Abstract
Background/Aim: Suppression of respiratory movement is crucial for safe and effective stereotactic body radiotherapy (SBRT). SyncTraX FX4 is a novel device for synchronous respiratory irradiation. The purpose of this study was to evaluate the efficacy and toxicity of SBRT using SyncTraX FX4 for patients with lung cancer. Patients and Methods: Patients treated with SBRT using SyncTraX FX4 between November 2017 and August 2020 were included. In all cases, fiducial markers were inserted into the lung, and the total dose administered was 55 or 60 Gy, depending on the distance from the central region of the lung. Acute and late toxicities were reported, and local control, progression-free survival, cancer-specific survival, and overall survival were analyzed. Results: We evaluated 16 patients and 17 sites. The median follow-up period was 14.4 months. In both the acute and late phases, one patient experienced grade 3 radiation pneumonitis; however, grade 4 or higher toxicities were not observed. There was no local recurrence during the observation period, and the overall survival, cancer-specific survival, and progression-free survival at 2 years were 54.6%, 85.1%, and 33.7%, respectively. Conclusion: SBRT with SyncTraX FX4 can provide safe and effective treatment for lung cancer patients in poor condition.
- Lung cancer
- lung metastasis
- stereotactic body radiotherapy
- SyncTraX
- real-time tumor tracking system
- RTRT
- radiotherapy
In Japan, the number of deaths from lung cancer is increasing as the population ages, with over 75,000 deaths expected in 2019. Moreover, in 2019, lung cancer was the leading cause of cancer-related deaths in Japan (1).
In Japan, surgery is the standard of care for early-stage non-small cell lung cancer (NSCLC) treatment. However, this modality is sometimes medically impossible due to patient conditions, such as poor performance status (PS) and low respiratory function. In these cases, radiotherapy, especially hypofractionated stereotactic body radiotherapy (SBRT), is performed (2-4).
SBRT involves large doses of highly concentrated radiation therapy delivered in a small number of fractions over a short period of time. High doses improve the therapeutic effect against cancer, while damaging normal tissue and worsening adverse effects. Therefore, SBRT must be operated with high accuracy and precision. Nevertheless, studies have reported good clinical results of SBRT for early-stage lung cancer (4-7).
During SBRT, organs around the diaphragm, such as the lungs and liver, shift due to respiratory motion. To combat this movement, several methods of respiratory motion management, such as chest compression, deep inspiration breath hold, and real-time tumor tracking are used. These techniques are vital for SBRT but are often difficult for patients in poor condition (8).
We performed SBRT for lung cancer using SyncTraX FX4 (Shimadzu, Kyoto, Japan) the new respiratory gating radiotherapy system. SyncTraX FX4 is a real-time tumor-tracking radiotherapy (RTRT) system in which a fiducial marker is implanted in the body, and when the marker enters a previously specified position, the linear accelerator is granted permission for irradiation (Figure 1 and Figure 2). Compared to the conventional RTRT system, the SyncTraX FX4 allows fluoroscopy from four directions, and the flat panel detector provides a wide field of view, allowing for greater flexibility in treatment planning (9, 10). We hypothesized that this machine would allow the safe administration of SBRT, even in patients whose respiratory status is not stable. In this study, we aimed to clarify the clinical advantages and toxicities of SyncTraX FX4.
Patients and Methods
Patients. Patients treated with SBRT using SyncTraX FX4 between November 2017 and August 2020 were included in this study. In all cases, diagnosis and staging were performed using computed tomography (CT) and fluorodeoxyglucose positron emission tomography CT before treatment. Pathologic confirmation of malignancy was performed whenever clinically feasible and not refused by the patient. In cases where malignancy could not be proven pathologically, it was judged from images and clinical history. Operability was confirmed through multidisciplinary conference discussions with respiratory medicine, surgery, and radiology physicians, and radiation oncologists. Eligibility criteria for SBRT included an Eastern Cooperative Oncology Group PS of 0-2, good or moderate respiratory function evaluated before beginning radiotherapy, and a single lesion ≤5.0 cm in length with no metastasis outside the lungs.
SBRT planning and delivery. Respiratory gated SBRT was delivered through the combination of a general linear accelerator and an RTRT system. For the RTRT system, one to four disposable gold fiducial markers (Olympus, Tokyo, Japan) were implanted around the tumor using bronchoscopy as an internal surrogate marker of respiratory movement.
A planning CT scan was obtained at 2.5 mm intervals during the exhalation phase without an intravenous contrast agent at least two weeks after implantation of fiducial markers. To measure the respiratory movement of the tumor, we performed a 4-dimensional CT simulation for all patients. Patients were immobilized in the supine position with their arms up on a Vac-Lok Cushion (CIVCO Medical Solutions, Coralville, IA, USA). Target contours were delineated on CT upon expiration breath-hold. Treatment planning was performed using RayStation version 6.0 (Ray Search Laboratories, Stockholm, Sweden).
The clinical target volume (CTV) was created from the gross tumor volume with no margin added. The planning target volume (PTV) was created by expanding the CTV by 4 mm, which included a margin to account for the daily set-up variations and inaccuracy of SyncTraX FX4.
The goal of SBRT was to deliver 55.0 Gy in 4 fractions (fr) or 60.0 Gy in 10 fr. When the tumor was close to the central region of the lung (within 2 cm of the proximal bronchial tree), 10 fr were used. The dose that covered 95% of the PTV was used as the dose prescription. Dose constraints for organs at risk (OARs) were determined using the JCOG0403 study (11) and the conformity index presented by Paddick was used to evaluate the plan (12). SBRT was delivered using True-Beam STx (Varian Medical Systems, Palo Alto, CA, USA), using 6-8 static non-opposing, non-coplanar fields, with 6-10 MV flattening filter free (FFF) photons. On weekdays 4 fr of 13.75 Gy were delivered; the estimated biologically effective dose (BED10 Gy) was 130.6 Gy.
Before each treatment session, we used cone beam CT for position matching, and bone, tumor, vessels, bronchioles, and fiducial markers were used as indicators, followed by RTRT system localization. If the fiducial markers were displaced, we took a new planning CT and altered the treatment plan accordingly.
We defined the template from the fiducial markers on the planning CT. A template size of 24×24 pixels and a search area of 40×40 pixels was chosen to track and irradiate within ±2.0 mm of the center of the gold markers on the CT. Every time SBRT was initiated for each field, the image on fluoroscopy at the end of rest expiration was obtained.
The fluoroscopic conditions of the RTRT system consisted of a voltage of 100-120 kV and a current of 80-120 mA. The frequency of fluoroscopic image acquisition was 15 frames per second, and the dose rate of the 6 MV FFF treatment beam from True Beam STx was 600 monitor units per minute and that of 10 MV FFF was 1,200 monitor units per minute. Any intra-fractional baseline shift of respiratory motion was corrected before irradiation was initiated in each direction.
Follow-up and statistics. The primary endpoints of this clinical study were treatment-related acute and late toxicities. The secondary endpoints were local tumor control (LC), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Only LC were calculated per tumor lesion; others were calculated per patient. All patients underwent clinical examination and CT scans for evaluation of the treatment results and adverse events six weeks after SBRT, then every three months thereafter. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (13). Late adverse events were defined as those that appeared more than 3 months after SBRT, and acute adverse events were defined as those that appeared earlier. Acute and late toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (14).
We examined LC, PFS, CSS, and OS with their 95% confidence intervals (CIs) using the Kaplan–Meier method. Survival curves were generated starting from the time of SBRT. All analyses were performed using SPSS version 27.0 (IBM, Armonk, NY, USA).
Results
Patient characteristics. Patient characteristics are shown in Table I. In total, 16 patients and 17 sites were treated with SBRT using SyncTraX FX4. One patient received SBRT twice at different times for intrapulmonary recurrence. The median age was 82 years (range=62-90 years), and 15 patients were male. The tumors were classified as T1a, T1b, T1c, and T2a for 1, 3, 8, and 5 patients, respectively. The histology was squamous cell carcinoma, adenocarcinoma, and unknown in 3, 7, and 7 sites, respectively. All patients were deemed ineligible for surgery due to their medical history and general condition. The total dose and number of fractions were 55 Gy in 4 fr for 15 sites and 60 Gy in 10 fr for 2 sites. The median CTV and PTV were 5.6 cm3 and 13.0 cm3, respectively. The median percentage of lung volume outside the PTV irradiated with 5 Gy (lung-V5Gy) was 15.2% and the median lung-V20Gy was 3.1%. The median conformity index of the treatment plans was 0.86.
The median observation period was 14.4 months overall, and the median observation period for surviving patients only was 17.1 months. Eight deaths occurred during the observation period, three of which were due to the primary disease.
Tumor response. After SBRT, 2, 9, 5, and 1 patients experienced complete response (CR), partial response (PR), stable disease (SD), and unknown response, respectively. One of the patients died from another disease 1.9 months after the start of SBRT and was not assessed because he had passed before his first CT.
Among patients with lesions classified as T1 tumors, 2, 6, and 3 patients experienced CR, PR, and SD, respectively. Of those with T2 tumors, 0, 3, and 2 patients experienced the same respective responses. During the observation period, five patients experienced distant recurrence, while none of the patients experienced local recurrence.
Adverse events. The adverse events during the observation period are shown in Table II. These adverse events were counted for each time they were treated. In the acute phase, grade 1, 2, and 3 radiation pneumonitis was observed in 3, 1, and 1 patients, respectively. Meanwhile, in the late phase, grade 1, 2, and 3 radiation-associated pneumonitis was observed in 7, 0, and 1 patients, respectively. Of the eight patients who developed radiation-associated pneumonitis in the late phase, six did not recover from the acute phase; two were counted as having late adverse events because they had pneumonitis within the irradiated area over time, but not in the acute phase. No adverse events of grade 4 or higher were observed in either phase.
Home oxygen therapy was introduced in one patient in the acute phase and two patients in the late phase. Grade 1 pleural effusion was observed in one patient in the acute phase and five in the late phase.
Survival. OS, CSS, PFS, and LC at 1 and 2 years were 73.7% (95%CI=51.6-95.8%) and 54.6% (95%CI=26.2-83.0%), 85.1% (95%CI=83.2-87.0%) and 85.1% (95%CI=83.2-87.0%), 52.4% (95%CI=26.5-78.2%) and 33.7% (95%CI=6.5-60.9%), and 100% and 100%, respectively. The Kaplan–Meier curves for OS, CSS, and PFS are shown in Figure 3.
Univariate analysis was performed using patient characteristics (Table III). Patients with a PS of 0 tended to have longer OS, CSS, and PFS than those with a PS of 1, but the difference was not significant.
Discussion
The outcomes of SBRT have been reported in numerous prospective and retrospective studies. For example, in JCOG0403, a prospective study in Japan of patients with cT1N0M0 NSCLC treated with SBRT (11), the 3-year OS, PFS, and LC rates were 59.9%, 49.8%, and 87.3%, respectively, among patients with unresectable cancer. Among those with resectable cancer, the OS, PFS, and LC rates were 76.5%, 54.5%, and 85.4%, respectively. During the observation period, 15 patients experienced grade 3 adverse events, and 2 experienced grade 4 adverse events. Another trial, RTOG0915, was conducted as a global multicenter study to clarify the clinical outcomes of SBRT for unresectable cT1/2N0M0 NSCLC (7). RTOG0915 was a prospective, phase 2, randomized study designed to compare the clinical outcomes of 34 Gy in 1 fr and 48 Gy in 4 fr of SBRT. The 5-year OS rate in the 48 Gy in 4 fr group was 41.1%, and the PFS rate was 33.3%. Moreover, five patients experienced grade 3 adverse events during the observation period. In the current study, adverse events of grade 3 or higher were observed in three patients, which was comparable to the results of previous studies. However, the OS and PFS of our study were inferior to those of previous studies. This could be because the median age of patients in our study was 82 years, whereas that of JCOG0403 was 78 years and RTOG0915 was 75 years; the higher age in our study could have increased the number of deaths from other causes. In addition, all cases in this study were of unresectable cancer, which is consistent with the JCOG0403 study that showed poor clinical outcomes in unresectable cases. Additionally, Watanabe et al. found that elderly patients with unresectable disease had a significantly worse OS than those with resectable disease (11, 15). These factors may have resulted in worse OS despite good CSS and LC in this study.
JCOG0403 and RTOG0915 included respiratory migration measures as required. Similarly, other studies have used respiratory migration measures to make the irradiation field as narrow as possible or used a wide field to include all phases of tumor migration with respiration (5, 15-18). The ESTRO ACROP consensus guidelines provide an option of respiratory movement management for treatment devices, although its use is not mandatory (2). However, in practice, due to specific patient conditions, such as postoperative lung cancer and chronic obstructive pulmonary disease, gating according to the respiratory phase proves challenging because of the patient’s inability to breathe steadily for a long expiratory phase in some cases. In other cases, using free breathing, because the margin must be wide enough to allow the tumor to move with respiration and still be within the irradiation range, the wide irradiation field may lead to fatal radiation pneumonitis. In particular, lung cancer with fibrotic changes is known to have greater respiratory migration, requiring wider margins for effective treatment and potentially higher risk of more serious adverse events (19). SyncTraX FX4, on the other hand, can narrow the allowable range of marker position to a minimum of 4 mm per side, keeping lesion position error within 4 mm even under free breathing. Furthermore, it can automatically recognize errors in the marker directly during treatment and make a decision on whether or not treatment is possible in a short period of time. Thus, the accuracy of the treatment position can be increased to a very high level compared to the time of planning, and we were able to provide effective and safe treatment while narrowing the irradiation field of lung using SyncTraX FX4.
In this study, FFF was employed to deliver the dose as quickly as possible, reducing the radiation dose and patient burden. Jaruthien et al. reported on SBRT with 6-10 MV FFF for early-stage NSCLC or lung metastases (20). The study reported an OS rate of 83.3% and an LC rate of 88.9% for 26 patients with NSCLC; no severe adverse events of grade 3 or higher were observed, and the results were comparable to previous studies that did not use FFF. Moreover, Juliane et al. reported that the use of FFF significantly reduced the treatment time (21). Thus, FFF can have the same clinical effect as a flattening filter, while shortening the treatment time. The use of FFF is recommended when using SyncTraX FX4 because it reduces the radiation dose associated with fluoroscopy as well as the physical burden on the patient. At the time of this study, Japanese law prohibited the simultaneous use of diagnostic kV X-rays and therapeutic MV X-rays. Therefore, the dose rate was set so that only half of the original dose rate of FFF could be used. Now that the law has been revised to allow simultaneous irradiation, SyncTraX FX4 has been updated, and irradiation at the original FFF dose rate is expected to be possible.
The Vero-4DRT and CyberKnife with Synchrony systems are similar to the RTRT system. However, the critical difference between these systems and the RTRT system is that they reproduce the respiratory movement of tumors by acquiring surrogate movements of the body surface (22). Therefore, errors may occur if the predicted model differs from the actual movement. In fact, some studies have reported that the movements of such markers do not always match those of tumors in organs that undergo respiratory movement, such as the lungs, liver, and pancreas (23-25). On the other hand, because the RTRT system can directly confirm the movement of the fiducial markers, it can provide highly accurate treatment according to the characteristics of each patient without such errors. In this study, we used spherical fiducial markers, which are recognized as the same shape regardless of the direction they are viewed, thus minimizing misrecognition of position.
This study included only SBRT for primary lung cancer. Lung cancer is not only primary, but also includes lung metastases that spread from various cancers. Among lung metastases, lung metastases from colorectal cancer are known to be resistant to radiotherapy (26). SBRT using SyncTraX FX4 has the potential to increase the dose to the tumor with less impact on the lungs due to the small PTV margin. Prospective studies will be needed to confirm whether the dose increase is associated with a therapeutic effect.
Limitations of the present study include its retrospective design, the small number of patients, and the short follow-up period. Moreover, we did not conduct a detailed analysis of secondary cancers and adverse events due to low-dose exposure from SyncTraX FX4. However, all patients included in the study were inoperable, chemotherapy was not indicated, and best supportive care was the only option. Thus, the good CSS and LC achieved through this method without serious adverse events was considered to be a sufficient therapeutic contribution.
In conclusion, SBRT with SyncTraX FX4 can provide safe and effective treatment for patients in poor condition.
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research (B) (19H03596) from the Ministry of Education, Science, Sports, and Culture of Japan.
Footnotes
Authors’ Contributions
Conceptualization, Y.H. (Yuichi Hiroshima); methodology, Y.H.; formal analysis, T.S. (Takuya Sawada) and T.I. (Toshiki Ishida); investigation, Y.H., T.S. (Takashi Saito) T.K. (Takayuki Kaburagi), and M.K.(Moriyuki Kiyoshima); resources, K.Y. (Kenji Yasue) and K.S. (Kazuya Shinoda); data curation, Y.H., T.S. (Takuya Sawada) and T.I.; writing – original draft preparation, Y.H.; writing – review and editing, T.O. (Toshiyuki Okumura) and H.S. (Hideyuki Sakurai); visualization, Y.H.; supervision, T.O.; project administration, Y.T. (Yoshio Tamaki) and H.S. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received April 5, 2022.
- Revision received April 21, 2022.
- Accepted April 26, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).