Patients
This prospective study included patients who were treated consecutively in the period from August 2016 to June 2019. At the time of analysis, each patient had a follow-up time of at least one year. Inclusion factors for SBRT of liver metastases are: liver metastases that are unresectable or medically inoperable due to comorbidities and which are verified by biopsy or CT / MR / PET imaging with an increase in tumor markers, <3 size metastases, size ≤ 6cm, stable primary tumor, good liver function, in good general condition (ECOG 0-2). Exclusion factors are observed and later confirmed, through diagnostic tests, disease progression at the time of CT simulation and crossing the dose constraints on healthy tissues.
Methods
Patients were simulated using four-dimensional computed tomography (4DCT, GE LightSpeed, 16 slice, slice thickness 1.25mm) in supine position using abdominal compression (Macromedics), with or without intravenous contrast [22]. For more accurate visualization and delineation, available pre-therapeutic diagnostic tests were registered (contrast-enhanced CT, MR, PET/CT). The target volume was contoured at the following phases of 4DCT: fb (free breathing), 0, 50, 90 and Min-IP (Minimal Intensity Projection) in the ARIA radiotherapy system (Varian Medical Systems Inc, Palo Alto, CA, USA), with target volume position check on all available diagnostic and 4DCT simulation images. By combining the contours in the mentioned phases, ITV (Internal Tumor Volume) was defined, which was named iGTV, and then PTV with a margin of 3-5 mm. Organs at risk were contoured according to the RTOG atlas and include: liver (liver contoured on fb series and Avg (Average) series, oesophagus, small intestine, large intestine, stomach, kidneys, spinal cord, spinal cord PRV, ribs and skin.
The prescribed dose was 60 Gy in 8 fractions (7.5 Gy daily; BED 105 Gy, α/β = 10), every other day. Planning was done using the Eclipse planning system, and the Accuros XB algorithm was used to calculate the dose. The two half-arc volumetric modulated arc therapy (VMAT) technique with a treatment couch rotation of ± 10° was used. The treatment was performed on a Varian Clinac DHX linear accelerator. Before each fraction, cone beam CT (CBCT) and online verification and correction of the patient's position and metastasis or metastases were performed. Checking the position of the target volume was controlled so that the liver contour on the obtained CBCT image overlapped with the liver contour obtained on the Avg series of simulation 4DCT, which was considered a surrogate for the liver position during treatment if metastases were not clearly visible [23,24].
Patients were monitored prospectively at quarterly intervals with control laboratory tests (blood count, liver biochemical tests) and radiological imaging. Radiographic response assessment was performed according to RECIST 1.1 criteria and was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). CR is defined as the total radiographic disappearance of all lesions. PR is defined as at least a 30% reduction in the amount of diameter of the target lesions. PD is defined as at least a 20% increase in the diameter of the target lesions. In addition to a relative increase of 20%, the lesion also had to show an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. SD is defined as neither a sufficient decrease to qualify for PR, nor a sufficient increase to qualify for PD [25].
Progression of the disease is considered to be the progression of the treated lesion, the appearance of new metastases in the liver, in the distant organs and/or lymph nodes. One-year local control is met if the treated lesion is without signs of disease progression. Patients were followed for local control for up to a year in case of disease progression which was not a consequence of the progression of the treated lesion. In case the patient would die within one year from the beginning of the treatment, it was considered that the local control was not met. One-year overall survival was measured from the day of commencement of the stereotactic radiotherapy treatment.
Statistical analysis
Standard descriptive methods (arithmetic mean with standard deviation, range of numerical feature from minimum to maximum value) were used in statistical data analysis. Student t-test was used to examine statistical significance. The difference was considered significant if p<0.05. StatsDirect Statistical Software (ver. 3.2.10) was used for statistical analysis.