Individually optimized contrast-enhanced 4D-CT for radiotherapy simulation in pancreatic adenocarcinoma

Wookjin Choi, Ming Xue, Barton Lane, Min Kyu Kang, Kruti Patel, William Regine, Paul Klahr, Jiahui Wang, Warren D'Souza, Wei Lu

*Contact: Wei Lu, Ph.D., luw@mskcc.org

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Introduction•Pancreatic adenocarcinoma (PDA)–Radioresistant–Neighboring organs : highly sensitive to radiation

•Critical to accurately and precisely delineate target volume of PDA– Similar density and CT number to normal tissue –Move a large amount up to 1 – 2 cm due to respiration

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Introduction•Clinic: CE 3D-CT followed by a 4D-CT

•Contrast-enhanced (CE) 3D-CT– Enhance tumor-to-pancreas contrast– Increase the difference in CT numbers

•4D-CT–Quantify and compensate tumor respiratory motion

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Limitations of CE 3D-CT + 4D-CT• Geometrical discrepancy between the two scans– Due to variations in patient position and breathing pattern – On average 12% of GTVs fell outside ITV

{Li et al., 2013. J of Radiation Research 54: 950-956}.• Tumor-pancreas boundary– Barely detectable in 4D-CT without contrast

• Surrogates of motion have to be used.

• Solution: combine the two scans into a single CE 4D-CT scan

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CE 4D-CT• It is all about timing!

• Conventional fixed-delay CE 4D-CT– 50 s : from start of injection to scanning central pancreas during

pancreatic phase– Large variations in the contrast arrival time (10 – 35 s) and

injection duration (30 – 60 s)

• Individually optimized-delay CE 4D-CT

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Methods• Ten PDA patients enrolled.• CE 3D-CT followed by 4D-CT on simulation date– Bolus tracking for contrast timing, total 90 mL– When a threshold of 150 HU was reached, the CE 3D-CT scan was

started• CE 4D-CT on film date – Test injection for contrast timing, 10 mL– Full (140 ml) injection based on the estimated time to peak

enhancement

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ROI in aorta

Estimate Time to Peak Enhancement

{Bae 2010. Radiology 256: 32-61}

Using a test injection enhancement curve {Xue et al., 2012. Med. Phy. 39: 3903-3903}.

Enhancement (HU)

Time (Sec)

0 5 10 15 20 25 30 35 45

105100

959085807570656055

Typical transit time

Injection duration Typical arrival

time

𝑇 𝑝𝑒𝑎𝑘=T ID+15 s+(T arr−20 s )

Tarr = 24.2 s

Tpeak

Pancreas

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We can determine optimal delay time Tdelay

Determine the Delay Time

4D-CT Acquisition Contrast Injection

LO

4D-C

T Sc

an L

engt

h

Org

an

Tpeak

Tdelay = LO/V- Tpeak

ContrastEnhancem

ent Curve

Time (s)

Enhancement (HU)

a

c

b

de

Time when the organ is scanned over (Lo/V)

Time when organ reaches peak enhancement Tpeak

Synchronize

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Visual Evaluation

CE 3D-CT CE 4D-CT4D-CT• Three physicians visually scored image quality, and contoured

the tumor (red, T) and pancreatic tissue (blue, P).

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Tumor-to-Pancreas Contrast• Tumor-to-pancreas contrast (C) and contrast-to-noise ratio (CNR)– ROIs : Tumor-pancreas boundary

• Inter-observer variations in contouring the tumor– Simultaneous truth and performance level estimation (STAPLE)

{Yang et al., 2014. Int J Radiat Oncol Biol Phys 89: 214-21}.

𝐶=|𝜇 (𝑃 ′ )−𝜇 (𝑇 ′ )|,

𝐶𝑁𝑅=𝐶𝜎 𝑓,

TP

Image noise was measured on subcutaneous fat

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Image Quality Scores CE 3D-CT 4D-CT CE 4D-CTGener

alImage Qualit

y

Anatomical details 4.1 ± 0.8 2.5 ± 0.6 3.6 ± 0.8Motion artifacts 3.9 ± 1.0 3.4 ± 0.9 3.7 ± 0.8Beam hardening 4.2 ± 0.8 3.3 ± 0.9 3.5 ± 0.8Enhancement 3.2 ± 1.0 1.7 ± 0.9 3.3 ± 1.0

Regional Vessel Definition 4.2 ± 1.1 2.7 ± 1.5 4.1 ± 1.3Overall Average 4.0 ± 0.5 2.6 ± 0.5 3.8 ± 0.4

Signed rank test (P) <0.001*,vs. 4D-CT

<0.001*,vs. CE 4D-CT

0.082,vs. CE 3D-CT

• Image qualities of CE 3D-CT and CE 4D-CT were comparable, and both were significantly better than 4D-CT.

* significant at 0.05, scores range from 1(poor) to 5(excellent)

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Quantitative Analysis CE 3D-CT 4D-CT CE 4D-CTPancreas (HU) 49.2 ± 12.3 44.6 ± 15.9* 75.5 ± 21.2*

Tumor (HU) 53.0 ± 9.2* 58.9 ± 14.3* 76.3 ± 15.0*

Tumor-to-pancreas contrast (HU) 15.5 ± 20.7 9.2 ± 9.2* 16.7 ± 12.3

Noise (HU) 12.5 ± 3.9* 19.4 ± 5.8 22.1 ± 5.7*

CNR 1.4 ± 1.9* 0.6 ± 0.7* 0.8 ± 0.6

• Tumor-to-pancreas contrast in CE 3D-CT and CE 4D-CT were comparable, and the later was higher than 4D-CT.

• Noise in CE 3D-CT was much lower than 4D-CT and CE 4D-CT.• CNR was not significantly different between CE 3D-CT and CE 4D-CT.

* significant at 0.05

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Tumor Volume and Motion 4D-CT CE 4D-CT P

Volume (cm3)

GTV50% 42.0 ± 35.1 22.8 ± 18.9 0.005*

IGTV4 56.0 ± 38.1 32.8 ± 26.4 0.005*

GTV Motion(mm)

LR 2.3 ± 1.7 1.1 ± 0.5 0.14AP 2.8 ± 1.6 2.6 ± 1.6 0.80SI 6.0 ± 1.7 5.4 ± 1.6 0.39

3D 7.2 ± 2.0 6.2 ± 1.9 0.17

• Both GTV50% in CE 4D-CT and GTV in CE 3D-CT (29.8 ± 16.6 cm3) were significantly smaller than GTV50% in 4D-CT.

• Tumor motion were comparable .

* significant at 0.05

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Inter-Observer Variation in Contouring Tumors

• Large inter-observer variations in all three CTs• STAPLE estimated the best agreement of a group of contours.

78.0%73.7%

66.0%66.5%72.7%

55.6%

72.2% 72.5%

61.9%

Sensitivity Specificity JaccardCE 3D-CT 4D-CT CE 4D-CT

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Conclusions• The CE 4D-CT was largely comparable to CE 3D-CT– Image quality, enhancement, and contrast

•High potential for simultaneously delineating the tumor and quantifying tumor motion with a single scan.

•Contrast enhancement in PDA is still poor, large inter-observer variations in contouring tumors.

Acknowledgements• Philips Healthcare, Inc.• NIH Grant R01CA172638• Clinical research team• Patients

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Thank you

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Breathing Signal (RPM)

4D-CT CE 4D-CT P

Average amplitude 0.83 ± 0.35 0.75 ± 0.26 0.51

Maximum amplitude 1.29 ± 0.53 1.22 ± 0.36 0.39

BPM 15.0 ± 2.49 16.3 ± 2.50 0.15

• Average and maximum amplitude were similar.• BPM (breaths per minute) was also comparable.

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PTV Volume

CE 3D-CT 4D-CT CE 4D-CT

Volume (cm3) 160.4±59.0 204.1 ± 94.0 145.4 ± 70.2

P 0.002*CE 3D-CT vs. 4D-CT

0.002*4D-CT vs. CE 4D-CT

0.16CE 3D-CT vs. CE 4D-CT

• Average PTV in CE 3D-CT and CE4D-CT were comparable.• But, both were significantly smaller than 4D-CT.

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Optimized-Delay CE 4D-CT vs. Fixed-Delay CE 4D-CT CE-4DCT Fixed-Delay Optimized-DelayContrast (mL) / rate (mL/s) 140 / 2.9 140 / 2.0QualitativeImage Score

General image quality 4.0 ± 0.7 3.6 ± 0.8Enhancement 4.4 ± 0.5 3.7 ± 0.8

Regional vessel definition 4.0 ± 1.3 3.5 ± 0.8

Pancreas enhancement (HU) 59.7 ± 13.8 75.5 ± 21.2{Cattaneo et al., 2010. Radio. Onc. 97: 525-529. Mancosu et al., 2008. Radio. Onc. 87: 339-342. }

• Fixed-delay CE 4D-CT showed better qualitative image scores. • Optimized-delay CE 4D-CT showed higher enhancement in HU.

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Estimate Time to Peak Enhancement

{Bae 2010. Radiology 256: 32-61}

ROI in aorta

Using a test injection enhancement curve {Xue et al., 2012. Med. Phy. 39: 3903-3903}.

Typical transit time

Injection duration Typical arrival

time

𝑇 𝑝𝑒𝑎𝑘=T ID+15 s+(T arr−20 s )

Tarr = 24.2 s