This retrospective study was approved by the institutional medical ethics committee of the Charité - Universitätsmedizin Berlin (EA1/214/16). We identified all patients with lung metastases treated with curative intended SFRS or fSBRT between January 2010 and December 2016. Cases with an initially limited number of lung metastases from various solid tumors or with oligo-progression after systemic therapy were selected for the study. Patients with disseminated disease or with a second malignancy were excluded. The data on patients’ demographics, e.g. primary tumor and metastases, disease stage as determined by computed tomography, magnetic resonance imaging or positron emission tomography, treatment parameters, follow-up and LC, overall survival (OS), progression-free survival (PFS), distant metastases-free survival (DMFS) were calculated. Clinical follow-up was performed at 6 weeks after SFRS/fSBRT and at 3, 6, 12, 18, and 24 months after treatment and annually thereafter. Acute and late adverse events were scored using NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Treatment planning and delivery
SBRT was delivered using CyberKnife (CK) and Novalis systems, both dedicated stereotactic linear accelerators. For respiratory motion compensation, the CyberKnife Synchrony® Respiratory Motion Tracking System was used. In general, one gold fiducial (1.0 mm x 5.0 mm) was placed centrally within the lung metastasis under CT-guidance in local anesthesia. For lesions larger than 2 cm feasibility of X-sight lung tracking was evaluated. If motion compensation was not possible (e.g. due to patients’ comorbidities or technical limitations) an internal gross tumor volume (IGTV), defined as the gross tumor volumes of all respiratory phases on a 4D CT was constructed. In these cases, patients were aligned on the spine. High-resolution thin-slice native planning CT of the chest with 1.0 to 2.0 mm slice thickness in supine position was performed.
The gross tumor volume (GTV) was delineated on all axial slices including spiculae in the lung window. The clinical target volume (CTV) was equal to the GTV. The planning target volume (PTV) was obtained by adding a 5-8 mm margin to the CTV
For CK treatments, doses were prescribed to the 70% isodose covering the PTV and a total maximum of 100%. Novalis treatment was planned with less inhomogeneous dose distributions with the 80% isodose line of the prescribed 100% dose encompassing the PTV and allowing a maximum of up to 110% (Figure 1).
The linear-quadratic model, assuming an alpha/beta ratio of 10 Gy for tumor, was used to calculate the biologically equivalent dose (BED) and the equivalent dose in 2 Gy fractions (EQD2) for PTV-encompassing total dose. Dose constraints to organs at risk for single fraction treatment are shown in Table 1. Treatment planning for CK was performed in Multiplan® (Accuray) using the Ray-Trace or Monte Carlo algorithm and for Novalis in iPlan® (BrainLAB) using the Pencil Beam algorithm.
Endpoints and statistical considerations
LC was defined as time from SFRS/fSBRT to tumor progression within the irradiation field or absence of progression at last available follow-up. LC was assessed using routinely CT scans every 3 months. PET-CT and/or biopsy of irradiated metastasis was performed in cases of uncertain progression detected on CT images. OS survival was calculated from the beginning of SFRS or fSBRT until the death of any cause or the date of last follow-up. The time to new metastases in the lung outside of the SFRS/fSBRT field or in other organs was defined as DMFS and was calculated from the start of SFRS/fSBRT. PFS was defined as the time from the start of SFRS/fSBRT until progression of the primary tumor, development of new metastases or local failure.
LC was compared between LM treated with SFRS and fSBRT. The different fractionation regimes in the same patient were allowed, thus fractionation impact on OS, PFS and DMFS could not be assessed.
OS, LC, DMFS and PFS after SFRS/fSBRT for lung metastases were calculated using the Kaplan-Meier method. Cox-regression analysis was used to obtain the Hazard Ratio (HR) and 95% confidence intervals (CI) for various covariates. Covariates with a p-value of 0.1 were included into the multivariate analyses carried out with a Cox proportional hazards model with a threshold of p<0.05. The chi-squared test was performed in order to compare variables between groups. A p-value of <0.05 was considered as statistically significant. The data processing and statistical analyses were accomplished using FileMaker Pro 15 Advanced, Excel 2010 and IBM SPSS Statistics 24 (SPSS Inc., Chicago, IL, USA).