Jose Belderbos radiotherapeut Emmy Lamers ... De... · De Hippocampus Oncologie in perspectief 5...
Transcript of Jose Belderbos radiotherapeut Emmy Lamers ... De... · De Hippocampus Oncologie in perspectief 5...
De Hippocampus
Oncologie in perspectief5 Juni 2014
Jose Belderbos radiotherapeutEmmy Lamers radiotherapeutisch laborant
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
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 AvoidanceSCLC (LD and ED)
PCI
full PCI HA-PCI • Monitoring cognitive sequelae : Neuro-cognitive tests6 times: Baseline and 4/8/12/18/24
• Repeat MRI
•Does HA-PCI increase QoL?• 168 pts will be included •10 fractions up to 25 Gy
R
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 hippocampusGondi V Radiother Oncol 2010;95:327-331.Ghia A Int J Radiat Oncol Biol Phys 2007;68:971-977.
Gondi N=1133Ghia N=272
• Occurrences of metasappears homogeneous
• PCI effect proportionalto coverage
0
20
40
60
80
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<5mm 5 to <10mm 10 to <15mm ≥ 15mm Total
Distance from Hippocampus
Relative
volum
e/occurren
ce m
etastases
%Volume
Gondi
Ghia
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 (α/β = 2 Gy)
V95 [%] Max ph. Dose [Gy] Mean BED [Gy]
Helical Tomo 97.6 12.8 4.9IMRT 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
38.0 Gy30.0 Gy29.0 Gy27.0 Gy12.0 Gy
38.0 Gy30.0 Gy29.0 Gy27.0 Gy12.0 Gy
38.0 Gy30.0 Gy29.0 Gy27.0 Gy12.0 Gy
38.0 Gy33.0 Gy30.0 Gy29.0 Gy27.0 Gy12.0 Gy
38.0 Gy33.0 Gy30.0 Gy29.0 Gy27.0 Gy12.0 Gy
38.0 Gy33.0 Gy30.0 Gy29.0 Gy27.0 Gy12.0 Gy
IMRT
VMAT@NKI
(Core) neuropsychological battery
PRO:EORTC QLQ C30, QLQ BN20, QLQ‐LC13; EQD5; MOS ScaleMotor 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 Trial 2 Trial 3LEEUWSMARAGDPAARDTENTSAFFIERHOTELGROTOPAALTIJGERPARELKOEHUT
HVLT‐R Recognition
J N J N J N J N
PAARD huis HUT TENTrobijn OPAAL SMARAGD bergGROT TIJGER SAFFIER katballon boot hond HOTELkoffie sjaal appartement KOELEEUW PAREL cent diamant
Lexical fluency
‘’B” “D” “H”01 ______________ ________________ ______________ 02 ______________ ________________ ______________ 03 ______________ ________________ ______________ 04 ______________ ________________ ______________ 05 ______________ ________________ ______________ 06 ______________ ________________ ______________ 07 ______________ ________________ ______________ 08 ______________ ________________ ______________ 09 ______________ ________________ ______________ 10 ______________ ________________ ______________ 11 ______________ ________________ ______________ 12 ______________ ________________ ______________ 13 ______________ ________________ ______________ 14 ______________ ________________ ______________ 15 ______________ ________________ ______________ 16 ______________ ________________ ______________ 17 ______________ ________________ ______________ 18 ______________ ________________ ______________ 19 ______________ ________________ ______________ 20 ______________ ________________ ______________
WAIS III DIGIT SPAN forward & backward
1‐76‐35‐8‐26‐4‐3‐9……………7‐1‐3‐9‐4‐2‐5‐6‐8
2‐45‐76‐2‐94‐9‐6‐8……………7‐2‐8‐1‐9‐6‐5‐3
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 mice11 Behavior
18 Sham7 Immunocytochemistry
36 animals11 Behavior
18 Radiation7 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
aknowledgementNKI‐AvL AmsterdamSanne SchagenMichiel de RuiterWillem BoogerdEugene DamenJudi van DiessenHarm van TinterenAnke van MourikCasper CarbaatKatrien de JaegerFrederike KoppePietje Muller‐TimmermansMargriet Kwint
KUL LeuvenDirk de RuysscherSabine DeprezStefan SunaertFrank van den HeuvelJohan VansteenkisteYolande LievensKatrien VandecasteeleRik AchtenPaul MeijdersChirs GoorPaul ParizelMatthew Holt