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Medikal Fizik

Çalışmaları

Zeynep Özen Acıbadem Altunizade

Hastanesi

BEST of ASTRO 9-10 Aralık 2017 - İSTANBUL

Treatment Planning and Delivery (in SRS/SBRT)

• Improving Quality and Consistency in Clinical Trials via Knowledge-

Based Planning, NRG Oncology RTOG 0631 (spine SRS)

Imaging for Response Assessment / Outcome analysis and modeling

• Diffusion Imaging Biomarkers of Regional White Matter Injury

Correlate with Change in Executive Function and Processing Speed

after Brain Radiotherapy

Major Themes


Improving quality and consistency in clinical trials via knowledge-based planning NRG Oncology

RTOG 0631 K. C. Younge1, R. Marsh2, D. Owen3, H. Geng4, Y. Xiao5, D. E. Spratt2, J.

Foy2, Q. R. J. Wu6, F. F. Yin7, S. Ryu8, and M. M. Matuszak1

1Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI, 3University of Michigan, Department of Radiation Oncology, Ann Arbor, MI, 4University of Pennsylvania, Philadelphia, PA, 5Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 6Duke Medical Center, Durham, NC, 7Duke University Medical Center, Durham, NC, 8Stony Brook University, Stony Brook, NY


Study Design / Purpose/Objective(s)

Challenging consistency and standardization of radiotherapy planning quality in multi-institutional clinical trials.

• Variations in plan quality / compliance affect outcome

• Experience at an institution correlates with plan quality

Aim: • To utilize knowledge-based planning (KBP) to produce high quality,

consistent, protocol compliant treatment plans (e.g. RTOG 0631; localized spine metastasis; phase II; effect of higher radiation dose on pain control and QOL; 16 Gy SRS).


• Training and validation dataset • KBP model applied to an validation cohort of 22

anonymized cases 16 Gy VMAT / single target • Original and KBP plans compared: protocol scores,

target conformity, gradient index, OAR dose, dose to surrounding normal tissues.

Study Design / Methods

0631 Protocol: • Target: 90% coverage.

80-90% coverage = acceptable (minor variation); < 80% coverage = unacceptable (major deviation)

• OAR: exceeding dose volume limits > 2.5-5 % = minor variation; exceeding them by > 5 % = major deviation. Any deviation of spinal cord dose constraint = unacceptable


Example RTOG 0631 Volumes


• All OARs were grouped into a single score. • Primary OAR: spinal cord, cauda equina (sometimes also esophagus and other

structures). • NonPTV: Ring around the target (limits for this structure are some of the most

frequently violated).


5

plans

17

plans

Results

1 = meets protocol 2 = acceptable variation 3 = unacceptable deviation

• Sub: plan submitted to 0631.

• Model prioritizes PTV coverage (all target scores are 1).

• KBP model generated plans meet all protocol objectives in a single optimization when tested on both internal and external RTOG 0631 cases.


Results

• Example where KBP

made a significant difference.

• Original submitted plan had a lot of high dose spillage around the PTV.

• Submitted plan scored a 3 for nonPTV dose, and the KBP plans scored a 2.

Target volume: vertebral body, both left and right pedicles, gross paraspinal or epidural lesions.


• The volume of PTV receiving prescription dose increased from 93.3 ± 3.2% to 99.5 ± 0.7% (P<0.001) when using KBP.

• High-dose spillage to surrounding normal tissues (V105%) showed no significant differences (2.1 ± 7.3 cc for manual plans to 1.2 ± 0.4 cc with KBP) but dosimetric outliers with large amounts of spillage were eliminated through the use of KBP.

Results


Authors’ Conclusions • Different tradeoffs are made between PTV coverage and cord

sparing. These types of decisions will be institution- and physician-dependent and will vary across cases.

• KBP plans will consistently make the same tradeoffs, depending on how the model was designed, is both an asset and a limitation.

• Incorporation of KBP models into the clinical trial setting may have a profound impact on the quality of trial results due to the increase in consistency and standardization of planning, especially for treatment sites or techniques that are non-standard.


Comments PRO:

• Inconsistency in treatment planning are affecting multi-institutional clinical trials

• Knowledge-based planning might become standard in multi-institutional trials to allow consistent planning

CON:

• Number of considered plans is quite low

• KBP could introduce bias and needs further studies


Diffusion Imaging Biomarkers of Regional White Matter Injury Correlate with Change in Executive Function and

Processing Speed after Brain Radiotherapy

K. R. Tringale, R. Karunamuni, T. Nguyen, T. M. Seibert, K. Leyden, V. Uttarwar, V. Murzin, D. C. Marshall, D. R. Simpson, P. Sanghvi, V.

Moiseenko, M. K. Gorman, N. Farid, N. White, A. M. Dale, C. McDonald, and J. A. Hattangadi

University of California, San Diego, La Jolla, CA


White matter radiation effects: demyelination, vascular changes Aim: To analyze region specific biomarkers of white matter (WM) integrity using diffusion imaging and test associations with executive functioning and processing speed in a prospective clinical trial. Hypothesis: Regional changes in diffusion biomarkers of WM damage correlate with changes in executive function and processing speed at 6-months post-radiotherapy.

Study Design / Purpose/Objective(s)


• Enables measurement of changes to subcortical structures, cortex, and white matter

– Most common white matter diffusion measurements

• Mean diffusivity (MD; average amount of water diffusion l in mm2/s)

• Fractional anisotropy (FA; coherence of the orientation of water diffusion)

White Matter Diffusion Imaging Biomarkers Diffusion-weighted imaging (DWI): measuring diffusion of water at the cellular level.

Diffusion tensor imaging (DTI): Extension of DWI; depicts the overall motion of water as an ellipse using a tensor model.

Measur

e

Definition Significance in WM

MD / 3 ↑: WM

disruption/edema/IQ

FA Degree of

directional bias

↓: Disrupted WM

integrity



56 subjects

26 subjects

At least 2 time points with both neurocognitive score and MRI

• 54% men (n=14)

• Mean age 49.2 years • Mean years of education 15.2 • 62% had gliomas (n=16)

• 46% had right-, 32% had left-hemispheric tumors (n=10, n=7)

• 50% had concurrent chemotherapy (n=13)

• 54Gy median prescription dose (50.4 - 60Gy)

Mean dose to ROIs ranged from 11.6 Gy to 21.5 Gy

Study Design / Methods • Known from previous study:

• MD increased consistently over time, with a greater rate of change at higher doses (linear with dose; significant at low doses only at later time points)

• FA decreased over time with greater rate of change at higher RT doses (linear with dose; significant even at low doses <10 Gy)

• This study:


Diffusion Biomarkers after Radiotherapy Over Time

Connor et al., Radiother Oncol 2016


DKEFS: Delis-Kaplan Executive Function

System WCST: Wisconsin Card Sorting Test

Executive Function (impulse control, emotional control, organizing, task initiation)

DKEFS Letter Fluency DKEFS Category Switching Total

WCST Total Errors

Processing Speed (speed to react to information they receive)

Trail Making Number Sequencing Trail Making Letter Sequencing

Linear mixed effects models for all time points (3, 6, 12 months after RT)


Linear mixed effects model with random subject intercept

Neurocogij = β0 + β1 x Monthj + β2 x Imaging + β3 x Imaging x Month + ui + eij

i = subject; j = visit; eij = error; ui = subject-specific

random intercept

Neurocogij = β0 + β1 x [Month]j + β2 x Imaging + ui + eij

Executive function

left dorsolateral and bihemispheric anterior cingulate WM

Processing Speed

bihemispheric inferior parietal and total right hemispheric WM

Software to segment regions of interest (ROIs); change in MD and FA

were calculated for each ROI


Executive Function Anterior Cingulate White Matter

P=0.04 NS

Worse

Better

Left

Worse

Better

Right

P=0.01 P=0.08

Results

Each subject is shown as a different color

Processing Speed Left Inferior Parietal White

Matter

P=0.03 NS Worse

Better


• Executive function (D-KEFS category switching total, mean change -.56, p=0.017; WCST mean change -.51, p=0.006) and processing speed (TM number sequencing, mean change -.40, p=.045) significantly declined post-RT.

• Change in executive function was positively correlated with age and years of education (r=.54, p=0.012; r=.53, p=0.013, respectively), while processing speed was negatively correlated with age (r=-.51, p=0.014).

• FA correlated with total right hemispheric WM (mean change .0074±.029) and all ROIs associated with executive function and processing speed.

• MD correlated with executive function ROIs, but remained relatively unchanged in ROIs associated with processing speed.

• MD of both left and right inferior parietal WM and right total hemispheric WM were positively correlated with processing speed.

Authors’ Conclusions


Comments

PRO: • Cognitive morbidity following radiation therapy has a profound impact. • Enhanced imaging techniques may enable us to detect subtle changes

associated with the onset and progression of cognitive impairment. CON: • Very similar to a study already published by the same group in

November 2016 (Radiother. Oncol.) • Unclear impact on treatment planning • Limitations include censoring high-dose regions, tumor progression,

confounding variables in neurocognitive performance, sample size, dynamic biologic changes post-RT


Overall Conclusions/Summary

• All 5 abstracts are about cutting edge research in radiation oncology physics aiming at

– Current approaches in using prior knowledge in treatment planning and delivery

– Outcome assessment via imaging techniques to be applied in planning and delivery


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