Dosimetric study of three‐dimensional static and dynamic SBRT radiotherapy for hepatocellular carcinoma based on 4DCT image deformable registration

Abstract The purpose of this work was to determine the actual dose received by normal tissues during four‐dimensional radiation therapy (4DRT) composed of ten phases of four‐dimensional computer tomography (4DCT) images. The analysis was performed by tracking the hepatocellular carcinoma SBRT. Data were acquired from the tracking of each phase with the beam aperture for 28 hepatocellular carcinoma patients, and the data were used to generate a cumulative plan, which was compared to a three‐dimensional (3D) plan formed from a merged target volume based on 4DCT images in a radiation treatment planning system (TPS). The change in normal tissue dose was evaluated in the plan using the parameters V5, V10, V15, V20, V25, V30, V35, and V40 (volumes receiving 5, 10, 15, 20, 25, 30, 35, and 40 Gy, respectively) in the dose‐volume histogram for the liver; the mean dose was analyzed for the following tissues: liver, left kidney, and right kidney. The maximum dose was analyzed for the following tissues: bowel, duodenum, esophagus, stomach, and heart. There was a significant difference in the dose between the 4D planning target volume (PTV) (average 115.71 cm3) and ITV (169.86 cm3). The planning objective was for 95% of the volume of the PTV to be covered by the prescription dose, but the mean dose for the liver, left kidney and right kidney had an average decrease of 23.13%, 49.51%, and 54.38%, respectively. The maximum dose for the bowel, duodenum, esophagus, stomach, and heart had an average decrease of 16.77%, 28.07%, 24.28%, 4.89%, and 4.45%, respectively. Compared to 3D RT, the radiation volume for the liver V5, V10, V15, V20, V25, V30, V35, and V40 using the 4D plans had a significant decrease (P ﹤ 0.05). The 4D method creates plans that permit sparing of the normal tissues more than the commonly used ITV method, which delivers the same dosimetric effects to the target.


| INTRODUCTION
Radiotherapy for inoperable primary and metastatic hepatocellular carcinomas has become feasible with three-dimensional radiation therapy (3DCRT) treatment planning and treatment delivery.
Liver radiotherapy remains challenging because of respiratory motion. 1 Four-dimensional computed tomography (4DCT), developed for radiotherapy treatment planning, is a dynamic volume imaging system for moving organs with an image quality comparable to that of conventional CT. 2 In recent years, 4DCT techniques have been used in clinical RT practice for hepatocellular carcinoma SBRT and other cancers, and they have shown promising results. The conventional 3D plans can result in geometric misses and include excess normal tissues. Thus, using 4DCT-based individualized internal target volume (ITV) for hepatocellular carcinoma plans can reduce the target volumes to spare more normal tissues and allow less off-target dosing compared with 3D plans. [3][4][5][6] A new technique of target tracking to specifically manage the detrimental effect of respiration on the delivered dose distribution has arisen in recent years. In 4D radiotherapy, the treatment plan is designed on each 4D CT image set (i.e., 4D treatment planning), and radiation is delivered throughout the patient's breathing cycle (i.e., 4D treatment delivery), which ensures adequate coverage of the tumor target without increasing the treated volume. However, the distinction in possible benefits between the two strategies may not be clear. Based on the assumption that each strategy is designed to achieve target coverage, it would be useful to know the relative difference in normal tissue dose provided by the two strategies. For a given patient, we want to determine the difference in liver dose among the strategies, assuming the delivery with the motion management strategy in question is ideal and without error. To achieve this aim, we evaluated the cumulative target tracking dose plans and 4DCT-based individualized ITV for hepatocellular carcinoma methods. Radiation-induced liver disease (RILD) is one of the most important treatment-related complications in the reports of hepatic irradiation. Dosimetric analysis has shown a correlation between dose-volume parameters and the risk of RILD. The purpose of this study was to define the potential impact of dosimetric differences in 3D and 4D planning for patients with hepatocellular carcinoma and to estimate the normal tissue complication probability (NTCP) of RILD.

2.A | Patients
We included 28 patients with pathologically proven HCC. These patients were randomly selected from a list of patients who were treated in our hospital between March 2010 and January 2018.
There were 12 women and 16 men with an average age of 56 years (age range: 52-60 years). Systems, Palo Alto, CA). The patients were immobilized with a vacuum pillow with their hands above their head. The CT scanning region extended from 4 cm above the upper edge of the diaphragm to 4 cm below the lower edge of the right kidney, with a 3-mm reconstruction slice thickness. These 4D CT data sets were comprised of a total of 28 CT scans per patient, taken at equally spaced intervals across the entire respiratory cycle (phase-based sorting in 4D CT reconstruction) 7 .The 4DCT images were transmitted to the  normalized the plan so that the 95% volume of PTV achieved the prescribed dose in the Eclipse 13.6 vision TPS. ③ The dose constraints for OAR were as follows: the mean dose to the normal liver was limited to 23 Gy, and the dose-volume histogram (DVH) of the normal liver was within the tolerance area (i.e., V5 < 86%, V10 < 68%, V20 < 49%, V30 < 28%, and V40 < 20%) 8   The dose for the left and right kidney and the maximum dose for the bowel, duodenum, esophagus, stomach, and heart were evaluated. Evaluation parameters for the 4D plan were the same as the 3D plan.  Table 2 shows dosimetric changes of OARs for ten cases using the 3D and 4D plans. Table 3 shows the radiation volume for the liver V5, V10, V15, V20, V25, V30, V35, and V40 when using the 3D and the 4D plans (P ﹤ 0.05).

| DISCUSSION
Our findings suggest that the 4D planning method is an effective means of treatment; it has features that make it superior to the 3D ITV method, which currently is the most common strategy implemented clinically to compensate for respiration-induced target motion. Essentially, the 4D plan method uses a smaller PTV, while using a similar target dose distribution of the planning CT. Because the 4D planning method accounts for the effects of respiratory motion by adjusting the dose within the target, the margin can be reduced relative to that in the ITV method plan, leading to less offtarget dosing of normal tissues. 10 Most centers have the ability to acquire 4D CT images, but they do not have the ability to perform 4D radiation delivery. Instead, 4D CT images are primarily used to define the ITV, which is essentially the envelope needed to enclose the target as it moves throughout the breathing cycle. The major tasks in 4D-RT are fundamentally the same as those that are currently in practice for 3D-RT. The workflow involves the key tasks of image acquisition, target delineation, and treatment planning and delivery. However, the process can be significantly more involved in its most explicit implementation.
To estimate a realistic dose delivered to the patients in the presence of respiratory motion, a four-dimensional dose calculation (4D dose) using DIR of 4DCT images has been studied. [11][12][13][14][15][16] In this study, we performed a 4D dose calculation. The 4D dose delivered to the target volume and normal organs during free-breathing RT for hepatocellular carcinoma was calculated using hybrid DIR for all phase images from 4DCT with the Finite Element Model. The goal was to evaluate the relative difference in the liver dose between an ideal implementation of the strategy and a 3D plan dose based on ITV of 4DCT. Differences were found between the 4D target tracking dose and the 3D dose. Based on these results, we can conclude that this difference was due to the movement itself. As expected, the strongest factor of producing a relative difference in liver dose was the amplitude of tumor excursion into respiration. The target tracking dose is delivered throughout the breathing cycle. The larger volume of the liver at the end of expiration has been shown to reduce the dose to the liver for a given beam aperture. 11,[17][18][19][20][21][22] In MIM Maestro, a rigid registration is initially applied, which is followed by a nonrigid registration. In this study, the rigid registration was defined automatically using the whole body as a starting point of the ROI for deformation. Nonrigid registration was performed using the intensity-based FFD algorithm. If the respiratory tumor motion is large, the DIR system needs to perform a large deformation to match the two images. However, in the current study, the magnitude of the respiratory motion is low. So, the accuracy of deform performed using our specifically 4DCT study. 23,24 The process of dose accumulation in this study was as follows: First, the corresponding dose distribution was obtained by designing the plan on 0% phase of 4DCT images, With the development of these technologies, the implementation of real four-dimensional radiotherapy will become possible soon.
The purpose of this study is to evaluate whether the four-dimensional plan to design process can spare the normal tissues more than the commonly used ITV method of the implementation of 4D therapy, thereby reducing cumulative dose in the implementation of 4D therapy, indirectly improving the therapeutic effect, and improving the operability of clinical application of 4D radiotherapy. This study is based only on dosimetric studies. However, how to achieve fourdimensional radiotherapy still faces many challenges. technology, and so on. [25][26][27] The free form deformable registration algorithm is used in the registration algorithm between different phases of 4DCT, which has strong robustness to image noise due to its deformation constraints.  Note: Statistically significant differences (P < 0.05).

| CONCLUSION
The 4D method is an effective and practical way to design treatment plans for tumors subject to respiratory motion. The 4D planning method has better targeting, which spares the normal tissues more than the commonly used ITV method, all while delivering the same dosimetric effects to the target.

CONF LICT OF I NTEREST
The authors declare no conflict of interest.