CyberKnife^® stereotactic radiation therapy for stage I lung cancer and pulmonary oligometastases: is fiducial implantation still relevant?—a cohort study

Introduction

Stereotactic body radiation therapy (SBRT) using a conventional linear accelerator (LINAC) or specific machine such as CyberKnife^® (Accuray Inc., Sunnyvale, USA) is one of the curative options available for treating unfit patients (ineligible for surgery) with stage I non-small cell lung cancer (NSCLC) (1-6). Local control rates with this technique are around 90–97% at 2–3 years of follow-up with low toxicities (7-12) for peripheral lesions and 87–89% for centrally located lesions (13). SBRT is also a suitable alternative to surgery for lung oligometastases (6,14,15). One of the advantages of the CyberKnife^® robotic radiotherapy system is the capacity for real-time tracking of tumors using one of the two methods available: Synchrony^®, which uses fiducials such as gold seeds or intravascular coils implanted near the tumor prior to treatment, or Xsight^® Lung (Lung Optimized Treatment^®), which can directly track the tumors without fiducials. Both of these techniques compensate for respiratory movement (16). A third treatment modality is available: Xsight^® Spine (Spine Supine^®), which uses the spine as a marker and locates the tumor according to its positional relationship with the spine. Of these three modalities, only Synchrony^® requires fiducials to be implanted near the tumor before treatment. After the introduction of these fiducial-less treatment options to the CyberKnife^® system, studies comparing the local control rates of Synchrony^® with gold seed or coil markers and Xsight^® Spine are needed—only a small number of studies have sought to do this to date. Only a few patients have been treated with Xsight^® Lung in our center, and so this technique was excluded from this study.

Our study aimed to identify whether there is a difference in local control or overall survival rates for patients with primary or secondary lung tumors treated with SBRT with or without prior fiducial marker implantation, we chose to separate coil and gold seed techniques for homogeneity reasons, in our experience, coils tend to be a little less accurately implemented and far away from the lesions than the gold seeds, it also seems to result in more tracking failure. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1245/rc).

Methods

Patients

We conducted a retrospective analysis of all the patients at the Institut de Cancérologie de Lorraine who underwent CyberKnife^® stereotactic radiotherapy for primary lung cancer or lung oligometastases from other cancers between January 2013 and July 2016. Patients’ clinical and dosimetric data were retrieved from the hospital’s electronic patient files (EPFs). The eligibility criteria for this study were as follows: patients were at least 18 years old, diagnosed with a stage I lung cancer or lung metastases from another cancer, and had a follow-up of at least 1 month. Histologic confirmation was not mandatory, especially in the event that tumors displayed a suspicious appearance on imaging (malignant characteristics), that patients were smokers or former smokers or had a prior lung cancer history, or where there was evidence of lesion growth on follow-up computed tomography (CT) scans and fluorodeoxyglucose (FDG) avidity on positron emission tomography (PET)/CT scans (17). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by regional ethics committee of Lorraine Cancer Institute (registration No. MR0004) and individual consent for this retrospective analysis was waived.

Treatment methods

Depending on the tumor location and the patient’s characteristics, one of the following methods was selected:

Synchrony^®

This method uses fiducials such as gold seed or coils implanted near the tumor prior to treatment to provide a level of accuracy within 1.5 mm. It is based on the simultaneous identification of internal and external movements using a combined tracking system composed of an external X-ray system for internal marker localization on kV images and a camera-based system to record movement of the patient chest using LED fixed on a vest. A correlation model is then constructed evaluating the relationship between those movements. Thanks to this correlation model, internal movement can be predicted using external movement and then used to guide to robotic linac to compensate for real time motion. A minimum of four to six fiducials are recommended by the manufacturer, most teams only implant two to three fiducials, its noteworthy that not all the fiducials need to be tracked during treatment. Gold seed implantation is usually performed by a radiologist under CT guidance when the patient’s health status and pulmonary function are compatible with the procedure and the risk of a clinically significant pneumothorax is low (18). A one-night hospitalization is required and a chest X-ray excluding major complications is performed before the patient is discharged. In the case of unfit patients for these procedures, such as patients with a WHO performances status ≥2, high Charlson score or incompatible cardiopulmonary function, intravascular markers such as coils are preferred, usually, endovascular embolization coils are placed via the femoral vein into subsegmental pulmonary artery branches near the tumor under biplane angiography guidance (19). An alternative to these procedures is the use of navigational bronchoscopy which result in a lower rate of pneumothorax and the possibility to perform a biopsy during the same procedure if needed (20), however this technique is not widely available at the moment.

Xsight^® Spine (Lung Optimized Treatment^®)

In this noninvasive method, when tumors are located close to the spine (less than 50 mm from the middle of the posterior wall of the vertebra), the spine can be used as a marker and linked to a 4D scan to obtain an internal target volume (ITV), which compensates for the absence of respiratory movement compensation due to the lack of direct tumor tracking.

Xsight^® Lung (Spine Supine^®)

Only a few patients have been treated with Xsight^® Lung in our center during this period mostly because the majority of our data comes from the early uses of lung SBRT in our institution, Xsight^® lung was not as effective as it is now and resulted in a lot of tumor detection failure in the early settings, we chose to use preferentially the other methods available as it also reduced the treatment volumes and the workflow on our simulation scanner.

Treatment planning

All patients were treated at the same institute: the Institut de Cancérologie de Lorraine in Nancy. A free-breathing CT scan without contrast encompassing the entire lung was obtained with millimeter-thick slices for the Synchrony^® method the patient block his breathing mid cycle during this scan, without forced inspiration or expiration to avoid motion blur; for Xsight^® Spine planning, a 10-phases 4D scan was acquired on a Philips Brilliance Big Bore^® CT scanner.

Gross tumor volume (GTV) was delineated by the physicians in the pulmonary window visualization settings. For Synchrony^®, this was undertaken on one CT. 2-mm geometric expansion was performed and adapted to anatomic boundaries to obtain the clinical tumor volume. For Xsight^® spine, an ITV was obtained after delineating the GTV on the 0%, 30%, 50% and 80% phases of the 4D-scan, merged together as an ITV and then checked on the 4D cinema mode and a subsequent 3-mm (for fiducials closer than 5cm of the spine) to 5-mm (for fiducials further than 5 cm of the spine) expansion was performed to obtain the planning target volume (PTV) depending on the distance between fiducials or spine and the tumor, PTV was not reduced according to organs at risk proximity, however PTV coverage was reduced if needed to respect dose constraints on those structures. All relevant organs at risk (OAR) were delineated, including at least the spinal cord, left and right lung, heart, esophagus, brachial plexus, bronchial tree, and large vessels.

Prescribed doses were 60 Gy in three fractions (21) for peripherally located lesions and 50 Gy in four or five fractions for central or ultra-central tumors (13,22), all delivered to the 80% isodose line.

Follow-up

Patients’ toxicities were assessed weekly during treatment, and patients had a follow-up appointment with the radiation oncologist 3 months after treatment completion. Reexamination was then conducted at most once every 3 months. A CT scan was performed at 3 and 6 months and at least annually after this period; in the event of suspicion of recurrence or progression, a PET-CT and biopsy were performed. Local control was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (23).

Statistical analysis

Quantitative parameters were described as mean, median, and interquartile range (IQR). The normality of the distribution was assessed by the Kolmogorov test. Qualitative parameters were described as frequency and percentage. Comparisons between the techniques were performed by the Kruskal-Wallis test for quantitative parameters and by the Chi-squared test or Fisher’s exact test for qualitative parameters.

Overall survival was defined as death from any cause from the end of radiotherapy to the date of death and metastasis-free survival was defined as death from any cause or metastatic recurrence. These were described with the Kaplan-Meier method. Local control was defined as the absence of progressive disease, which was defined as: local enlargement >20% according to Evaluation Criteria in Solid Tumors v1.1 (23) or confirmed by PET-CT and/or biopsy. It was described as the inverse of the cumulative incidence function to take into account death whatever the cause and metastatic recurrence as competing risks. Late toxicities were described with the cumulative incidence function to take into account death as a competing risk.

Within the subgroup analyses, local control and late toxicities were compared between the techniques with the Gray’s test and acute toxicities with the Chi-squared test or Fisher’s exact test. Statistical significance was set at 0.05. Statistical analyses were performed with SAS software, version 9.2 (SAS Institute Inc., Cary, NC, USA).

Results

A total of 294 patients were treated with CyberKnife^® stereotactic radiotherapy at our institute between January 2013 and July 2016 and were included in our study; 294 tumors were treated. A total of 122 were metastases from a distant cancer, 89 were stage I NSCLC, and 83 were not histologically confirmed. Of the 294 tumors, 191 were treated with Synchrony^® (119 with gold seeds and 72 with coils) and 103 with Xsight^® Spine. 32 patients were excluded for missing data. The median follow-up was 31.6 months (IQR, 18.1–50.2 months).

Tumors characteristics and dosimetric data

Tumor characteristics at baseline are summarized in Table 1. Of the 294 tumors treated, 42% were metastases, 30% were stage I NSCLC, and 28% were not histologically confirmed. The most represented primary cancers were lung (47%), unknown (28%), rectal (5%), head and neck (3%), kidney (3%), and colon (3%). Most tumors were located in the upper pulmonary lobes: upper right (37%) and upper left (25%). The median GTV volume was 3.1 cm³ (IQR, 1.5–7.3 cm³), the median PTV volume was 19 cm³ (IQR, 11.2–31 cm³), and the median PTV/GTV ratio was 5.5 (IQR, 3.8–8.6).

The dosimetric data are summarized in Table 2. The fractionation schemes were 60 Gy in three fractions (67%), 50 Gy in four fractions (23%), or 50 Gy in five fractions (7%). The dose constraints for OAR were respected: V20Gy <10% in 94.44% of cases, V10Gy <17% in 86.44% of cases and V5Gy <50% in 99.44% of cases.

Local control, overall survival, and metastasis-free survival

Table 3 summarizes the results for local control, overall survival, and metastasis-free survival. Of the 294 patients treated, 28 experienced local relapses.

Local control at two and five years were respectively 92.22% (95% CI: 0.885–0.951) and 85.35% (95% CI: 0.787–0.990) (Figure 1). The subgroup analysis (Table 4) showed no statistical differences in local control rates between the three modalities for tumor type (primary, metastases or unknown), tumor location (lower, middle or upper lobe, GTV size, PTV size, or PTV/GTV ratio.

Figure 1 Local control according to the tracking technique used.

Overall survival at two and five years were respectively 84.32% and 59.14% (Figure 2). Metastasis-free survival at two and five years were respectively 82.83% and 55.75%. Metastasis-free survival and Overall survival rates did not significantly differ between techniques at 2 and 5 years (P=0.664) and P=0.586, respectively.

Figure 2 Overall survival according to the tracking technique used.

Toxicities

Acute and late toxicities are shown in Table 5. No grade 4 or 5 toxicities were reported. One acute grade 3 pneumothorax occurred after gold seed implantation; this resolved after surgical management. We reported only two cases of late pneumonitis, one grade 3 in the coil group and one grade 2 in the Xsight^® Spine group. Both were radiation induced and resolved after treatment. Pneumothorax and intra-alveolar hemorrhage (IAH) occurred in respectively 36.13% and 7.56% of the gold seed group. Grade ≥2 acute pneumonitis, cough, dyspnea, and asthenia were present respectively in 1.36%, 0.68% 2.16%, and 1.02% of cases. The overall grade ≥2 acute toxicity rate (excluding pneumothorax and IAH) was 5.10%.

Late pneumonitis, cough, dyspnea, and asthenia rates were respectively 0.8%, 0.5%, 5.3%, and 0.4% with an overall grade ≥2 late toxicity rate of 6.1%.

Discussion

In our study, the main analysis revealed local control rates of 92.22% and 85.35% at two and five years and overall survival rates at two and five years of 84.32% and 59.14%, rates which are consistent with those reported in the literature (13,14,24-26) for CyberKnife^® or LINAC-based treatment.

Overall survival, local control, and metastasis-free survival rates did not differ significantly between patients receiving Synchrony^® (both type of fiducials) or Xsight^® Spine (respectively P=0.586, P=0.685, and P=0.664), which implies that Xsight^® Spine is not only noninvasive and safe but also as effective as Synchrony^®, in appropriately selected patients, especially in terms of local control. Unlike previously published studies with fewer patients (27,28), the subgroup analysis revealed that local control rates did not differ significantly between techniques within tumors grouped by location, GTV, PTV, or PTV/GTV ratio (Table 4). This highlights the fact that, even when larger tumors and tumors situated in the lower lobes or with larger PTV seemed to have lower local control rates, the techniques evaluated in this study tended to be equally effective in each of those situations, and so the choice of technique should not depend on these tumor characteristics. However, Xsight^® Spine had a nonsignificant tendency to be less effective than the other techniques when the GTV was greater than 10 cm³ and/or the PTV was greater than 30 cm³, with respective local control rates of 73.85% and 66.96%. This highlights the need for caution regarding PTV margins and the use of high-performing 4D-CT in these scenarios.

We reported only two acute grade 3 toxicities: one pneumothorax after gold seed implantation and one radiation-induced pneumonitis. One late grade 3 radiation-induced pneumonitis was reported; both cases of pneumonitis resolved after medical treatment. No grade 4 or 5 toxicities were reported. Because of the retrospective nature of our study, we chose to only report grade ≥2 toxicities, which are much more significant for patients than grade 1 and more likely to be reported in EPFs. Surprisingly, symptomatic rib fractures and chest pain were not reported in any patients’ files despite having probably occurred in some cases, but none were reported by the patients nor the physician. Acute toxicities differed significantly between groups in terms of pneumothorax and IAH. This directly relates to the transthoracic gold seed implantation only used in the gold seed group; pneumothorax occurred in 36.17% of patients in this group, which is consistent with data from previously published studies (29,30), although only 5.88% of patients in this group required surgery or insertion of a chest tube for a grade 2 or 3 pneumothorax. This highlights the fact that this procedure is not harmless and should be avoided if clinically possible or replaced by navigational bronchoscopy when available, since this procedure seems clinically safer and can achieve biopsy in the same procedure (20). Overall grade ≥2 acute (excluding pneumothorax and IAH) and late toxicity rates did not differ significantly between groups. We tried to conduct a subgroup analysis to account for an effect of GTV size, PTV size, and PTV/GTV ratio on acute and late significant pulmonary toxicities but, due to the limited number of grade ≥2 toxicities, the analysis lacked statistical power and was not performed.

In our population, there were significant differences between the characteristics of the tumors of patients in the gold seed, coil and Xsight^® Spine groups in terms of tumor type (metastasis, primary, or unknown; P=0.003), location of primary cancer (P=0.040), and location (P=0.001). This could be explained by the fact that since the pulmonary diameter in the upper lobes is smaller, the treated lesions are more likely to be close to the spine and patients in this setup accessible for spine tracking, most vulnerable patients with non-histologically confirmed tumors were ineligible for lung biopsy and thus ineligible for gold seed implantation, meaning they received noninvasive radiotherapy treatment with Synchrony^® using coils or Xsight^® Spine. Population groups also differed significantly in PTV size and PTV/GTV ratio. The median PTV volume was 19 cm³ (IQR, 11.2–31 cm³) and the median PTV/GTV ratio was 5.5 (IQR, 3.8–8.6); both were significantly different between groups (respectively P<0.001 and P=0.002), which is explained by the fact that patients treated with Xsight^® Spine received a 4D-CT scan and ITV-based treatment, resulting in a higher volume of treated lung.

Dosimetric data were significantly different between treatment groups in terms of dose and fractionation regimens (P=0.016), respect to dose constraint thresholds, in particular V10Gy <17% and V5Gy <30% (respectively P=0.002 and P=0.004). Indeed, the Xsight^® Spine treatment planning used often more fractionated regimens: 33% of patients in this group received 50 Gy in four fractions versus 19% and 15% of patients in the gold seed and coil groups, respectively, however every patient received regimens with a biologically equivalent dose superior to 100 Gy as clinically recommended (31). Dose thresholds were more frequently exceeded with this technique than with other techniques, particularly for the V10 and V5 values detailed above, where there were significant differences between treatment groups (P≤0.002 and P≤0.004 respectively). This is certainly related to the use of an ITV with Xsight^® Spine and therefore a larger PTV for the same GTV size. Although Xsight^® Spine used more fractionated regimens, there was no difference between groups in terms of median overall treatment time (P=0.309).

Marker less irradiation is certainly a good noninvasive treatment, but it cannot be performed in all cases. Intravascular marker placement is highly safe and incases where Xsight^® Spine cannot be used, markers should be placed intravascularly (32).

To our knowledge, our cohort represents the largest sample size reported to date, and despite the retrospective nature of this study, we were able to suggest that fiducial-less CyberKnife^® stereotactic radiation therapy resulted in satisfactory local control rates, with no significant difference in toxicity between techniques and no significant difference in local control and overall survival rates according to tumor location, GTV, PTV, or PTV/GTV ratio. This study is an actualization of our previous publication (28), reporting survival results and a longer follow-up. We sought to investigate another fiducial-less treatment modality, the Xsight^® Lung treatment method. Unfortunately, our center has only used this technique widely since 2018, and not enough patients have been treated with it to perform an adequate analysis. Further research using large sample sizes are needed to investigate this modality.

The main limits of our study are that among others, it’s retrospective nature, the lack of clear data about biologically equivalent dose (BED) and dose fractionation, which are correlated with local control in many published studies, and the presence of significant differences between the groups in terms of tumors characteristics could results in difference between groups in terms of local control even if BED was always superior to 100 Gy (33,34).

Conclusions

This study suggests that fiducial-less SBRT using Xsight^® Spine offers local control and overall survival rates comparable with those obtained with Synchrony^®. Fiducial implantation could therefore be safely avoided, which also offers cost-effectiveness advantages. Noninvasive techniques seems safe to be prioritized whenever possible without, regardless of tumor size or location.

Acknowledgments

Funding: This work was supported by Lorraine Cancer Institute.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1245/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1245/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1245/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1245/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by regional ethics committee of Lorraine Cancer Institute (registration No. MR0004) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Park HS, Detterbeck FC, Madoff DC, et al. A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 4: systematic review of evidence involving SBRT and ablation. J Thorac Dis 2022;14:2412-36. [Crossref] [PubMed]
2. Bade BC, Blasberg JD, Mase VJ Jr, et al. A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 3: systematic review of evidence regarding surgery in compromised patients or specific tumors. J Thorac Dis 2022;14:2387-411. [Crossref] [PubMed]
3. Detterbeck FC, Mase VJ Jr, Li AX, et al. A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 2: systematic review of evidence regarding resection extent in generally healthy patients. J Thorac Dis 2022;14:2357-86. [Crossref] [PubMed]
4. Detterbeck FC, Blasberg JD, Woodard GA, et al. A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 1: a guide to decision-making. J Thorac Dis 2022;14:2340-56. [Crossref] [PubMed]
5. Khalifa J, Lerouge D, Le Péchoux C, et al. Radiotherapy for primary lung cancer. Cancer Radiother 2022;26:231-43. [Crossref] [PubMed]
6. Lévy A, Darréon J, Mornex F, et al. Lung metastases radiation therapy. Cancer Radiother 2022;26:244-9. [Crossref] [PubMed]
7. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070-6. [Crossref] [PubMed]
8. van der Voort van Zyp NC, Prévost JB, Hoogeman MS, et al. Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: clinical outcome. Radiother Oncol 2009;91:296-300. [Crossref] [PubMed]
9. Yuan XS, Chen WC, Lin QR, et al. A propensity-matched analysis of stereotactic body radiotherapy and sublobar resection for stage I non-small cell lung cancer in patients at high risk for lobectomy: the results in a Chinese population. J Thorac Dis 2021;13:1822-32. [Crossref] [PubMed]
10. Dong B, Zhu X, Jin J, et al. Comparison of the outcomes of sublobar resection and stereotactic body radiotherapy for stage T1-2N0M0 non-small cell lung cancer with tumor size ≤ 5 cm: a propensity score matching analysis. J Thorac Dis 2020;12:5934-54. [Crossref] [PubMed]
11. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 2020;38:2830-8. [Crossref] [PubMed]
12. Chang JY, Mehran RJ, Feng L, et al. Stereotactic ablative radiotherapy in operable stage I NSCLC patients: Long-term results of the expanded STARS clinical trial. J Clin Oncol 2021;39:8506. [Crossref]
13. Bezjak A, Paulus R, Gaspar LE, et al. Safety and Efficacy of a Five-Fraction Stereotactic Body Radiotherapy Schedule for Centrally Located Non-Small-Cell Lung Cancer: NRG Oncology/RTOG 0813 Trial. J Clin Oncol 2019;37:1316-25. [Crossref] [PubMed]
14. Wang Z, Kong QT, Li J, et al. Clinical outcomes of cyberknife stereotactic radiosurgery for lung metastases. J Thorac Dis 2015;7:407-12. [PubMed]
15. Rieber J, Streblow J, Uhlmann L, et al. Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy". Lung Cancer 2016;97:51-8. [Crossref] [PubMed]
16. Darréon J, Bouilhol G, Aillières N, et al. Respiratory motion management for external radiotherapy treatment. Cancer Radiother 2022;26:50-8. [Crossref] [PubMed]
17. Berman AT, Jabbour SK, Vachani A, et al. Empiric Radiotherapy for Lung Cancer Collaborative Group multi-institutional evidence-based guidelines for the use of empiric stereotactic body radiation therapy for non-small cell lung cancer without pathologic confirmation. Transl Lung Cancer Res 2019;8:5-14. [Crossref] [PubMed]
18. Scher N, Bollet M, Bouilhol G, et al. Safety and efficacy of fiducial marker implantation for robotic stereotactic body radiation therapy with fiducial tracking. Radiat Oncol 2019;14:167. [Crossref] [PubMed]
19. Nuyttens JJ, Prévost JB, Praag J, et al. Lung tumor tracking during stereotactic radiotherapy treatment with the CyberKnife: Marker placement and early results. Acta Oncol 2006;45:961-5. [Crossref] [PubMed]
20. Bowling MR, Folch EE, Khandhar SJ, et al. Fiducial marker placement with electromagnetic navigation bronchoscopy: a subgroup analysis of the prospective, multicenter NAVIGATE study. Ther Adv Respir Dis 2019;13:1753466619841234. [Crossref] [PubMed]
21. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 2003;124:1946-55. [Crossref] [PubMed]
22. Chang JY, Li QQ, Xu QY, et al. Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: how to fly in a "no fly zone". Int J Radiat Oncol Biol Phys 2014;88:1120-8. [Crossref] [PubMed]
23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. [Crossref] [PubMed]
24. Janvary ZL, Jansen N, Baart V, et al. Clinical Outcomes of 130 Patients with Primary and Secondary Lung Tumors treated with Cyberknife Robotic Stereotactic Body Radiotherapy. Radiol Oncol 2017;51:178-86. [Crossref] [PubMed]
25. Jung IH, Song SY, Jung J, et al. Clinical outcome of fiducial-less CyberKnife radiosurgery for stage I non-small cell lung cancer. Radiat Oncol J 2015;33:89-97. [Crossref] [PubMed]
26. Nuyttens JJ, van der Voort van Zyp NC, Verhoef C, et al. Stereotactic body radiation therapy for oligometastases to the lung: a phase 2 study. Int J Radiat Oncol Biol Phys 2015;91:337-43. [Crossref] [PubMed]
27. Guo Y, Zhuang H, Zhao L, et al. Influence of different image-guided tracking methods upon the local efficacy of CyberKnife treatment in lung tumors. Thorac Cancer 2015;6:255-9. [Crossref] [PubMed]
28. Khadige M, Salleron J, Marchesi V, et al. Cyberknife(®) stereotactic radiation therapy for stage I lung cancer and pulmonary metastases: evaluation of local control at 24 months. J Thorac Dis 2018;10:4976-84. [Crossref] [PubMed]
29. Patel A, Khalsa B, Lord B, et al. Planting the seeds of success: CT-guided gold seed fiducial marker placement to guide robotic radiosurgery. J Med Imaging Radiat Oncol 2013;57:207-11. [Crossref] [PubMed]
30. Trumm CG, Häussler SM, Muacevic A, et al. CT fluoroscopy-guided percutaneous fiducial marker placement for CyberKnife stereotactic radiosurgery: technical results and complications in 222 consecutive procedures. J Vasc Interv Radiol 2014;25:760-8. [Crossref] [PubMed]
31. Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 2004;101:1623-31. [Crossref] [PubMed]
32. Nakamura M, Nishimura H, Nakayama M, et al. Dosimetric factors predicting radiation pneumonitis after CyberKnife stereotactic body radiotherapy for peripheral lung cancer. Br J Radiol 2016;89:20160560. [Crossref] [PubMed]
33. Zhao L, Zhou S, Balter P, et al. Planning Target Volume D95 and Mean Dose Should Be Considered for Optimal Local Control for Stereotactic Ablative Radiation Therapy. Int J Radiat Oncol Biol Phys 2016;95:1226-35. [Crossref] [PubMed]
34. Binkley MS, Trakul N, Jacobs LR, et al. Colorectal Histology Is Associated With an Increased Risk of Local Failure in Lung Metastases Treated With Stereotactic Ablative Radiation Therapy. Int J Radiat Oncol Biol Phys 2015;92:1044-52. [Crossref] [PubMed]