Chan M reported [9] that there was no significant difference between the use of 3 D CBCT and 4 D CBCT in liver radiotherapy. To reduce the CBCT scanning time, we used 3 D CBCT image guidance. Markus Oechsner reported [16]that AIP is more suitable for 3D CBCT than MIP. Bedos L et al. also believed that [13] CBCT was an average image and that registration with the planned AIP image can represent the patient's breathing pattern, so we used AIP as the reference image for registration with 3D CBCT images for liver SBRT. In the inter- and intra-fraction CBCT, the liver contour can be clearly displayed (Fig. 1), and the registration error of the two therapists (inter-observer error) was less than 1 mm in the ML, SI and AP directions (SD).
Our results showed that the liver position and the setup errors for the inter-fraction were considerable, and there was a significant correlation between the setup errors and the liver position errors. Meanwhile, the liver baseline drifts demonstrated large systematic and random errors in the ML, SI and AP directions, which were 1.25 mm and 1.64 mm, 6.12 mm and 4.57 mm, and 1.41 mm and 1.79 mm, respectively. Case RB et al. [10] found that in patients with free breathing, the systematic error and random error of the liver position baseline drifts in the ML, SI and AP directions were 1.5 mm/1.8 mm, 3.1/3.6 mm, and 1.6/2.7 mm, respectively. The error in the SI direction in that report was significantly smaller than ours. The main reason for this difference was that in that report, the patients planning used end-expiratory CT and the same respiratory phase CBCT image for registration. In our study, the free breathing average CBCT and AIP CT were used for registration. Dhont J reported [19] that the liver baseline drifts between inter-fractions were 1.6 ± 1.3, 3.0 ± 1.2 mm, and 2.1 ± 1.4 mm in the ML, SI, and AP directions, respectively.
In our study, the liver position errors and baseline drifts in the intra-fraction were significantly reduced compared to those in the inter-fraction, indicating that using CBCT to correct the liver position was effective. The baseline drifts in the ML, SI, and AP directions were 0.99/1.60 mm, 2.03/2.46 mm, 1.02/2.07 mm, respectively, similar to the Case RB report using CBCT (1.2/2.2 mm 1.4/3.0 mm 1.0/1.9 mm, respectively) [10]. Bedos L. et. al. [13]used a KV plain film to acquire the end-expiratory image to analyse the patient's intra-fraction errors and found that the 99% intra-fraction error in the SI direction was within 5 mm, which was smaller than in our study. However, the images were collected before the treatment beam was on, and the acquisition time was limited, which cannot represent intra-fraction errors. Another report showed that the medians (ranges) of the baseline drifts were 1.87 (0.06–12.04) mm, 0.35 (0-3.39)mm and 1 (0.02–7.21)mm in the SI, LR and AP directions, respectively [20]. However, this study defined the baseline as the average position in the breathing cycle during treatment. In our study, the baseline was defined in 4D CT, and the intra-fraction CBCT was used to evaluate intra-fraction errors. The average frame number of the intra-fraction CBCT was 467 frames, and the average acquisition time was 84.9 seconds, which can include approximately 20 breathing cycles. Xu Q et al. [21]used liver markers to evaluate the baseline displacement, and they found that the baseline displacement of ML, AP and SI were 2.1 ± 2.3 mm, 2.9 ± 2.8 mm, and 6.4 ± 5.5 mm, respectively. By using 4D CT as a reference, the baseline drifts were significant during treatment according to these reports and our findings. In other words, the vertebral bone cannot be used for position verification for liver SBRT due to the considerable liver baseline drifts.
CBCT using two-dimensional projections (fluoroscopy) can evaluate the stability of respiratory motion during the entire respiratory cycle. Dhont J et al. [19] used a single metal marker to analyse the SI direction of respiratory motion The amplitude change over 5 mm was 53% for the inter-fraction and 28% for the intra-fraction. Shimohigashi Y S et al. [22] reported that in using abdominal pressure, the average movement in the SI direction was 5.3 mm, and the maximum value was 14.8 mm. The medians (ranges) of the intra-fraction amplitude variation across all patients were 4.3 (1.6-6.0) mm, 0.5 (0.2–2.2) mm and 1.5 (0.3–3.3) mm in the SI, LR and AP directions, respectively [20]. In the current study, the variation of the respiratory motion amplitude among 4D CT, the inter-fraction CBCT and the intra-fraction CBCT in the SI direction was small (the average amplitude was 13.39 mm, 13.12 mm and 12.09 mm, respectively), indicating that the overall patient respiratory motion amplitude was relatively stable. However, for individuals, there was a large difference. The variation of the respiratory motion amplitude for the intra-fraction CBCT ranged from − 171.04–60.00%, and the overall difference was 1.03 ± 4.35 mm. In 69% of cases, the overall difference was less than 5 mm. However, because we only evaluated a single breathing cycle using fluoroscopy, this cannot represent the real respiratory motion state during the whole treatment process (it was a snapshot image like 4D CT). The respiratory motion amplitude and baseline may change during the treatment process, and this uncertainty was more obvious when the movement was greater than 7 mm [19]. Meanwhile, the report noted that the accuracy of the 4D CT phase classification according to amplitude was higher than that of the phase classification according to time [23]. Therefore, if 4D CT was used, the change in the motion amplitude and the baseline drifts should be completely evaluated and understood when determining the PTV margin.
Considering the baseline drifts, Dhont J et al. recommended the 8 mm PTV margin for liver [19].Worm ES et al. [24]reported that when the target area was delineated using 4D CT with moderate ventilation, a 10 mm PTV margin in the SI direction and 5 mm AP and ML directions should be used. Case RB [10] found that the patient's respiratory motion changed little during radiotherapy, and the results were not statistically related to the time of radiotherapy. Although there were large variations of the respiratory motion amplitude in our study, this cannot be a main reason to expand the PTV margin. Fortunately, the respiratory movement is a 3D movement around the baseline mainly in the SI direction. The baseline drift was a systematic error, which can induce a systematic dose deviation, and the amplitude changes were random errors, which can blur the dose around the target edge. Therefore, the baseline drift in the intra-fraction is the most important error when determining the PTV margin. According to the results in our study, the 5 mm PTV margin was sufficient in the ML and AP directions, but there needs to be a 6.80 mm PTV margin in the SI direction.
Since metal markers were not implanted in or near the tumour, the three-dimensional position deviation of the tumour cannot be analysed using two-dimensional projections. Therefore, implanted metal markers [25]or MR [3]should be used to obtain more soft tissue information and to further analyse the respiratory motion amplitude changes and baseline drifts. If we want to comprehensively analyse the variation of respiratory motion, we need automatic methods to evaluate the two-dimensional projections during whole treatments.