Toxicities of the whole kidney SABR cohort treated at our institution were not available at the time of this study. Rather, we selected for inclusion a contemporaneous cohort of kidney SABR patients to those we observed with bowel stricture. This was a pragmatic sample size based on availability of imaging data due to software upgrades. This included all 36 consecutive patients treated from January 2018 to February 2021 for whom online image guidance registration dicom files were available. Lesion sizes smaller or equal to 4 cm were prescribed 26 Gy in a single fraction (SF) and lesion sizes greater than 4 cm were prescribed 42 Gy in three fractions (MF) [20]. Renal metastasis were prescribed 20 Gy in a SF.
Each patient was simulated with a four-dimensional CT scan (4DCT) in free breathing on a Brilliance Big Bore 16-slice CT scanner (Philips Healthcare, Andover, MA, USA). Images were sorted into 10 phase-based bins with a bellows system for the respiratory trace (Philips Healthcare). The pixel spacing was either 1.17 mm or 1.37 mm. The slice thickness was 2 mm with the exception of two patients where 1 mm was used. The planning CT was the average intensity projection (AIP) of the 10 phase images in 30/36 patients, the AIP of the exhale phase images (typically phase 40% to phase 70%) in 5/36 patients who were treated with respiratory gating and a 3D exhale breath hold acquisition in 1/36 patient. Patients were immobilized at simulation and during treatment with the BodyFix vacuum drape (Elekta, Stockholm, Sweden).
The tumour was delineated on the planning CT to generate an internal target volume (ITV). The ITV covered the residual motion in the gating window as estimated on the 4DCT in respiratory gating cases and the estimated variation between repeat breath holds in the breath hold case. A planning target volume (PTV) was generated through a 5 mm isotropic expansion of the ITV. Dose distribution was optimized and calculated to the PTV by using the Eclipse treatment planning system (Varian Medical Systems, Palo Alto) with Photon Optimization algorithm (v15.6 or v15.1) for optimization and AcurosXB algorithm (v15.6 or v15.1) reporting dose to medium for dose calculation. The dose calculation grid was 2.5 mm or 1.25 mm in plane, and 2 mm in the supero-inferior direction. All patients were planned with volumetric modulated arc therapy (VMAT) with the exception of one patient planned with 3D conformal radiation therapy (3DCRT) and one patient with intensity-modulated radiation therapy (IMRT). According to our protocol, all plans underwent patient-specific QA pre-treatment that generally included a 4DCT review, treatment plan review and 3D calculation and delivered log file based pre-treatment QA with a 2%/2 mm Gamma passing rate.
Optimization was performed using bowel loops, bowel PRV, or the bowel bag contours. Clinical normal tissue dose constraints used are shown in the Additional file 1. Dose limits considered were based on the QUANTEC recommendations (SB D30cc < 12.5 Gy, LB D1.5cc < 26 Gy and STO D5cc < 22.5 Gy in the SF patient cohort and SB D0.03cc < 30 Gy, LB D1.5cc < 42 Gy, STO D0.03cc < 30 Gy, and STO D5cc < 22.5 Gy in the MF patient cohort) [21,22,23]. The metric LB D0.03cc was also investigated in both cohorts.
Interfraction motion may be due to daily variation in organ shape or size, weight loss during the course of treatment, radiation damage, or change in tumour size [24]. Interfraction positional change was measured from the CBCT acquired for setup at time of treatment; the CBCT acquired immediately prior to treatment was used (PRE CBCT). Intrafractional variation may be caused by respiratory motion, peristalsis, or cardiac motion [24]. Intrafraction motion was measured by using the first CBCT acquired after some dose had been delivered to the patient (MID CBCT). All CBCTs were acquired with either 125 kVp or 140 kVp with 2 mm slice thickness with the exception of 2 CBCTs with 1 mm slice thickness. The pixel spacing was either 0.91 mm or 0.51 mm.
SB, LB, and STO were retrospectively delineated in treatment position on all PRE CBCTs and MID CBCTs. Bowels were segmented by contouring each bowel loop independently from each other (‘bowel loop technique’). In the case of streak artefacts due to bowel gas motion during CBCT acquisition, organ edges were approximated. CBCT quality was classified qualitatively as ‘excellent’, ‘good’, and ‘approximate’ depending on how well bowel edges could be determined visually. The registration used to match the tumour on the CBCT to the planning CT performed by the radiation oncologist at time of treatment was applied, and the OAR contours on the CBCT were copied to the planning CT. Dose metrics were then extracted for each OAR based on their position on the planning CT, PRE CBCT, and MID CBCT.
Location of OARs was quantified through the determination of the shortest distance between the ITV and the OAR, denoted dist(ITV,OAR). In order to do so, the ITV contour was successively expanded with 1 mm isotropic margin. The overlap between the expanded ITV and OAR was determined after each expansion. The shortest distance between the two structures was defined as being the first distance in which the overlap between the two structures returned a non-null structure.
Interfraction motion was quantified by calculating the difference between the shortest distance on PRE CBCT and on planning CT, \({\Delta {\text{dist}}}_{{\text{CT}}}^{{\text{PRE}}}={\text{dist}}^{{\text{PRE}}}\left(\text{ITV},\text{OAR}\right)-{\text{dist}}^{{\text{CT}}}(\text{ITV},\text{OAR})\). An OAR closer to the ITV on PRE CBCT compared with its distance on CT had \({\Delta \text{dist}}_{{\text{CT}}}^{{\text{PRE}}}<0\). A similar quantity was defined to quantify intrafraction motion \({\Delta \text{dist}}_{{\text{PRE}}}^{{\text{MID}}}={\text{dist}}^{{\text{MID}}}\left(\text{ITV},\text{OAR}\right)-{\text{dist}}^{{\text{PRE}}}(\text{ITV},\text{OAR})\). The mean and standard deviation of the magnitude of the interfractional and intrafractional variation, \(\left|\left.{\Delta \text{dist}}_{{\text{CT}}}^{{\text{PRE}}}\right|\right.\) and \(\left|\left.{\Delta \text{dist}}_{{\text{PRE}}}^{{\text{MID}}}\right|\right.\), were reported.
To test if a variation in \({\Delta \text{dist}}_{{\text{CT}}}^{{\text{PRE}}}\) or \({\Delta \text{dist}}_{{\text{PRE}}}^{{\text{MID}}}\) leads to a variation in the planned dose per fraction to OAR, the Pearson correlation coefficient (r) between \(\Delta \text{dist}\) and the difference between the near to maximum planned dose per fraction of this OAR on PRE CBCT and on planning CT, \({\Delta \text{D}0.03\text{cc}}_{{\text{CT}}}^{{\text{PRE}}}={\text{D}0.03\text{cc}}^{{\text{PRE}}}-{\text{D}0.03\text{cc}}^{{\text{CT}}}\), or on MID CBCT and on PRE CBCT, \({\Delta \text{D}0.03\text{cc}}_{{\text{PRE}}}^{{\text{MID}}}={\text{D}0.03\text{cc}}^{{\text{MID}}}-{\text{D}0.03\text{cc}}^{{\text{PRE}}}\), was calculated.
In the case where a dose limit was exceeded in a given fraction by using structures on PRE CBCT, a new treatment plan was generated to investigate if dose to organs could have been lowered while preserving adequate target coverage. To do so, dose optimization and calculation was first performed by using contours determined on the PRE CBCT to perform the optimization with the objectives used in the original treatment plan. If constraints were still not met, a knowledge-based planning (KBP) model (RapidPlan v15, Varian Medical Systems, Palo Alto) was used to further improve the model (KBP model was not available at time of original treatment planning). Metric extraction, determination of the shortest distance between the ITV and OAR and dose optimization and calculation were performed by using the Eclipse Scripting Application Programming Interface (ESAPI v16.1, Varian Medical System, Palo Alto).
Statistical significance of the difference in the medians was determined with a Wilcoxon signed rank test for equal sample size and a Wilcoxon rank sum test otherwise by using the Scipy v1.5.2 module. The null hypothesis was rejected at the 5% significance level (p-value < 0.05).
