Controlling Variability in Lung Cancer

Response Assessment

Ricardo S. Avila

May 13, 2010

 Therapy Assessment
Characteristics Assessment
• Late stage • Tumor response
• ID new lesions
• Thick Slice CT

?
Tumor Size

4 cm lesion

Dt

Time Start Assess

Therapy Response
 RECIST
8mm DD, 13 pixels
73% DVolume
Target Lesion Measurement

Progressive
Disease
DD = +20%
RECIST: Sum of LD

4cm lesion Unaided

Disease
Stable
Interpretation

DD = -30%

Response
weeks

Partial
Erasmus et. al., JCO 2003
Erasmus et. al., JCO 2003
Intra-observer error
Intra-observer error
PD:
PD:9.5%
9.5% ofoftumors
tumors

Response
Complete
PR: 3% of tumors
Time PR: 3% of tumors
Inter-observer
Inter-observererror
error
PD: 30% of tumors
PD: 30% of tumors
Baseline PR:
PR:14%
14% ofoftumors
tumors
& Treat
Assess
Response
 We Can Do Better
Improve
• Accuracy
• Precision
To Improve
Target Lesion Measurement

Progressive
• Interval (Dt)

Disease
• Study N
RECIST: Sum of LD

4cm lesion

Disease
Stable
Aided 3D
Interpretation

Response
Partial
Dt

Response
Time Complete

Early Detection
& Nodule Sizing
 Detecting a 50 Micron
Displacement

Patton and Byron Nature Reviews Drug Discovery 2007

 Computed Tomography

Siemens Emotion 16
16 Slice Scanner
1.00mm Slice Thickness

B30s Kernel B60s Kernel

GE LightSpeed Ultra
8 Slice Scanner
1.25mm Slice Thickness

Very Low Dose Low Dose

 Measurement Challenges
Patient/Lesion Presentation
– Size
– Complexity
– Changes over time (necrosis)

Scanners
– Hardware (collimation)
– Software (releases)

Protocols
– ScanRx
– Contrast
– Patient position

Observer
– Seed points/ROI 5mm 2.5mm
– Data Interpretation
 Volumetric Algorithm Challenges
Boundary Identification Challenges
• Vascular network (Ev)
No/Small DI

• Bronchial network (Eb)

• Pleura (Ep)
• Sub-voxel edge (Es)

Errors at 2 time points

Ev

Volumetric error strongly Ep

ra
depends on lesion size and

eu
Pl
slice thickness Es
 Technical Focus Areas
• Open Image Archives
– LCA’s Give-A-Scan Project
– OSA’s Interactive Science Publishing
– RSNA’s Ad Hoc Committee on Open Image Archives

• Understanding Measurement Performance

– Benchmarks: NIST Biochange and Volcano
– QIBA: Phantom Data Studies
– QIBA: Measurement Performance on Clinical Data
– Kitware Pocket Phantom

• Open Source Algorithms and Models

– Lesion Sizing Toolkit
– COPD Modeling and Quantification

• Establishing Standards for Clinical Trials

– QIBA: Volumetric CT Profiles
 Quantitative Identification of
Patient Sub-Populations
• Analysis of imaging and clinical data can
potentially identify patient populations that
respond more favorably to lung cancer therapy

– Drug Efficacy
• Lung Damage Assessment
– COPD impacts aerosolized drug delivery
– Lung Cancer Risk

– Safety
• Cardiovascular damage
Lung Cancer Alliance’s
Give-A-Scan Project
 A Lung Cancer Alliance Project
• Pilot project started in 2008
• Process and procedures were created for
accepting and anonymizing datasets
• ~30 individuals expressed interest in participating
• 17 scans received, but 2 were not readable
• Over 6 GB of image and meta data was collected
• 9 patient scans have been prepared for public
dissemination on a LCA website.
Give-A-Scan Website
Dataset includes:
• Age
• Gender
• Cancer Type
• Cancer Stage
• Family History

4 of the 9
subjects are
never smokers
 Legal Documents
A large amount of effort spent on developing
the legal framework
• Informed Consent
• End User License

An open set of legal resources for open

image archives would benefit many projects
New CT Pocket Phantom
 New CT Pocket Phantom
Goal:
To characterize the fundamental imaging
characteristics of CT acquisitions performed in
the Roche ABIGAIL study
– 3D Resolution & Sampling Rate
– Noise Characteristics
– X-ray Attenuation Performance

Acrylic Delrin Teflon

Urethane
 New CT Pocket Phantom
Manufactured 21 phantoms and deployed
them into the Abigail phase II clinical trial
Fully Automated Phantom Analysis
 Several Studies Underway
Resolution vs. Distance to Isocenter
In-Plane PSF s
s = 0.53 mm s = 0.45 mm s = 0.47 mm s = 0.54 mm
D = 112 mm D = 49 mm D = 62 mm D = 118 mm

s = 0.53 mm s = 0.45 mm s = 0.44 mm s = 0.51 mm

D = 114 mm D = 43 mm D = 32 mm D = 104 mm

Standard Kernel
Bone Kernel
Lung Kernel
 Comparison of the New Pocket
Phantom with a Catphan Phantom
Calibration Study
– Siemens Sensation 64 CT Scanner
– 6 pocket phantoms placed in/near an
anthropomorphic chest phantom
– Catphan phantom also scanned
– Varied slice thickness, mA, kVp, and
pitch

Pearson’s Correlation Coefficients

– CT Density = 0.999 (P < 0.001)
– Noise = 0.940 (P < 0.001)
– Resolution = 0.929 (P < 0.001)
 Open Source
Lesion Sizing Toolkit
 The Lesion Sizing Toolkit

http://public.kitware.com/LesionSizingKit/
The
The Lesion
Lesion Sizing
Sizing Toolkit
Toolkit (LST)
(LST) is
is aa free
free and
and open
open source
source
software
software architecture
architecture designed
designed toto accelerate
accelerate thethe development
development
and
and evaluation
evaluation of
of quantitative
quantitative lesion
lesion sizing
sizing algorithms.
algorithms.
 Developed in 2008
Focused on Dissemination in 2009

RSNA

Quantitative Reading
Room of the Future
Showcase

Open Source Medical

Imaging Software Course

Benchmarks

Volcano 2009
 OSA ISP Special Issue on
Imaging for Early Lung Cancer Detection
Lung Cancer Risk
 Lung Cancer Formation
• Significant tissue damage occurs as
a result of particulate matter (PM)
deposition Hyaline
Cartilage

• Deposition is a function of air flow

dynamics and PM characteristics

• Histology and CFD has shown up to

a 100x greater PM deposition at:
– Airway bifurcations
[Broday, Aerosol Science and Tech. 2004]
– Respiratory bronchioles
[Churg & Brauer, Ultrastructural Path. 2000]

• Bifurcation and peripheral lung

tissues likely exhibit some of the
earliest preneoplastic changes in Balashazy et al., J Appl Physiol 2003.
response to PM exposure
Bifurcation Calcification in HRCT
Bifurcation Calcification
Open Image Archive 1.25mm Slice
Thickness w/
Bone Kernel
 Lung Cancer Risk Index (LCRI)
Features

1. Bifurcation Damage Index (BDI)

• HRCT w/ B60f edge enhancing kernel
• Mean of 5 airway bifurcations (~20min)

2. FEV1/FVC
• Decline associated with lung cancer risk
• Follow ATS spirometry guidelines
BD CD

Classifier
• Linear

Method is Independent of Age, Gender, Pack Years…

 BDI vs. FEV1/FVC

r
ghe
Hi

r
we
Lo
er
gh
Hi

r
we
Lo

Regression line is for cancer cases scanned

at 1mm slice thickness and FEV1/FVC > 55%
 Initial Performance Analysis
Conditional Logistic Cochran-Mantel-
Dataset Regression Haenszel
(Odds ratio for a D 0.033 in LCRI
(crude estimate)
with 1:3 matching )

OR = 1.84
108 Cases 67% sensitive
CI: 1.18-2.85
Full Dataset 72% specific
p-value = 0.0067

OR = 2.89
79 Cases 100% sensitive
CI: 1.02-8.19
1mm Only 74% specific
p-value = 0.0467

Conclusion:

Individuals with higher LCRI are more likely to have lung cancer
Data on 21 Cancers and 121 Controls
COPD

COPD
 Lung Cancer Risk Findings
• Investigating a new quantitative imaging biomarker

• Airway bifurcations are calcifying in a relationship with

FEV1/FVC
• In control cases, a significant trend observed between
LCRI and age*pack years (P = 0.006)
• Odds Ratio for LCRI is better than FEV1/FVC
– LCRI = 2.73 (CI: 1.35-5.51, P = 0.005)

– FEV1/FVC = 0.44 (CI: 0.24-0.83, P = 0.005)

• Opportunities exist to identify new lung cancer patient

sub-populations
 Give-A-Scan Patient Donated Dataset
Never Smoker, Cancer at 62, FEV1/FVC=84%
Right

2.5mm
2.5mm Scan
Scan
Standard
Standard
Kernel
Kernel
Left
Measuring Progress 7 Workshops since 2004
1 Interim COPD Meeting
Interim PCF/Cornell Database
Meetings
Annual NCIA
QIBA Workshop Give-A-Scan
FDA COPDGene?
NIST

Standards & Large Open Image

FDA Approval Databases
Accelerate
Development of
Therapy
Assessment
Methods
Algorithms &
Reproducibility
Reference
& Comparison
Methods

Early Clinical Trials Open Source

BioChange & Volcano Publications Lesion Sizing Toolkit
QIBA Studies CT COPD Algorithms

Oncology Workshop Reports

Quantitative CT Monograph
ISP Oncology Special Issue
Thank You
 Lung Cancer Risk Index
Cancers and Age & PY Matched Controls (+/-10)

PY = 5 15 20 28 30 40 45 59 60 63 66 68 72 75 92
Age = 64 51 59 51 57 48 58 60 69 54 64 57 68 74 62

Cancer Subjects Sorted by Increasing Pack Years

A control case was permitted to be used for more than 1 cancer case
 Lung Cancer Risk Index
Cancers and Age & PY Matched Controls

1.0 mm CT
Thickness
Threshold

1.25 mm CT
Thickness
Threshold

PY = 5 15 20 28 30 40 45 59 60 63 66 68 72 75 92
Age = 64 51 59 51 57 48 58 60 69 54 64 57 68 74 62

Cancer Subjects Sorted by Increasing Pack Years

A control case was permitted to be used for more than 1 cancer case
 New Study Results
(We are now using FEV1/FVC before bronchodilator)
 New Study Results
(We are now using FEV1/FVC before bronchodilator)

Thymoma

Carcinoid of
the Thymus

AAH