We reviewed 59 patients (48 males and 11 females) who had primary or metastatic hepatobiliary cancer (liver, bile duct, and gallbladder) and underwent radiotherapy using the SDX system with normal lung function from May, 2014 to March, 2018. Among these 59 patients, we initially excluded 17 patients with only the data either from CBCT alignment or from vertebral alignment. The remaining 42 patients were eligible for the following two analyses. Twenty-three patients were analyzed to compare the correlation between CBCT and two alignment methods (vertebra and stent) on orthogonal images. Twenty-eight patients with either stent or embolized materials (lipiodol) were eligible for the analysis of body related factors. Flow chart of the recruited patients is shown in Figure 1. Patient characteristics are listed in Table 1.
2.2 SDX system
The SDX system (SpiroDynr’X system®, Muret, France) was used in simulation and radiotherapy for patients with computer-controlled voluntary breath hold. The system includes the SDX module, video goggles, utility module, calibration syringe, laptop, and SDX software. The SDX module is comprised of a sensor connected to a mouthpiece and spirometer. Patient feedback can be set by using nose clips to force breathing from the mouth, and video goggles allow the patient to watch their own spirometry pattern to improve breath holding.
2.3 Simulation and preparation
All patients were immobilized with vacuum cushions, and underwent computed tomography (CT) simulation using a Philips Brilliance Big Bore CT (Philips, Eindhoven, Netherlands) for treatment planning. When the CT images were acquired, patients were asked to inhale to reach the predefined range and then hold the breath. The target volume and organs at risk were contoured and planned using the EclipseTM (V13.0, Varian Medical Systems Inc., Palo Alto, CA, USA) treatment planning system.
The BHLs of deep inspiration were practiced and determined in simulation. When patients used the SDX system for the first time, they breathed freely through the spirometer until being instructed to take a full inspiration in order to determine the inspiratory capacity; they did these three times to assure the reproducibility of breathing patterns. The BHL was defined as 85% of the maximum inspiratory capacity to ensure the patient’s tolerance to complete multiple breathing cycles during fractionated radiotherapy [17, 18]. Inspiration zone (breath-hold range) was defined as the BHL + 0.1 L (Supplementary Figure 1A).
2.4 Radiotherapy with image guidance
The linear accelerator used for radiotherapy was the TrueBeam system (Varian Medical System Inc., Palo Alto, CA, USA), with 6 MV or 10 MV photons. The kV-orthogonal images (75 kV, 200 mA, 25 ms and 95 kV, 200 mA, 200 ms) or cone-beam (CB) CT (125 kV and 264 mAs) were taken before each treatment using Varian’s On-Board Imager® (OBI) system to confirm the accuracy of position, and the treatment couch was immediately adjusted to correct for the positional errors (Figure 2). With the longer time required to take CBCT, some patients were not able to hold their breaths for acquiring CBCT. In comparison, kV-orthogonal images, which took shorter acquisition time, were technically applicable and more frequently used in our patients. Generally, the kV-orthogonal images were more frequently obtained than CBCT for the best acquisition in a single breath hold. CBCT was needed when the alignment of the treated targets required the structural information inside the liver, especially in patient with no placement of fiducial markers. For the treatment session, the breath-hold range was displayed on the SDX module and patients started taking a breath to reach the BHL (Supplementary Figure 1B). Patients needed to maintain breath-holds for at least 25 seconds with the same inspiratory volume every time, for radiation dose delivery and image acquisition.
2.5 Analysis of the accuracy of different image-guided alignment markers
In each fraction of treatment, acquired CBCT or orthogonal kV images were compared with the planning images for the alignment and the inter-fractional positional errors by a qualified radiation oncologist. The inter-fractional positional errors were recorded in the anterior-posterior (AP), cranial-caudal (CC), and right-left (RL) directions. The shifts derived from CBCT alignment were used as baseline, and Pearson’s correlation coefficient was calculated to compare the accuracy of using different alignment markers on kV-orthogonal images (Figure 3).
2.6 Statistical analysis
This is a retrospective analysis of a patient cohort for DIBH in hepatobiliary radiotherapy. Each breath-hold value of patients during their treatment was collected. The BHL variation (ΔBHL) was defined as the standard deviation in difference between each breath-hold value and the baseline BHL. Mean BHL was defined as the average of each patient’s BHL during treatment. A total of 239 kV-orthogonal images by OBI system were analyzed for positional errors based on the stent/lipiodol position close to the tumor in the AP, CC, and RL directions. Patients were divided into two groups by the cutoff value close to mean BHL or ΔBHL to compare the position shifts. Body weight and height of patients were measured on the simulation day. IBM SPSS Statistics version 22.0 software (IBM Corp., Armonk, NY) was used for Pearson correlation analysis. Data were presented as the mean ± standard deviation for the indicated metrics. Differences between pairs of physique group were tested using the Student’s t-test, and a p value less than 0.05 was considered statistically significant.