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Dushyant Sahani, M.DDushyant Sahani, M.DDirector of CT
Associate Professor of Radiology Massachusetts General Hospital
Harvard Medical SchoolEmail-dsahani@partners.org
Director of CTAssociate Professor of Radiology Massachusetts General Hospital
Harvard Medical SchoolEmail-dsahani@partners.org
CT Perfusion Imaging: Technique and Applications in the Body
CT Perfusion Imaging: Technique CT Perfusion Imaging: Technique and Applications in the Body and Applications in the Body
AcknowledgementsAcknowledgementsAcknowledgements• Oncology
– C Willett MD.– A Zhu MD– L Blaszkowsky MD– T Lynch MD– S Yoon MD
• TIMC (3D Lab)– G Harris PhD – A Singh MD – W Cai PhD– X Ma MD
• Oncology– C Willett MD.– A Zhu MD– L Blaszkowsky MD– T Lynch MD– S Yoon MD
• TIMC (3D Lab)– G Harris PhD – A Singh MD – W Cai PhD– X Ma MD
• Correlative Science(Steele Lab)
– R Jain PhD– D Duda PhD– Y Boucher PhD
• Radiology– A Kambadakone MD– O Catalano MD– A Galluzzo MD– H Pien PhD– G Sorensen MD– Sanjay Saini MD– Peter Mueller MD
• Correlative Science(Steele Lab)
– R Jain PhD– D Duda PhD– Y Boucher PhD
• Radiology– A Kambadakone MD– O Catalano MD– A Galluzzo MD– H Pien PhD– G Sorensen MD– Sanjay Saini MD– Peter Mueller MD
RECIST= Response Evaluation Criteria in Solid Tumors
WHO = World Health Organization
18 mm
RECIST
WHO
29 mm
59 mm
Conventional method of monitoring treatment response is change in tumor size
Monitoring Response to Conventional Chemotherapy
Monitoring Response to Conventional Monitoring Response to Conventional ChemotherapyChemotherapy
RECIST 1.010 Target Lesions (>1-2 cm)
5 max in an organ
Non-target lesions
RECIST 1.15 Target Lesions (>1 cm)
2 max in an organ
Short-axis of LN>15 mm
Eisenhauer EA et al. EJC 2009
Therasse P et al. JNCI 2000
Therasse P et al. EJC 2006
RECIST WHOType of metric Uni-dimensional Bi-dimensional (CP)
MAD X LPDCR (Complete Response)
Total disappearance Total disappearance
PR (Partial Response)
30% decrease 50% decrease
PD (Progressive Disease)
20% increase 25% increase
SD (Stable disease)
Neither PR or PD criteria met
Neither PR or PD criteria met
Monitoring Response to Chemotherapy
Monitoring Response to Monitoring Response to ChemotherapyChemotherapy
• Tumor morphology–Confluent, Irregular borders–Unusual configuration;
Circumferential (eg. mesothelioma)–Lesion length > 1.5-2 times lesion
width• Discordant results due to RECIST
technique–Uni-dimensional measurement–Shape changes may confound results
• Tumor morphology–Confluent, Irregular borders–Unusual configuration;
Circumferential (eg. mesothelioma)–Lesion length > 1.5-2 times lesion
width• Discordant results due to RECIST
technique–Uni-dimensional measurement–Shape changes may confound results
Limitations of RECIST guidelinesLimitations of RECIST guidelinesLimitations of RECIST guidelines
Volume: 73.286cm3
5.7 months
13.8 months 18.6 months
2.3 months0 months
19.6 monthsVolume: 161.591cm3Volume: 59.677cm3
Liver tumor treated with chemotherapy
Tumor volumetry is a better representative of tumor burden
Monitoring Response to Chemotherapy: Tumor Volume
Monitoring Response to Monitoring Response to Chemotherapy: Tumor VolumeChemotherapy: Tumor Volume
Prasad SR. Radiology 2002. Husband JE et al. BJC 2004
Good Responders Poor Responders≥ 15% decrease in tumor density <15% decrease in tumor density
Tumor Density: Choi criteriaTumor Density: Choi criteria
* ROI drawn around the margin of the entire tumor† Portal venous phase images for the tumor density measurement in abdomen
¥ Multiple lesions - Mean HU of all the lesions
Choi et al J Clin Oncol 2007, Choi et al The Oncologist 2008
PRE
96HU 54HU 25HU28HU
POST PRE POST
Conventional Imaging LimitationsConventional Imaging LimitationsConventional Imaging Limitations
• Evaluates the gross anatomical change of molecular events
• Time lag- typically weeks to months elapse before change observed
• Cannot measure early changes of disease process
• Changes do not necessarily correlate with disease process
• Cannot measure drug distribution
• Evaluates the gross anatomical change of molecular events
• Time lag- typically weeks to months elapse before change observed
• Cannot measure early changes of disease process
• Changes do not necessarily correlate with disease process
• Cannot measure drug distribution
Novel Oncologic DrugsNovel Oncologic Drugs
AngiogenesisAngiogenesisAngiogenesis• The development of new vessels from preexisting
ones*• Essential step in establishment and growth of
malignancies• Allow tumor progression from in-situ lesion to
invasive
• The development of new vessels from preexisting ones*
• Essential step in establishment and growth of malignancies
• Allow tumor progression from in-situ lesion to invasive
*(Risau W.,1997) *(J. Folkman,1995)Image Courtesy: O Clement MD, Paris, Fr.
Drug DevelopmentDrug DevelopmentDrug Development
–It takes an average of $802M and 12 years to bring a new drug to the market
0 2 4 6 8 10 12
Preclinical
Phase I
Phase II
Phase III
LT animal
NDA
$335M
$142M
$137M
$174M
$14M
From: DiMasi, 2003
SUVs 4.5 1.24 0.75
Baseline 1 month 16 months
Demetri et al N Engl J Med 347:472-480, 2002
FDG-PET Imaging of Imatinib(Gleevec, Novartis) on GIST
FDG-PET Imaging of Imatinib(Gleevec, Novartis) on GIST
BLOOD FLOWFDG-PETENDOSCOPY
baseline
2 weeks following therapy
40 ml/100gm/min
90 ml/100gm/min
Imaging Biomarker Selection: Drug MechanismImaging Biomarker Selection: Imaging Biomarker Selection: Drug MechanismDrug Mechanism
Willett CG et al. Nat Med. 2004 Feb;10(2):145-7
Pre-treatment 10 days Post-Avastin
Image Biomarker-Good ResponseImage BiomarkerImage Biomarker--Good ResponseGood Response
Image Biomarker- Poor ResponseImage BiomarkerImage Biomarker-- Poor ResponsePoor Response
Pre-treatment 10 days post-Avastin
Microvascular StructureMicrovascularMicrovascular StructureStructure
Jain et al., Nat Rev Cancer 38:266, 2002
Normal tissueNormal tissue Tumor tissueTumor tissue
DilatedTortuousSpatially
heterogeneous
DilatedTortuousSpatially
heterogeneous
OrganizedArtery-venous network
Tumor Vasculature Abnormalities Influences Contrast Enhancement
Kinetics on DCE CT/MR
Tumor Vasculature Abnormalities Tumor Vasculature Abnormalities Influences Contrast Enhancement Influences Contrast Enhancement
Kinetics on DCE CT/MRKinetics on DCE CT/MR
• Blood Flow• Blood Volume• Mean Transit Time• Permeability
• Blood Flow• Blood Volume• Mean Transit Time• Permeability
BF
PS
RELIABLE:Iodine Concentration (mg/ml)
CT attenuation
CONVENIENT:• Available technique• High spatial resolution• Low inter-tester variability
• Software is commercially available
RELIABLE:Iodine Concentration (mg/ml)
CT attenuation
CONVENIENT:• Available technique• High spatial resolution• Low inter-tester variability
• Software is commercially available
= linear related
Why CT?Why CT?Why CT?
Miles KA. Acad Radiol 2000;7:840–50
Technique: Site selectionTechnique: Site selection
• Non-contrast CT to cover the entire organ–5mm helical
• 2 cm tumor/4 slices (non-necrotic portion) to be covered for dynamic imaging is selected
• 4 cm with 64-MDCT
• Non-contrast CT to cover the entire organ–5mm helical
• 2 cm tumor/4 slices (non-necrotic portion) to be covered for dynamic imaging is selected
• 4 cm with 64-MDCTSahani DV et al. Radiology 05/07Goh V et al. Radiology 06, ER 07
• Contrast injected at 4-7 cc/ sec• Delay = 5-8 sec (abd) 10 sec (pelvis)• Cine acquzition
–4 contiguous 5 mm slices X 30-120 sec (every 1-2 sec)
–kVp 80-100 and mA 100-160–Limited data –4 slices once every 10-20 sec for 4-6 minutes
• Contrast injected at 4-7 cc/ sec• Delay = 5-8 sec (abd) 10 sec (pelvis)• Cine acquzition
–4 contiguous 5 mm slices X 30-120 sec (every 1-2 sec)
–kVp 80-100 and mA 100-160–Limited data –4 slices once every 10-20 sec for 4-6 minutes
Scaning TechniqueScaning Technique
Sahani DV et al. Radiology 05/07Goh V et al. Radiology 06, ER 07
CTp Technique: Rectum CTp Technique: Rectum
CTp Technique: Abdomen
CTpCTp Technique: Technique: Abdomen Abdomen
CTp Techniques and Protocols
CTp Techniques and Protocols
Technique Protocol Benefits limitations
First pass 20-30 sec cine Breath-holdLess radiation
Inadequate PS measurement
Permeability (PS) Cine 45-120 secLimited scan every 10-20 seconds for 4-6 minutes
Permeability Susceptible to MotionMore radiation
Parameters computedParameters computed
• BF = Blood flow• BV = Blood volume• MTT = Mean transit time• PS = Permeability surface
• BF = Blood flow• BV = Blood volume• MTT = Mean transit time• PS = Permeability surface
Parameters dependent on the scanning technique and mathematic modeling
CT Perfusion (GE)1
Functional CT (Siemens)2
Brilliance (Philips)
Mathematic Model
Deconvolutionmethod
Two-compartment model
Slope method
Principle of the Model
Impulse residue function (IRF) which is time enhancement curve of tissue due to idealized instantaneous injection of one unit of contrast
One way transfer of CM from intra to extra-vascular space proportionate to blood clearance constant, α
Perfusion is ratio of max slope of tissue enhancement curve to max arterial enhancement
Parameters measured
BF, BV, MTT, PS BV and Permeability MTT, time to peak enhancement
Advantages BF, BV, MTT and PS can be calculated using a single CT study
1. Simple analysis2. Efficient in calculation of rate constant K value
1. Short scan duration2. “No venous outflow” is true3. No recirculation
Limitations Partial volume averaging correction required
Assumes that back flux of CM from EVS to IVS is negligible for first 1-2 min
Sensitive to image noise
1Sahani et al, Radiology 2005, 2Ng et al, Radiology 2006
Perfusion CT Parameters and Significance
Perfusion CT Parameters and Significance
Parameter BF BV MTT PS
Definition Flow rate through vasculature in tissue region
Volume of flowing blood within a vasculature in tissue region
Average time taken to travel from artery to vein
Total flux from plasma to interstitial space
Marker Tumor VascularityTumor grade
Mitotic activity and vascularity.
Perfusion pressure
Immature leaky vessels.
Staging, Grading and PrognosisClinical
Application Author
(Journal/Year)Observations
Head and neck Zima et al (Am J Neuroradiol 2007)
Hermans et al (Int J Radiat OncolBiol Phy 2003)
Upper aerodigestive tract cancers with high BF and BV values respond well to induction chemotherapyHead and neck cancers with lower perfusion rate (BF) show poor response to radiotherapy (high local failure).
Lung Li et al (Clinical Radiology 2008) Lung cancers with distant metastases have high BF, BV and and different histological types of lung cancer show no difference in perfusion characteristics
Breast Hirasawa et al(Acad Radiol 2007) Nonscirrhous carcinomas have high BF values compared to scirrhouscarcinomas
Liver Zhu et al (The Oncologist 2008)
Sahani et al (Radiology 2007)
Patients with progressive disease (HCC) had lower baseline MTT values
Well differentiated HCCs show high BF, BV, PS and low MTT values than poorly differentiated HCCs
Pancreas d’Assignies et al (Radiology 2008)
Park et al (Radiology 2009)
Benign endocrine tumors have high BF values. Malignant tumors with liver & lymphnodal metastases have long MTTPancreatic cancers with high baseline KTrans values responded better to concurrent chemoradiation
Colon and Rectum
Sahani et al (Radiology 2005)
Bellomi et al (Radiology 2007)
Rectal cancers with high baseline BF and low MTT responded poorly to chemoradiationRectal cancers with high baseline BF and BV showed good response to chemoradiation
Monitoring Antiangiogenic Response: CT perfusion
Monitoring Monitoring AntiangiogenicAntiangiogenic Response: CT Response: CT perfusion perfusion
Pre- Avastin 10 day Post- Avastin
Favourable ResponseDrop in Blood Flow
Drop in Blood Volume
Monitoring Response to Antiangiogenic(Avastin) Therapy in HCCMonitoring Response to Monitoring Response to AntiangiogenicAntiangiogenic((AvastinAvastin) Therapy in HCC) Therapy in HCC
Parameter Pre Avastin Post Avastin P value
Blood Flow (ml/100mg/min)
105 ± 92.9 50 ± 28.8 0.014
Blood Volume (ml/100mg)
5.4 ± 3.9 2.7 ± 1.1 0.009
Mean Transit time (sec) 7.3 ± 2.8 8.8 ± 2.3 0.009
Permeability Surface (ml/100mg/min)
34.28 ± 14 21.9 ± 8.2 0.003
P value from ‘paired student t test’ between the means of pre and post Avastin
Zhu et al. The Oncologist (2007)
BF = 9.89 ml/100g /min
BV = 0.42 ml/100g
MTT= 11.42 sec
PS= PS= 1.44 ml/100g /min1.44 ml/100g /min
HU= 37,21
BF = 38.1 ml/100g /min
BV = 1.65 ml/100g
MTT=4.38 sec
PS= PS= 5.29 ml/100g /min5.29 ml/100g /min
HU= 49,12
Permeability Surface = 8.57 ml/100g /minBlood Flow = 86.3 ml/100g /min
BaselineBaseline
Lung Cancer Response to CXT
Permeability Surface = 5.24 ml/100g /minBlood Flow = 47.6 ml/100g /min
Post CXTPost CXT
CTP1 CTP2 CTP3
BF 90.3±65 72.65±50 63.5±55
BV 3.36±1.46 2.58±1.4 2.4±2
MTT 4.96±3.3 5.51±3.2 2.9±2.2
PS 13.1±5.87 10.1±6.3 ±6.1
Monitoring Treatment Response
Clinical Application
Author (Journal/Year) Observations
Liver Zhu et al (The Oncologist 2008) Fall in BF, BV, PS and rise in MTT after
antiangiogenic treatment in HCC
Rectum Sahani et al (Radiology 2005)
Bellomi et al (Radiology 2007)
Willett et al (Nature Medicine 2004)
Fall in BF and rise in MTT after chemoradiation in rectal cancerFall in BF, BV and PS after chemoradiation in rectal cancerFall in BF and BV after antiangiogenic treatment in rectal cancer
Pre- Avastin
Post- Avastin
BF MTT
BF MTT
24.3 ml/100g/min
13.9 ml/100g/min
7.9 sec
13.9sec
Sarcoma: Sarcoma: AntiangiogenicAntiangiogenic T/tT/t
BLOOD FLOWPETENDOSCOPY
baseline
2 weeks following therapy
40 ml/100gm/min
90 ml/100gm/min
Monitoring Antiangiogenic (Avastin) Response in Rectal CancerMonitoring Monitoring AntiangiogenicAntiangiogenic ((AvastinAvastin) ) Response in Rectal CancerResponse in Rectal Cancer
Willett CG et al. Nat Med. 2004 Feb;10(2):145-7
Rectal Cancer: CTp changes following Treatment
Rectal Cancer: Rectal Cancer: CTpCTp changes changes following Treatmentfollowing Treatment
MGH Experience
Willett C et al. JCO 2009
Validation and ReproducibilityClinical
Application Author (Journal/Year) Observations
Lung Ma et al (BMC Cancer, 2008) BF, BV and PS values of peripheral lung cancer correlated
positively with MVD
Liver Sahani et al (Radiology 2007) Reproducibility of BF, BV, PS and MTT values with high correlation and variability of 4% in HCC
Pancreas d’Assignies et al (Radiology 2008)4.Abe et al29 (Radiat Med 2005)
BF values of pancreatic endocrine tumors correlated well with
MVDGood linear correlation of BF measured by and CTp in pancreatic tumors
Colon & Rectum
Goh et al (Am J Roentgenol 2006)
Li et al (World J Gastroenterol 2005)
Quantitative perfusion measurements are reproducible in colorectal cancerBF values of colorectal carcinomas did not correlate with MVD
Chan NG et al. CTp JCAT 2009
CTp Challenges CTpCTp Challenges Challenges
• Limited sample volume (2-4 cm)–Choice of location for the
investigation critical • The CTp parameters are
estimates of tissue perfusion • Patient motion can impact
perfusion values
• Radiation dose is an issue
• Limited sample volume (2-4 cm)–Choice of location for the
investigation critical • The CTp parameters are
estimates of tissue perfusion • Patient motion can impact
perfusion values
• Radiation dose is an issue
FDA: High Radiation Doses at Cedars-Sinai Hospital
Radiation Overdoses Point Up Dangers of CT Scans
FDA: High Radiation Doses at FDA: High Radiation Doses at CedarsCedars--Sinai HospitalSinai Hospital
Radiation Overdoses Point Up Radiation Overdoses Point Up Dangers of CT ScansDangers of CT Scans
• Appropriate indication• Appropriate indication
Strategies to Lower CTP DoseStrategies to Lower CTP DoseStrategies to Lower CTP Dose
• Appropriate indication• Compromise resolution and SNR
–5-10 mm thickness–Low dose kVp 80-100 mA100-160–2 second temp resolution–Cine < 40 sec–Appropriate scan delay based on the
circulation time
• Appropriate indication• Compromise resolution and SNR
–5-10 mm thickness–Low dose kVp 80-100 mA100-160–2 second temp resolution–Cine < 40 sec–Appropriate scan delay based on the
circulation time
SummarySummarySummary
• Imaging integral to monitoring treatment response in Oncology trials and decision-making –Expectations are changing –Beyond 2D measurements
• Volume• Density • Function • Combination
• Imaging integral to monitoring treatment response in Oncology trials and decision-making –Expectations are changing –Beyond 2D measurements
• Volume• Density • Function • Combination
SummarySummarySummary
• CT perfusion imaging is an evolving field – redefines CT as a technique that can now depict
vascular physiology in addition to detailed anatomy– Is getting increasingly important in trials for
targeted therapies • Protocol customization is mandatory
– to enable relevant tumor vascular physiology data– Radiation dose optimization
• Data is specific to protocol and processing method
• CT perfusion imaging is an evolving field – redefines CT as a technique that can now depict
vascular physiology in addition to detailed anatomy– Is getting increasingly important in trials for
targeted therapies • Protocol customization is mandatory
– to enable relevant tumor vascular physiology data– Radiation dose optimization
• Data is specific to protocol and processing method
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