Volumetric MRI Analysis of Plexiform Neurofibromas in Neurofibromatosis Type 1

Objectives

Plexiform neurofibromas (PNs) are complex, histologically benign peripheral nerve sheath tumors that are challenging to measure by simple line measurements. Computer-aided volumetric segmentation of PN has become the recommended method to assess response in clinical trials directed at PN. Different methods for volumetric analysis of PN have been developed. The goal of this study is to test the level of agreement in volume measurements and in interval changes using two separate methods of volumetric magnetic resonance imaging analysis.

Methods

Three independent volume measurements were performed on 15 PN imaged at three time-points using 3DQI software at Massachusetts General Hospital (MGH) and National Cancer Institute (NCI) and MEDx software at NCI.

Results

Median volume differences at each time-point comparing MGH-3DQI and NCI-3DQI were −0.5, −4.2, and −19.9 mL; comparing NCI-3DQI and NCI-MEDx were −21.0, −47.0, and −21.0 mL; comparing MGH-3DQI and NCI-MEDx were −10.0, −70.3, and −29.9 mL. Median differences in percentage change over time comparing MGH-3DQI and NCI-3DQI were −1.7, 1.1, and −1.0%; comparing NCI-3DQI and NCI-MEDx were −2.3, 3.3, and −1.1%; comparing MGH-3DQI and NCI-MEDx were −0.4, 2.0, and −1.5%. Volume differences were <20% of the mean of the two measurements in 117 of 135 comparisons (86.7%). Difference in interval change was <20% in 120 of the 135 comparisons (88.9%), while disease status classification was concordant in 115 of 135 comparisons (85.2%).

Conclusions

The volumes, interval changes, and progression status classifications were in good agreement. The comparison of two volumetric analysis methods suggests no systematic differences in tumor assessment. A prospective comparison of the two methods is planned.

Introduction

Plexiform neurofibromas (PNs) are histologically benign nerve sheath tumors typically associated with neurofibromatosis type-1 (NF1). These tumors develop along multiple branches of peripheral nerves and can be large, or irregularly shaped, making standard linear measurements unreliable. PNs are well visualized by magnetic resonance imaging (MRI) using short tau inversion recovery (STIR) sequence, and can be contoured using computer-aided volumetric lesion segmentation methods . Volumetric evaluation has become the method of choice to determine tumor response and time to disease progression in recent clinical trials for NF1-related PNs .

In the phase 1 trial of the MEK inhibitor selumetinib, 71% of patients with inoperable PN experienced at least 20% volume reduction, and in some cases, improvement in clinical symptoms . If the ongoing phase 2 trial confirms a similar response rate and proves that the moderate size decreases are indeed associated with clinical improvement, selumetinib may become the first medical therapy approved by the US Food and Drug Administration (FDA) for the treatment of PN.

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Methods

Patients

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MRI Acquisition

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Image Analysis

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Statistical Analysis

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Results

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Table 1

Three Independent Volumetric MRI Measurements of 15 PN Imaged at Three Different Time-points

ID PN Location Time-point 1 MRI Time-point 2 MRI Time-point 3 MRI MGH-3DQI NCI-3DQI NCI-MEDx MGH-3DQI NCI-3DQI NCI-MEDx MGH-3DQI NCI-3DQI NCI-MEDx 1 Abdomen 2568.7 3013 3302 4204.5 4127 4533 4724.3 4930 5150 2 Neck, chest 588.2 599 647 682.7 674 753 743.6 746 818 3 Neck, chest 893.0 824 892 1112.1 1087 1244 1399.5 1380 1425 4 Back 129.4 126 147 137.3 135 150 151.7 149 170 5 Brachial plexus 359.0 444 591 421.1 514 659 527.6 657 771 6 Chest 1861.3 1856 1838 1938.9 1964 2030 2253.1 2273 2283 7 Chest, left arm 1243.0 1426 1564 1377.9 1690 1820 1880.8 2060 2287 8 Face 180.1 155 177 175.7 173 181 204.8 194 201 9 Lower leg 255.4 285 270 299.1 329 328 270.5 303 290 10 Neck 152.0 151 162 175.8 180 188 257.7 256 288 11 Orbit 91.8 88.3 87.8 82.2 96.7 106 63.0 76.7 79.3 12 Orbit, face 175.1 180 168 211.4 201 194 241.9 200 194 13 Pelvis 987.5 988 970 993.8 1086 1133 1098.5 1146 1196 14 Abdomen, pelvis 1021.2 868 836 1634.6 1311 1282 2864.1 2949 2835 15 Pelvis, thigh 1755.2 1859 2068 2867.2 3081 3195 3134.1 3902 3916

MGH, Massachusetts General Hospital; MRI, magnetic resonance imaging; NCI, National Cancer Institute; PN, plexiform neurofibroma.

The customary reporting style at MGH is to give all values with decimals, whereas at NCI volumes over 100 mL are rounded to the nearest whole. The smallest volume in the dataset is 63.0 mL (PN11, MGH-3DQI, time-point 3), and the largest volume is 5150 mL (PN1, NCI-MEDx, time-point 3). Volume trends by age are provided in Supplementary Fig S1 .

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Table 2

Summary of Volume Measurement Differences

A. Volumes Time-point 1 MRI Time-point 2 MRI Time-point 3 MRI MGH-3DQI—NCI-3DQI Volume difference:

Median (range) mL* −0.5

(−444.3 to 153.2)

P = .45 −4.2

(−312.1 to 323.6)

P = .42 −19.9

(−767.9 to 41.9)

P = .035 *Corresponding relative volume difference—% of mean (PN ID) 0.1 (PN13)

15.9 (PN1); 16.2 (PN14) 2.4 (PN10)

20.3 (PN7); 22.0 (PN14) 0.9 (PN6)

21.8 (PN15); 19.0 (PN12) Relative volume difference

Median (range)—% of mean** 5.7

(0.1–21.2) 5.0

(1.3–22.0) 4.3

(0.3–21.8) **Corresponding absolute volume difference—mL (PN ID) 103.8 (PN15)

0.5 (PN13); 85.0 (PN5) 10.4 (PN12)

8.7 (PN2); 323.6 (PN14) 205.7 (PN1)

2.4 (PN2); 767.9 (PN15) Number of PN with <20% relative volume difference 14 13 13 NCI-3DQI—NCI-MEDx Volume difference:

Median (range)—mL* −21.0

(−289.0 to 32.0)

P = .071 −47.0

(−406.0 to 29.0)

P = .0024 −21.0

(−227.0 to 114.0)

P = .018 *Corresponding relative volume difference—% of mean (PN ID) 15.4 (PN4)

9.2 (PN1); 3.8 (PN14) 4.2 (PN13)

24.7 (PN1); 2.2 (PN14) 13.2 (PN4)

10.4 (PN7); 3.9 (PN14) Relative volume difference

Median (range)—% of mean** 7.7

(0.6–28.4) 4.5

(0.3–24.7) 4.3

(0.4–16.0) **Corresponding absolute volume difference—mL (PN ID) 48.0 (PN2)

0.5 (PN11); 147.0 (PN5) 8.0 (PN8)

1.0 (PN9); 145.0 (PN5) 50.0 (PN13)

10.0 (PN6); 114.0 (PN5) Number of PN with <20% relative volume difference 14 14 15 MGH-3DQI—NCI-MEDx Volume difference:

Median (range)—mL* −10.0

(−733.3 to 185.2)

P = .21 −70.3

(−442.1 to 352.6)

P = .015 −29.9

(−781.9 to 47.9)

P = .010 *Corresponding relative volume difference—% of mean (PN ID) 6.4 (PN10)

25.0 (PN1); 19.9 (PN14) 9.8 (PN2)

27.6 (PN7); 24.2 (PN14) 1.3 (PN6)

22.2 (PN15); 22.0 (PN12) Relative volume difference

Median (range)—% of mean** 6.4

(0.1–48.8) 9.8

(3.0–44.0) 9.5

(1.0–37.5) **Corresponding absolute volume difference—mL (PN ID) 10.0 (PN10)

1.0 (PN3); 232.0 (PN5) 70.3 (PN2)

5.3 (PN8); 237.9 (PN5) 74.4 (PN2)

29.1 (PN14); 243.4 (PN5) Number of PN with <20% relative volume difference 12 11 11

B. Interval Changes Time-points 1–2 Time-points 2–3 Time-points 1–3 MGH-3DQI—NCI-3DQI Difference in % change

Median (range)—% −1.7

(−20.0 to 26.7)

P = .56 1.1

(−49.7 to 14.9)

P = .80 −1.0

(−59.3 to 27.0)

P = .27 Largest discrepancy in interval change—% (PN ID) 63.7 vs 37.0

(PN1) 75.2 vs 124.9

(PN14) 180.5 vs 239.7

(PN14) Number of PN with <20% difference in interval change 13 14 11 Number of PN with concordant disease status assessment 14 14 12 NCI-3DQI—NCI-MEDx Difference in % change

Median (range)—% −2.3

(−11.2 to 11.2)

P = .60 3.3

(−11.0 to 12.4),

P = .095 −1.1

(−8.2 to 20.5)

P = .60 Largest discrepancy in interval change—% (PN ID) 65.7 vs 54.5

(PN15) 27.0 vs 14.5

(PN3) 109.9 vs 89.4

(PN15) Number of PN with <20% difference in interval change 15 15 14 Number of PN with concordant disease status assessment 13 13 13 MGH-3DQI—NCI-MEDx Difference in % change

Median (range)—% −0.4

(−31.2 to 26.4)

P = .68 2.0

(−45.9 to 14.4)

P = .39 −1.5

(−58.7 to 28.0)

P = .64 Largest discrepancy in interval change—% (PN ID) −10.5 vs 20.7

(PN11) 75.2 vs 121.1

(PN14) 180.5 vs 239.1

(PN14) Number of PN with <20% difference in interval change 13 14 11 Number of PN with concordant disease status assessment 12 12 12

MGH, Massachusetts General Hospital; MRI, magnetic resonance imaging; NCI, National Cancer Institute; PN ID, plexiform neurofibromas identification.

In large tumors, absolute volume differences tend to be greater, but in proportion to their size smaller lesions can have more measurement discrepancy; therefore, we provide both the numeric and relative differences. The volume differences were calculated by subtracting one volume from the matching other, as listed in the header, and ranged from −781.9 mL (PN15, MGH3DQI vs NCI-MEDx, time-point 3) to 406.0 mL (PN1, MGH-3DQI vs NCI-3DQI, time-point 2). Relative volume differences were calculated using the absolute volume differences between the matching pairs (irrespective of negative or positive values), and comparing to the mean of the same pairs. PN ID refers to the lesion identification as listed in Table 1 .

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Discussion

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Supplementary Data

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Figure S1

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Figure S2

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Figure S3

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References

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Volumetric MRI Analysis of Plexiform Neurofibromas in Neurofibromatosis Type 1

Objectives

Methods

Results

Conclusions

Introduction

Methods

Patients

MRI Acquisition

Image Analysis

Statistical Analysis

Results

Discussion

Supplementary Data

References

Further Reading

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