogerd
Eugene Damen
Judi van Diessen
Harm van Tinteren
Anke van Mourik
Casper Carbaat
Katrien de Jaeger
Frederike Koppe
Pietje Muller‐Timmermans
Margriet Kwint
KUL Leuven
Dirk de Ruysscher
Sabine Deprez
Stefan Sunaert
Frank van den Heuvel
Johan Vansteenkiste
Yolande Lievens
Katrien Vandecasteele
Rik Achten
Paul Meijders
Chirs Goor
Paul Parizel
Matthew Holt