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Volumetric Measurement of Tumors David F. Yankelevitz, MD.

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1 Volumetric Measurement of Tumors David F. Yankelevitz, MD

2 Why Measure Tumor Volumes? Surrogate for knowing the amount of viable tumor Implied is this: –Larger volumes, therefore progression –Smaller volumes, therefore response

3 How do we measure volumes? Surrogates –Uni-dimension (RECIST) –Bi-dimension (WHO) –Tri-dimension Genuine volume measurements

4 Advantages of Volume Measurements Greater proportional change –26% diameter increase corresponds to 100% volume increase Measurement of asymmetric growth Tumor volume doubling time

5 Days to ERCT from initial CT Initial nodule diameter (mm) Doubling time (days) 3090120150180 281012.41 (24 vs 93%) 10.7510.5510.4410.37 (4 vs 12%) Expected Change in Diameter

6 Asymmetric Growth SPN (6.9 mm) at baseline and 36 days later Virtually unchanged according to 2D metrics Apparently benign (DT=9700) Area: 36.5 mm 2 Perimeter: 22.7 mm Length: 8.27 mm Width: 5.62 mm Area: 36.6 mm 2 Perimeter: 23.4 mm Length: 8.23 mm Width: 5.66 mm

7 Volumetric Analysis 3D analysis reveals significant growth along scanner axis! (DT = 104, malignant)

8 8 mm Stable Nodule

9 Volumetric Growth Rate Analysis 8 mm stable pulmonary nodule at baseline and 181 days later MVGI = 0.57%

10 10 mm Malignant Nodule

11 Volumetric Growth Rate Analysis 10 mm malignant pulmonary nodule at baseline and 32 days later MVGI = 22.0% -- Squamous Cell Carcinoma

12 Inputs Into Volume Estimates Accuracy of measuring device (machine) –Inplane (x,y), out of plane (z) Ability to define borders of target (anatomic) –Removal of attached structures CAD –Defining edges Margin of tumor Adjacent edema/inflammation –Stability of structures

13 10mm Slice Thickness (Anisotropic) © ELCAP 2002

14 5mm Slice Thickness © ELCAP 2002

15 2.5mm Slice Thickness © ELCAP 2002

16 1mm Slice Thickness © ELCAP 2002

17 Headline Courtesy of University of Erlangen, Department of Radiology and Institute of Medical Physics SOMATOM Sensation 64 6 sec for 400 mm 64 x 0.6mm (2x32) Resolution 0.4 mm Rotation 0.37 sec 120 kV / 100 mAs

18 Headline Courtesy of University of Erlangen, Department of Radiology and Institute of Medical Physics SOMATOM Sensation 64 6 sec for 400 mm 64 x 0.6mm (2x32) Resolution 0.4 mm Rotation 0.37 sec 120 kV / 100 mAs

19 Volumetric CT Scanning

20 Accuracy of Area Measurements

21 Deformable Synthetic Nodules

22 Volumetric Measurement - Synthetic Nodules Volume Error:(3-6 mm) = 1.1% RMS, 2.8% max (6-11 mm) = 0.5% RMS, 0.9% max Function of nodule size Yankelevitz, et al. Radiology 2000

23 Removal of Attached Structures Jan 27 1999, (X,Y) resolution: 0.1875 mm, Slice thickness : 1 mm Images ©1999, ELCAP Lab, Weill Medical College of Cornell University

24 Solid Nodule Segmentation

25

26 Images ©1999, ELCAP Lab, Weill Medical College of Cornell University 74-Day Doubling Time Volumetric Doubling Time Estimation

27 Limitations of Segmentation

28 Part-Solid Nodule: Complex Segmentation

29 Abutting Pleura: Limitations of Segmentation

30 Nonsolid Nodule: Indistinct Border

31 Less Natural Contrast

32 SPICULATED NODULE Instructions to Thoracic Radiologists were “Draw the Boundary of the Nodule”

33 SPICULATED NODULE Expert Number 1 Contour

34 SPICULATED NODULE Expert Number 2 Contour

35 SPICULATED NODULE Comparison of Contours

36 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

37 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

38 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

39 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

40 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

41 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

42 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

43 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

44 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

45 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

46 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

47 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

48 Motion Artifact – Patient Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

49 Nonsolid nodule: Adenocarcinoma, bronchioloalveolar subtype

50 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

51 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

52 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

53 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

54 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

55 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

56 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

57 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

58 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

59 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

60 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

61 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

62 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

63 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

64 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

65 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

66 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

67 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

68 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

69 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

70 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

71 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

72 Motion Artifact – Cardiac Motion Images ©1996-2002, ELCAP Lab, Weill Medical College of Cornell University

73 Nodule Growth Rates Exponential Growth Model Nodule Doubling Time (DT) Traditional 2D Approximation

74 Appropriate Time to Follow-up CT When should the follow-up CT be done? where  d  is the reliably-detectable percent volume change, a function of initial nodule size  d  = two standard deviations of PVC in stable nodules by size category DT D = 400 days for baseline cases DT D = upper bound on doubling time for repeat cases example: 208 days for 3 mm nodule

75 Time to Follow-up CT Appropriate time to follow-up CT by initial nodule size detected on baseline or repeat screening Time to Follow-up CT (days) for nodules detected on Size (mm)  (d) (%)BaselineRepeat 2 - 5 37.0 182 95 5 - 8 21.2 111 26 8 - 11 15.0 81 12

76 Review of Literature Limited data on comparison of 3D volume measurements to 2D or 1D, notably for large lesions Most report that volume is better for large ‘well-defined’ abnormalities Limited impact on change in category for RECIST

77 Summary Technology has greatly improved –Measuring device –Image processing Little work has been done in regard to complex abnormalities Potential to markedly improve response estimates

78 Volumetric Measurement of In Vivo Nodules Although we had quantified the relative error in phantom nodule measurement by size, the error for in vivo nodules must be greater –partial volume –vascular geometry –motion artifacts

79 Assessment of In Vivo Volume Estimates Rescanning in short interval –Smallest change in true nodule volume –Difficult study due to dose concerns Stable nodules –Scans more easily obtained (screening) –Accounts for small errors in patient positioning and scanner calibration drift

80 Cases 262 HRCT scans of 120 stable nodules –Standard dose, small FOV, HRCT –Nodules 2-11 mm in diameter –Determination of stability based on radiologist evaluation over period of 2 or more years –Assessment of technical artifacts Incomplete acquisition System error –Assessment of motion artifacts Five-point scale Patient motion (gross movement, respiration) Cardiac motion 20 HRCT scans of 10 malignant nodules

81 Artifacts Motion artifact and technical artifact in 262 CT scans by initial nodule size Technical Motion Artifact ScoreAny Artifact NoneMinimalModeratePronouncedSevere Artifact Size (mm) 2 - 5 355 8 2 7 121 5 - 8 121 4 7 2 115 8 - 11 1 5 1 5 0 0 7 Any size 5811314 9 2 26 (22%) of cases had to be excluded due to technical or motion artifacts

82 Stable Nodules Frequency distribution of 94 stable nodules by initial size and time to follow-up CT Time to Follow-up CT (months) 0 - 66 - 1212 - 30Any Interval Size (mm) 2 - 5 21 29 1363 5 - 8 11 12 225 8 - 11 2 2 2 6 Any size 34 43 1794

83 Monthly Volumetric Growth Index Monthly Volumetric Growth Index, MVGI –Percent change in volume per month –Remaps growth estimates into two distinct classes Reeves, et al. RSNA 2001

84 Nodule Growth Rates MVGI = 32.5 MVGI = 15.1 MVGI = 4.3

85 MVGI of Stable Nodules Mean and standard deviation of monthly volumetric growth index of 94 stable nodules by initial size and time to follow-up CT Time to Follow-up CT (months) 0 - 6 6 - 12 12 - 30Any Interval Size (mm) MeanSDMeanSDMeanSDMeanSD 2 - 5-0.052.48 0.202.28-0.331.60 0.012.21 5 - 8-0.321.82 0.821.54-0.110.49 0.241.68 8 - 11-0.682.36 0.050.74-0.230.68-0.131.23 Any Size-0.172.22 0.372.04-0.241.41 0.062.02 Overall mean 0.06% Std. Err. of the Mean 0.21%

86 MVGI of Stable Nodules Mean and standard deviation of monthly volumetric growth index of 94 stable nodules by initial size and time to follow-up CT Time to Follow-up CT (months) 0 - 6 6 - 12 12 - 30Any Interval Size (mm) MeanSDMeanSDMeanSDMeanSD 2 - 5-0.052.48 0.202.28-0.331.60 0.012.21 5 - 8-0.321.82 0.821.54-0.110.49 0.241.68 8 - 11-0.682.36 0.050.74-0.230.68-0.131.23 Any Size-0.172.22 0.372.04-0.241.41 0.062.02 SD decreases with increasing size SD decreases with increasing time to follow-up CT

87 PVC of Stable Nodules Mean and standard deviation of percent volume change of 94 stable nodules by initial size and time to follow-up CT Time to Follow-up CT (months) 0 - 6 6 - 12 12 - 30Any Interval Size (mm) MeanSDMeanSDMeanSDMeanSD 2 - 5 1.1510.5 3.5420.0-0.1725.2 1.9818.5 5 - 8-0.886.02 5.8612.9-3.7413.1 2.1310.6 8 - 11-5.539.11-1.026.29-1.8610.0-1.567.47 Any Size 0.159.09 3.9817.7-0.3522.3 1.7916.1

88 PVC of Stable Nodules Mean and standard deviation of percent volume change of 94 stable nodules by initial size and time to follow-up CT Time to Follow-up CT (months) 0 - 6 6 - 12 12 - 30Any Interval Size (mm) MeanSDMeanSDMeanSDMeanSD 2 - 5 1.1510.5 3.5420.0-0.1725.2 1.9818.5 5 - 8-0.886.02 5.8612.9-3.7413.1 2.1310.6 8 - 11-5.539.11-1.026.29-1.8610.0-1.567.47 Any Size 0.159.09 3.9817.7-0.3522.3 1.7916.1 SD decreases with increasing size SD increases with increasing time to follow-up CT

89 Malignant Nodules Monthly volumetric growth index of 10 malignant nodules with initial size, time to follow-up CT, and histologic diagnosis Initial Time to Follow-upHistologic CaseDetectionSize (mm)CT (days)MVGI (%)Diagnosis 1 Baseline 9.3 20 51.2Adenocarcinoma 2 Baseline 10.4 32 22.0Squamous Cell 3 Baseline 11.1 84 18.7Large Cell 4 Baseline 8.3 197 7.73Adenocarcinoma 5 Repeat 2.8 58 37.3Adenocarcinoma 6 Repeat 10.6 12 36.5Squamous Cell 7 Repeat 5.1 33 33.3Adenocarcinoma 8 Repeat 6.9 36 22.4Adenocarcinoma 9 Repeat 7.3 42 5.37Adenocarcinoma 10 Repeat 9.8 34 5.01Large Cell

90 Comparison of MVGI Values All of the stable nodules had values within two standard deviations of the corresponding mean value by size, while each of the 10 malignant nodules exceeded that corresponding value.

91 Conclusions The mean value of MVGI for stable nodules was 0.06% and its standard error was 0.21%. All of the stable nodules had values within two standard deviations of the corresponding mean value by size, while each of the 10 malignant nodules exceeded that corresponding value. Conclusion: Three-dimensional computer methods can be used to reliably characterize growth in small solid pulmonary nodules. Factors affecting the reproducibility of growth rate estimates include the initial nodule size, the timing of the follow-up scan, and the presence of patient-induced or technical artifacts.

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