The first internal electromagnetic motion monitoring implementation for stereotactic liver radiotherapy in China: procedures and preliminary results

Respiratory motion may compromise the dose delivery accuracy in liver stereotactic body radiation therapy (SBRT). Motion management can improve treatment delivery. However, external surrogate signal may be unstable and inaccurate. This study reports the first case of liver SBRT based on internal electromagnetic motion monitoring (Calypso, Varian Medical Systems, USA) in China. The patient with a primary liver cancer was treated with respiratory-gated SBRT guided by three implanted electromagnetic transponders. The treatment was carried out in breath-hold end-exhale with beam-on when the centroid of the three transponders drifted within 5 mm (left–right (LR), anterior–posterior (AP) and cranio-caudal (CC) directions) from the planned position. The motion monitoring treatments were delivered in breath-hold end-exhale mode with the energy of 6 MV in FFF mode with 1200 monitor units (MU) per minute. For each fraction, QA results, intertransponder distances, geometric checks as well as tumor motion logs were explicitly recorded. Comparing with the plan data, distance variances between each two transponders were − 0.56 ± 0.32 mm, 0.17 ± 0.33 mm and − 0.82 ± 0.68 mm. Geometric residual, the pitch, roll and yaw angles were 0.48 ± 0.21 mm (threshold 2.0 mm), 2.17° ± 1.85° (threshold 10°), − 2.42° ± 1.51° (threshold 10°) and 1.67° ± 1.07° (threshold 10°), respectively. The delivery time of the five fields were 13.8 s, 13.1 s, 11.2 s, 11.6 s, and 11.6 s with the average value of 12.3 ± 1.1 s. Treatment duration of each fraction ranged from 6.2 to 21.4 min, with the average value of 11.3 ± 5.0 min. The first case of liver SBRT patient of China based on internal electromagnetic motion monitoring was performed. The system had a high tracking accuracy, and it did not delay the treatment time. In addition, the patient did not show any severe side effects except for grade I myelotoxicity. The internal electromagnetic motion monitoring system provides a real-time and direct way to track liver tumor targets.


Introduction
Due to large and irregular respiratory movements, motion management is still a challenge for stereotactic liver radiotherapy. It is reported that liver can move up to 3.5 cm and even 7.5 cm due to normal and deep inspiration (Fernandes et al. 2015;Kirilova et al. 2008;Shimohigashi et al. 2017;Colvill et al. 2020). Besides, liver motion also includes its deformation, patients' inconsistent motion pattern between treatment fractions, making it more challenging for liver radiotherapy treatments.
Nowadays, cone beam computed tomography (CBCT) and magnetic resonance imaging (MRI)-guided treatment technologies have been deployed on linear accelerators (linacs) for image-guided radiation therapy (Sweeney et al. 2012;Lagendijk et al. 2014;Velec et al. 2019). However, liver targets are not typically distinct based on X-ray technologies. Furthermore, CBCT could result in excess radiation dose to the patient (Li et al. 2018;Quinn et al. 2011). In consideration of avoiding excessive dose, CBCT are often applied for localization rather than continuous tracking. Although MRI-guided treatment technologies can provide continuous tracking without excessive imaging dose, such systems are very expensive and thus hinder their extensive application (Herrmann et al. 2019).
In recent years, many motion management technologies have been developed for tumor radiotherapy, such as Active Breathing Coordinator™ (ABC, ELEKTA, Sweden) (Brock et al. 2011), Real-time Position Management™ (RPM, Varian Medical Systems, USA) (Lee et al. 2014), Optical Surface Management System (OSMS, Varian Medical Systems, USA) (Ma et al. 2018), etc. All these methods are noninvasive (external) approaches to track inspiratory change or in vitro optical markers as surrogates for the tumor position. External motion monitoring is readily accessible and can automatically halt (gating) the treatment if external markers' movements exceed the preplanned thresholds. However, the correlation between external and internal motion is unstable, and sometimes the external monitoring can be inaccurate (Ge et al. 2013;George et al. 2006). Therefore, it is optimal that gating directly relies on internal motion monitoring, and the necessity for direct internal movement monitoring has become essential.
Recently, an internal electromagnetic motion monitoring system (Calypso, Varian Medical Systems, USA) has been developed, which is a real-time and direct approach to localize and track targets in prostate cancer (Li et al. 2007;Kupelian et al. 2007), lung cancer (Sawant et al. 2009;Montanaro et al. 2018) and pancreatic cancer (Shinohara et al. 2012), etc. This system received Conformité Européenne marking and US Food and Drug Administration clearance for general implantation in soft issues in 2014. Thereafter, the first case of liver motion management radiotherapy based on this system was deployed at University of Louisville in March 2015 (James et al. 2015(James et al. , 2016, and the first clinical experience including accuracy of dosimetry and geometry were reported from Aarhus University Hospital in April 2015 (Poulsen et al. 2015). High dosimetric accuracy and benefits for liver stereotactic body radiation therapy (SBRT) based on this system were successively reported in the last decade (Bertholet et al. 2018;Worm et al. 2018;Skouboe et al. 2019).
It seemed that, because of low popularity rate of this system, invasive puncture and ignorant selection of appropriate patients, there was no liver SBRT case reported in China since this system appeared. In consideration of challenges in liver radiotherapy and advantages of this tracking system, we attempted to implement this system for motion management of liver treatments. To our knowledge, we are the first institution to use this system for liver radiotherapy in China. In this paper on our first experiences, a summary medical physics report for the first one liver radiotherapy based on this system was given. Operation procedures and a homemade motion tracking video signal synchronizing device were also elaborately described.

The patient
Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article. The patient was a 44-year-old male and diagnosed with liver cancer in 2012. Since then, he received 20 times of interventional therapy and 4 times of microwave treatment. In addition, he has also taken adefovir dipivoxil and entecavir for anti-hepatitis B virus therapy since 2017. The patient is healthy before, and has no history of heart disease or hypertension, no allergy history of food and drugs, no operative history and no disease history in other system. In March 2019, a routine medical examination report showed that he had 3.3 ng/mL AFP and 2.74 ng/mL CEA. An epigastric CT examination indicated that a possibility of lesions in lower left inner lobe of liver. Then, the patient considered receiving a radiotherapy treatment for a primary liver cancer (CTV: 25 cm 3 ).

Transponders implantation, fixation and CT scanning
The transponders are elliptic cylinders with a frequency of 25 Hz, an 8.7 mm length and a 1.3 mm diameter, and were implanted into the patient's body by 17G needles as shown in Fig. 1C and D.
Guided by CT simulator, three electromagnetic transponders were implanted percutaneously with 17G needles in close proximity to the target. They were implanted around (at the top, side and bottom of) the PTV to make sure the centroid could locate inside the CTV or PTV. The internal electromagnetic motion management is working in a direct way by monitoring the real-time signals transmitted by the beacons.
A breath-hold end-exhale scan and a free-breath scan, both with 1 mm slice thickness, were acquired 5 days after transponder implantation. An in-house developed vacuum cushion was used for patient immobilization and no abdominal compression was applied.

Treatment planning
CT positioning, tumor and organs at risk contouring were the same as regular processes. The slice thickness of CT images should be in the range of 1.0-1.5 mm to ensure that the beacons would not be lost in adjacent image slices. Prior to planning, beacons were found and marked by the "Calypso Beacon Detection" function in the Contouring Module (Eclipse 13.6, Varian Medical Systems, Inc. USA) (Fig. 2).
The planning target volume (PTV) was formed by expanding the CTV by 5 mm margins in the left-right (LR), anterior-posterior (AP) and cranio-caudal (CC) directions. The plan was a five-field intensity modulated radiation therapy (IMRT) with a mean dose of 100% of the prescription dose cover 95% volumes of PTV. That is, the plan was normalized to meet the requirement that 95% volumes of PTV should receive at least 100% of the prescription dose. Fraction dose of 4 Gy with 12 fractions were prescribed to the 100% dose level. All three transponders were marked in the plan, and their center-of-mass position was recorded as the isocenter.

QA and delivery
Prior to every fraction treatment, a QA test was made to keep the accuracy of the tracking system isocenter. The QA fixture is a white cube block containing 3 beacon transponders for performing the QA procedure, and the array is a plate placed above the fixture or the patient for tracking the beacons movements inside the patient's body.
To ensure proper operation of the system, QA procedures must be performed daily. The QA procedures in this article were done by the QA fixture (Fig. 3, Left). Subsequently, distance offsets of the measured position of the QA fixture isocenter from the calibrated isocenter positions in the lateral (left-right), longitudinal (inferior-superior) and vertical (anterior-posterior) directions were recorded. Finally, the isocenter offsets were calculated by the following equation: where x, y and z mean the offsets in the lateral, longitudinal and vertical directions, respectively. The isocenter offsets must be less than or equal to 2 mm to ensure the QA procedure to pass. After the patient and array setup were done, the system detected the intertransponder distances inside the patient's body prior to dose delivery. The motion monitoring treatments were delivered in breath-hold end-exhale mode with a VitalBeam Linac equipped with the tracking system. The energy was 6 MV in FFF mode with a dose rate of 1200 monitor units (MU) per minute.
A home-made tracking video signal synchronizing device was equipped to transmit the video signals of the internal electromagnetic motion, OSMS (Optical Surface Monitoring System) and RPM (Real-time Position Management) from the control room to the treatment room via a three-channel switch. In this study, the video signal of the Calypso was transmitted to the treatment room and shown in front of the patient. The patients could observe his/her own motion signal and stabilize his/her respiratory movements simultaneously to adjust motion deviations towards zero.  Supplementary Information) is the flowchart of implementing the internal tracing system for liver radiotherapy. Figure 1 shows the comparison of CT images of the same patient by a free-breath scan and a breath-hold end-exhale scan. Figure 2 shows the planning and DVH results. Table S1 (in Supplementary Information) summarizes the mean and max doses for CTV, PTV, Liver and Spinal Cord.

Figure S1 (in
By summarizing the 12 times of QA test results, it was shown that the tracking system has 1.08 ± 0.26 mm, − 0.54 ± 0.37 mm and 0.8 ± 0.27 mm offsets in the lateral, longitudinal and vertical directions, respectively ( Table S2 in Supplementary Information). The isocenter offset, which was determined by the above three offsets, was 1.52 ± 0.24 mm.  Supplementary Information) shows the intertransponder distances offsets of the measured positions from the distances in the plan. Comparing with the plan data, distance variances between each two transponders were − 0.56 ± 0.32 mm, 0.17 ± 0.33 mm and − 0.82 ± 0.68 mm. Subsequently, positions of the three transponders determined the target positional deviations, including the geometric residual (0.48 ± 0.21 mm, threshold 2 mm), the pitch (2.17° ± 1.85°, threshold 10°), roll (− 2.42° ± 1.51°, threshold 10°) and yaw (1.67° ± 1.07°, threshold 10°) angles (see Table S4 in Supplementary Information for each fraction).
In the breath-hold end-exhale periods, motion amplitudes were reduced from 3.8 mm (1.2-4.0 mm) to 0.6 mm (− 2.5 to − 1.9 mm) in the LR direction, from 8.8 mm (− 1.0 to 7.8 mm) to 2.5 mm (− 5.0 to − 2.5 mm) in the IS direction and from 11.7 mm (− 2.8 to 8.9 mm) to 1.9 mm (− 4.0 to − 2.1 mm) in the AP direction (Fig. 4 C and D). For the sake of investigating how much the tracking system could affect the treatment time, delivery time for each field and treatment duration for each fraction were recorded. The delivery time of the five fields were 13.8 s, 13.1 s, 11.2 s, 11.6 s, and 11.6 s with the average value of 12.3 ± 1.1 s (Fig. S2A, Supplementary Information). Treatment durations of each fraction were also recorded from the beginning to the end of the tracking (Fig. S2B, Supplementary Information). The durations were ranging from 6.2 to 21.4 min, with the average value of 11.3 ± 5.0 min. Due to CBCT scan, image registration and couch shifts, durations of the last two fraction were about 20 min.

Discussion
First, a thorough literature search was carried out with respect to the keyword "calypso & radiotherapy" via the Web of Science. It was found that only three articles were reported by Chinese institutions. Two of them were talking about the accuracy evaluation (Dai et al. 2018(Dai et al. , 2019, and the third was focusing on algorithms comparison for localizing prostate tumor (Zheng and Dai 2013). All of them were medical physical researches rather than clinical experiences. Therefore, based on the aforementioned literature search, it can be concluded that we are the first institution to utilize internal tracing system for precise liver radiotherapy in China. The first implement of internal motion monitoring for liver treatment in the world was carried out in March 2015, and the first paper was published in April 2015 by two different groups.
The main processes of using this system are the same as the regular radiotherapy except for CT-Guided beacon implantation, beacon marking, etc. The main differences to regular radiotherapy are that beacons for tracking must be implanted before CT positioning, and then, the beacons are tracked during the treatment. Apart from that, QA and array setup must be done prior to tracking and treatment to make sure the setup offsets distributing in an acceptable range.
The liver of this patient has a movement of up to 2 cm which is a big challenge for non-motion managed radiotherapy. Although respiration management techniques such as ABC and RPM were utilized for assisting precise radiotherapy, these were all performed indirectly. Since this was the first patient who received the Calypso treatment in our hospital, the treatment plan was carefully designed. Firstly, the maximum dose was constrained to below 115% in case of off-target risks during treatments. Secondly, five-field rather than more fields were used for the IMRT plan for the sake of less normal liver dose receiving and easier dose delivery. Thirdly, for safety considerations, dose constrains of the plan were following regular IMRT rules rather than SBRT ones. The 100% isodose line has a good conformity with regard to the PTV. This can be attributed to that the PTV's approximately spherical shape. Mean doses for CTV and PTV have reached the prescription. Mean dose for liver and max dose for spinal cord were in a safe range. Besides, max dose for CTV is lower than that of PTV, indicating that the max dose point located in PTV rather than CTV. This may be attributed to that, in the optimization step, constrains were only given to PTV and no constrains were applied to CTV. As the dose was delivered in a breath-hold end-exhale phase, it can be assumed that it is still safe for the patient.
The QA results indicated that the tracking system was considerably stable during the 12 fractions, which ensured the isocenter stability for the subsequent patient and array setup. The transponders' positional variances were very small in the liver and guaranteed the accuracy of target tracking. Geometry check results indicated the target was located in the correct positions which was beneficial to the following treatments.
During the tracing procedure, the available time for dose delivery is very short, as shown in the light gray areas of Fig. 4A. The reason is that there was a gating interlock to control the beam-on and -off and only the end-exhale phases were used for dose delivery. In practice, therapists saw the liver tumor motion in real-time. That is, when the patient was exhaling, curves of three directions were moving towards 0. Then, therapists told the patient to hold the breath using the talkback system. It is expected that using the end-exhale phases and observing the tracking curves, doses could be precisely delivered.
Although breath-hold end-exhale could favor high dose delivery and reduce the overall treatment time, it is still a challenge for elder patients. Figure 4B shows the third patient being treated in our hospital by the tracking system on 15th April, 2020, who was male with the age of 83 years. It is clearly seen that it is very hard for the patient to hold-breath during the beam-on cycle, and a big base-line drift could be seen in Fig. 4C. For the sake of a more stable motion during breath-hold period, a tracking video signal synchronizing device was designed to transmit the video signals of the internal electromagnetic motion, OSMS and RPM from the control room to the treatment room via a three-channel switch. As is shown in Fig. 4B, the patient could observe his own target motion curves by a mini screen which is connected to a VGA signal cable, and the screen displayed exactly the same motion curves as that of the screens in the control room. Thus, the patient could make the tracking signal more stable during the beam-on phase by adjusting his own breath motion. Using the video signal synchronizing device, it is clearly seen from Fig. 4D that the motion curves are more stable than that in Fig. 4C. In short, the video signal synchronizing device could give to more stable breath-hold phases, accurate treatment positions of the target and fewer treatment interruptions for each fraction.
The patient was keeping breath-hold for just five short time and was easily adapt to the treatment style in each fraction. Base lines in the short delivery time almost have no drifts (Fig. 4A). The tracking system did not notably lengthen the treatment time compared to the one without the system in our hospital. After the radiotherapy completed, the patient only showed grade I myelotoxicity and became better with symptomatic treatment before discharging from the hospital.

Conclusions
To our knowledge, we are the first institution to implement the internal electromagnetic motion monitoring system for motion management of liver radiotherapy in China. The system was stable during the treatments, had a high tracking accuracy, and it did not delay the treatment time. Geometry residuals and rotations could be maintained lower than 1 mm and 3°, respectively. A video signal synchronizing device was designed to reduce the respiratory motions in the range of ~ 2 mm. This system provides a real-time and direct way to track targets compared to other motion management techniques such as OSMS, RPM and ABC. In addition, introduction of the system to linacs did not bring about severe side effects to patients. It is hoped that our first experience and preliminary results can provide helpful reference to liver SBRT colleagues in not only China but also all around the world.