Cancer is a major public health problem worldwide, of which lung carcinoma is one of the most common types of malignant tumor, and is the leading cause of cancer death in China and USA in both males and females (1, 2). Multiple primary lung cancers (MPLC) were first proposed and described in 1920s (3). These represent an interesting subgroup of cancer cases which may occur after curative resection of bronchogenic carcinoma (4). Incidences were reported from 0.5% to 10% in lung cancers (4), and they may appear as unilateral or bilateral, synchronous or metachronous.

The feasibility of surgery was reported earlier (3, 4), but with the update of radiotherapy technology, more and more reports have been reported where radiotherapy was used in the treatment of MPLC, especially for inoperable patients. Federico et al. (5) believed that palliative radiotherapy could provide an acceptable symptom-free quality of life for synchronous bilateral lung cancer patients who may not be suitable for surgery in 2001, although with poor median overall survival. Loo et al. (6) suggested that intensity-modulated radiotherapy (IMRT) could be considered as an effective treatment for synchronous bilateral cancers, unfortunately from only one case with a Varian 2100EX linear accelerator system. Sinha et al. (7) believed that stereotactic body radiation therapy (SBRT) based on linac accelerator may be a possibly safe and potentially effective treatment option for individuals with bilateral lung cancers who were medically inoperable, by reviewing the outcomes of 10 patients.

In recent years, stereotactic body radiation therapy (SBRT) has been applied as a clinical treatment option in the treatment against some lung cancers (8–12). SBRT is characterized by the delivery of high doses of ionizing radiation in few fractions, which results in a higher biological effective dose (BED), and better tumor control probability (TCP) and lower normal tissue complication probability (NTCP). The radiotherapy equipment that can perform SBRT, which can be performed either with a traditional linear accelerator or a robotic arm (Cyber-Knife^®), would generally more accurately track the movements of tumors and take corresponding compensation methods, so SBRT should be more accurate than traditional radiotherapy (13–16).

With the invention of the Cyber-Knife (Accuray incorporated, sunnyvale, CA, USA), because of its powerful function such as the precise image-guided radiotherapy through a dual kV X-ray imaging system and the capacity for real-time monitoring tumors, which can be achieved with a Synchrony^Ⓡ system (17), it has been increasingly employed for SBRT of lung cancers (18, 19).

In clinical practice, the design of an SBRT plan for synchronous bilateral lung cancer can be implemented in two ways based on a Cyber-Knife system. One of them is to superimpose two targets into an overall target structure, and then complete the dosage optimization of two separate targets in only one plan, this optimization method is called single planning (Plan S); the other is to optimize the dosage of the two targets separately, which means that two plans need to be completed independently, and then superimpose the dosage of the two plans, this optimization method is called double plannings (Plan D). The authors have not found any comparative study on the dosimetry of Plan S and Plan D for synchronous bilateral lung cancer. Therefore, in this study, we aimed to compare the dosimetric and biological difference of single planning and double plannings for synchronous bilateral lung cancer SBRT planning based on Cyber-Knife, and hence provide reference for clinical practice.

The results showed that the dosimetry of the Planning target volumes (PTVs) and the OARs for synchronous bilateral lung cancer SBRT plans designed by both Plan S and Plan D could meet the clinical prescription requirements. The transverse section isodose line distribution of the two plans is shown in Figures 1A, B , it can be seen from the figure that different plans can well surround the target areas. However, for the isodose line of 40Gy, 25Gy, 10Gy, the Plan D tends to involve less tissue volume relative to Plan S, especially for the low-dose isodose lines (25Gy and 10Gy). Therefore, the Plan D would irradiate less normal tissues. We compared the two planning methods from the dosimetric and biological parameters, and the results were as follows.

The robotic arms of the Cyber-Knife system can focus radiation rays from different directions to the target areas, and it has accurate image-guided technology, and has advanced tumor tracking system Synchrony Respiratory (Accuray Inc.,Sunnyvale, CA), these functions all can be used to compensate for the effect of tumor movement due to breathing (29); Cyber-Knife can also use the optical imaging equipment to track the movement of external markers to predict the position of the tumor, guiding the radiation to the tumor (30); the equipped KV X-ray imaging system can realize real-time correction of positioning and treatment errors during the treatment process, and realize sub-millimeter-level high-precision treatment (31),the superior performance of Cyber-Knife enables it to meet the basic requirements of implementing SBRT technology. This study is based on the fifth-generation Cyber-Knife system that uses single planning (Plan S) and double plannings (Plan D) to design SBRT plans for synchronous bilateral lung cancer. The results showed that the dosimetry of both PTVs and OARs for synchronous bilateral lung cancer SBRT plans designed by Plan S and Plan D could both achieve the clinical prescription requirements. The results show that the dose distribution of PTV1 and PTV2 for Plan S and Plan D are similar, but the hot spots of PTV1 and PTV2 in Plan D are relatively higher. Regarding the CI, HI, GI values of the targets, the results show that the CI, GI values of the targets in Plan D are relatively smaller, while the HI value is relatively larger, which indicates that the Plan D has better dose conformity and the dose outside the targets falls faster, but the dose uniformity in the targets is relatively poorer. For the organs at risk(OARs), the results show that the combined lungs, heart, spinal cord, trachea, bronchus and esophagus have lower volume doses, indicating that Plan D can better protect normal tissues. The dosage of the OARs in Plan D is lower, this is mainly because the Plan D method is to optimize the dose separately for each target, the total number of radiation fields is larger and spatial freedom is greater, which can make the dose distribution better. As a result, the dose can be focused on the target areas, so Plan D can better protect the normal tissues compared to Plan S. According to the calculation results of the EUD, it can be found that the EUD values of the PTVs in Plan D is larger, and the EUD values of combined lugs, heart, spinal cord and esophagus are smaller, so the results indicate that the targets can receive a larger radiation dose and can better protect the normal tissues in Plan D. In this study, we have not found the suitable biological model parameter values for the trachea and bronchus, so their EUD values were not calculated in the article. Only ten patients with synchronous bilateral lung cancer were selected for prospective exploration in this study, so the number of sample is relatively small. And the biological model and model parameters of this study are based on the earlier studies, so the accuracy of the parameters of different tumors and normal tissues needs further research.

Both the dosimetric and biological results in this paper indicate that the Plan D approach in SBRT for synchronous bilateral lung cancer can better protect normal tissues and is relatively safer in clinical radiotherapy applications. Although Plan D shows safer advantages in both dosimetric and biological parameters, Plan D means that two plans need to be designed, which may result in more monitor units (MU) in the actual dose transmission, and more treatment time would be required in Plan D relative to Plan S. The Plan D may take 15 more minutes, and deliver 44 more beams in average than the Plan S. And Plan D approach may increase the complexity of quality assurance (QA) and quality control (QC). Since this study is based on the Cyber-Knife system to design SBRT plans for synchronous bilateral lung cancer, the actual treatment is to complete the irradiation in two separate plans for Plan D, so the Cyber-Knife can track and locate one tumor at a time, the accuracy of tumor location would be higher; for Plan S, the special algorithm of Cyber-Knife system makes it impossible to track the movement of two separate tumors at the same time, which may affect the accuracy of tumor positioning.

One of the advantages of Cyber-Knife is that it can perform image-guided radiotherapy effectively, so assuming that the pros and cons of the two planning methods are not considered from the perspective of dosimetry and biology, but only from the aspect of powerful image-guided function for Cyber-Knife, it is better to design SBRT plan with Plan D method for synchronous bilateral lung cancer. However, synchronous bilateral lung cancer in clinical practice is rare, when Cyber-Knife is used for SBRT treatment, it would mean longer treatment time and almost double radiotherapy costs for Plan D. Therefore, in order to improve the efficiency of treatment and reduce the cost of radiotherapy for patients, some Cyber-Knife radiotherapy centers may actually adopt the Plan S approach to design SBRT plans for synchronous bilateral lung cancer. Unfortunately, from the perspective of dosimetry and biology, this study has concluded that the Plan D method has more advantages in theoretical value than the Plan S method, in order to further provide dosimetric and biological theories and supports for adopting Plan D approach to design SBRT plans for synchronous bilateral lung cancer, this is also the purpose of the author to carry out the research.

In summary, the dosimetric and biological comparison between Plan S and Plan D based on Cyber-Knife for synchronous bilateral lung cancer showed that double plannings (Plan D) can better protect normal tissues, and it can ensure that the target volumes have enough dose distribution, therefore, it was suggested to design double plannings (Plan D) for synchronous bilateral lung cancer SBRT planning based on Cyber-Knife in clinical practice.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

XG, HS, FW, have contributed equally to this work and share first authorship. HZ and ZD have contributed equally to this work and share the corresponding authorship. All authors contributed to the article and approved the submitted version.

This study is sponsored by 234 discipline peak-climbing plan of First Affiliated Hospital of Navy Medicial University (2019YPT004). Shenzhen Postdoctoral Research Funds (25005), Basic and Applied Basic Research Foundation of Guangdong Province (2020A1515110335), Sanming Project of Medicine in Shenzhen (SZSM201612063) and Shenzhen Key Medical Discipline Construction Fund (SZXK013).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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