Table 1.
Patient characteristics.
Fig 1.
Flow diagram for the patient selection process.
Abbreviations; PBT: Proton beam therapy; HCC: Hepatocellular carcinoma; Gd-EOB-DTPA MRI: Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging; CT: Computed tomography; FLR: Focal liver reaction; v-TD: Visual-threshold dose; dFLR: destined FLR area.
Fig 2.
Gd-EOB-DTPA MRI scans showing changes in the irradiated HCC and the background liver after PBT.
On the follow-up Gd-EOB-DTPA MRI scan, FLR did not appear 1 month later in this case. The contours of the FLR were made manually on MR images at 3 or 6 months after PBT. The dFLR contour (50% isodose line in this case) is defined as the area irradiated at doses exceeding the TD at planning MRI and gradually shrinks to the FLR area at 3 or 6 months after PBT. HCC, white arrow head; dFLR contour, yellow; FLR contour, green line. Abbreviations; Gd-EOB-DTPA MRI: Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging; HCC: Hepatocellular carcinoma; PBT: Proton beam therapy; FLR: Focal liver reaction; destined FLR area: dFLR; TD: Threshold dose.
Fig 3.
Method for defining the TD for FLR using hepatobiliary phase Gd-EOB-DTPA MRI at 3 months after PBT.
The isodose lines were transferred onto each Gd-EOB-DTPA MRI. (a) The isodose lines are displayed as 50%, 40%, 30% and 20% lines. These dose lines were compared with the FLR contour on the planning MRI. (b) The medial dose line (45% line; brown) between the selected two doses (40% and 50% lines) was added. Finally, using these three isodose lines, the dose distribution contours that were most similar to the FLR contour were defined. In this case, TD was defined by the 45% dose line as 29.7 CGE. FLR contour, red (on the left side); 50% isodose line, red; 45% isodose line, brown; 40% isodose line, green; 30% isodose line, blue; 20% isodose line, yellow. Abbreviations; TD: Threshold dose; FLR: Focal liver reaction; Gd-EOB-DTPA MRI: Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging; PBT: Proton beam therapy; CGE: Cobalt Gy equivalent.
Fig 4.
Representative examples of the volume changes of the dFLR or FLR area at planning and on follow-up MRI (upper stage, cranial section; lower stage, caudal section).
The dFLR area including the HCC gradually shrank after PBT. dFLR area at planning (252 cm3), green; FLR area at 3 months (107 cm3), sky blue; FLR area at 6 months (72 cm3), red; HCC, yellow. Abbreviations; dFLR: destined focal liver reaction area; FLR: Focal liver reaction; HCC: Hepatocellular carcinoma; PBT: Proton beam therapy; v-TD: visual-threshold dose.
Fig 5.
Distribution of the prescribed dose (%) (a) and the threshold doses calculated using EQD2 (b).
Abbreviations; EQD2: Equivalent doses in 2 CGE fractions; CGE: Cobalt Gy equivalent; Fr: Fractions.
Table 2.
Threshold doses for focal liver reaction.
Table 3.
Fig 6.
Bland–Altman plot for the method comparison study (n = 24).
The small dashed line denotes bias (mean difference) and the large dashed lines denote 95% limits of agreement (2 SD of difference). Abbreviations; SD, standard deviation; FLR: Focal liver reaction.
Fig 7.
Volume change in the FLR as a function of time (months) after PBT.
The square plots (red) show the FLR volume relative to the volume at 3 months (V(1), V(3) and V(6) data), and the circles (black) with error bars denote the mean and the standard deviations of the volume. The solid and dashed curve show the mean value and one standard deviation the calculated result of Eq (1), respectively. The two direction arrow shows the range of dFLR calculated using the v-TD (refer to Table 2). The relative dFLR volume calculated from v-TD for 30% and 50% of the prescription dose were estimated to be 2.4±0.3 and 1.7±0.4, respectively, and were found to be similar (within the standard deviation) to the V(0) (cFLR) of Eq (1) rather than the value of a linear function. Abbreviations; FLR: Focal liver reaction; PBT: Proton beam therapy; Eq: equation; dFLR: destined focal liver reaction area; v-TD: visual-threshold dose; cFLR: calculated FLR.
Table 4.
The diversity of threshold doses for the focal liver reaction.