Jose Belderbos radiotherapeut Emmy Lamers ... De... · De Hippocampus Oncologie in perspectief 5 Juni 2014 Jose Belderbos radiotherapeut Emmy Lamers radiotherapeutisch laborant

De Hippocampus

Oncologie in perspectief5 Juni 2014

Jose Belderbos radiotherapeutEmmy Lamers radiotherapeutisch laborant  

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 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

100

<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 Delayed recall

LEEUWSMARAGDPAARDTENTSAFFIERHOTELGROTOPAALTIJGERPARELKOEHUT

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

20

TRAILMAKING A and B

Trials A Trails B

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 

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 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