IntroductionStereotactic ablative radiotherapy (SABR) is an effective treatment for early stage non-small cell lung cancer (NSCLC) with excellent local control (LC) rates (>90% at 2 years)1Timmerman R Paulus R Galvin J et al.Stereotactic body radiation therapy for inoperable early stage lung cancer., 2Ricardi U Badellino S Filippi AR. Stereotactic radiotherapy for early stage non-small cell lung cancer., 3Palma D Visser O Lagerwaard FJ Belderbos J Slotman BJ Senan S. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: A population-based time-trend analysis.. It is the treatment of choice for Stage I medically inoperable NSCLC patients.4Swaminath A Wierzbicki M Parpia S et al.Canadian phase III randomized trial of stereotactic body radiotherapy versus conventionally hypofractionated radiotherapy for stage I, medically inoperable non–small-cell lung cancer – rationale and protocol design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial.,5Ettinger DS Wood DE Aisner DL Akerley W Bauman JR Bharat A. Non-small cell lung cancer, NCCN clinical practice guidelines in oncology, Version 3.2020. Compared to conventional radiotherapy, SABR utilizes increased precision with image guidance, higher conformity with steep dose drop offs, and larger dose per fraction in fewer fractions to deliver higher biologically effective doses to tumors while minimizing dose to nearby normal tissue.6Potters L Kavanagh B Galvin JM et al.American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy. Specialized planning, immobilization, and dose delivery techniques are required to achieve this precision given a geographic miss would have higher implications.7Bissonnette J-P Purdie TG Higgins JA Li W Bezjak A. Cone-beam computed tomographic image guidance for lung cancer radiation therapy., 8Grills IS Hugo G Kestin LL et al.Image-guided radiotherapy via daily online cone-beam CT substantially reduces margin requirements for stereotactic lung radiotherapy., 9Purdie TG Bissonnette J-P Franks K et al.Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: Localization, verification, and intrafraction tumor position. Components of this include four-dimensional computed tomography (4DCT), used to create an internal gross tumor volume (IGTV)10Chang JY Dong L Liu H et al.Image-guided radiation therapy for non-small cell lung cancer., 11Ezhil M Vedam S Balter P et al.Determination of patient-specific internal gross tumor volumes for lung cancer using four-dimensional computed tomography., 12Brandner ED Chetty IJ Giaddui TG et al.Motion management strategies and technical issues associated with stereotactic body radiotherapy of thoracic and upper abdominal tumors: A review from NRG oncology. that accounts for tumor motion during respiration, as well as linear accelerator-mounted cone-beam computed tomography (CBCT), used to make precise adjustment to patient set-up prior to treatment delivery.9Purdie TG Bissonnette J-P Franks K et al.Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: Localization, verification, and intrafraction tumor position.Utilizing these strategies allows for smaller planning target volume (PTV) margins than conventional radiotherapy.9Purdie TG Bissonnette J-P Franks K et al.Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: Localization, verification, and intrafraction tumor position.,13Wierzbicki M Mathew L Swaminath A. A method for optimizing planning target volume margins for patients receiving lung stereotactic body radiotherapy. PTV margins are required to account for intrafractional shifts, random error, and systematic error encountered during treatment.14van Herk M Remeijer P Lebesque J V The probability of correct target dosage: Dose-population histograms for deriving treatment margins in radiotherapy. Since the development of SABR, 5-10 mm PTV margins have been used by many institutions and continue to be a common standard.1Timmerman R Paulus R Galvin J et al.Stereotactic body radiation therapy for inoperable early stage lung cancer.,4Swaminath A Wierzbicki M Parpia S et al.Canadian phase III randomized trial of stereotactic body radiotherapy versus conventionally hypofractionated radiotherapy for stage I, medically inoperable non–small-cell lung cancer – rationale and protocol design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial.,13Wierzbicki M Mathew L Swaminath A. A method for optimizing planning target volume margins for patients receiving lung stereotactic body radiotherapy.,15Li W Purdie TG Taremi M et al.Effect of immobilization and performance status on intrafraction motion for stereotactic lung radiotherapy: Analysis of 133 patients. However, there have been advancements in image guidance, delivery techniques, and immobilization devices since the inception of SABR. Modern volumetric modulated arc therapy (VMAT) using flattening-filter-free (FFF) beams allows for much higher dose rates than intensity-modulated radiotherapy (IMRT) with flattened beams.16Yan Y Yadav P Bassetti M et al.Dosimetric differences in flattened and flattening filter-free beam treatment plans. Higher dose rates result in reduced treatment times, potentially leading to decreased intrafractional motion.9Purdie TG Bissonnette J-P Franks K et al.Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: Localization, verification, and intrafraction tumor position.,17Vloet A Li W Giuliani M et al.Comparison of residual geometric errors obtained for lung SBRT under static beams and VMAT techniques: Implications for PTV margins. These factors may allow us to reduce PTV margin sizes while maintaining efficacy. This study has two purposes. The first is to evaluate the current PTV margin size and determine whether this can be reduced. The second is to analyze the dosimetry of 5 mm PTV margins compared to the calculated 3 mm PTV margins.MethodsPost-treatment CBCT intrafractional shift data from 33 patients with early-stage NSCLC treated with 4 or 8 fractionation lung SABR from 2016-2019 was analyzed to determine a PTV margin with a probability of IGTV coverage of ≥95% of the prescription dose in 90% and 99% of patients. The mean displacements of the IGTV in longitudinal, vertical, and lateral directions were analyzed in a total of 173 post-treatment CBCTs. The PTV setup margin (MPTV) for lung SABR was then calculated using the van Herk formula as follows:

MPTV=α∑+β(σ2+σp2)1/2−−βσp

(1)

where α is 2.5 when 90% of patients receive minimum 95% of dose to IGTV and 3.36 when 99% of patients receive minimum 95% of dose to IGTV, Σ is the standard deviation (SD) of the systematic error calculated using the mean displacements of intrafractional shifts of each patient, σ is the SD of the random error calculated using the standard deviation of the shifts of each patient, β is 0.84 for an approximate prescription isodose level of 80% for minimum 95% PTV, and σp is 0.64 cm to accommodate for lung penumbra.14van Herk M Remeijer P Lebesque J V The probability of correct target dosage: Dose-population histograms for deriving treatment margins in radiotherapy.,15Li W Purdie TG Taremi M et al.Effect of immobilization and performance status on intrafraction motion for stereotactic lung radiotherapy: Analysis of 133 patients.,18Sonke J-J Rossi M Wolthaus J van Herk M Damen E Belderbos J. Frameless Stereotactic Body Radiotherapy for Lung Cancer Using Four-Dimensional Cone Beam CT Guidance.

To validate 3 mm PTV margins, 36 consecutive patients with early-stage NSCLC treated with lung SABR using 48 Gy in 4 fractions, 10XFFF energy (maximum dose rate 2400 MU/min), and 5 mm PTV margins from 2016-2019 were included. For tumors superior to the carina, immobilization was accomplished with a long thermoplastic shell, no abdominal compression, and shoulder retractors (Combifix, CIVCO Radiotherapy, Orange City, Iowa, USA). Immobilization for tumors below the carina utilized a vacuum mold and either arms up with a pneumatic belt for abdominal compression, or arms down and a bridge and respiratory plate for abdominal compression (Body Pro-Lok, CIVCO Radiotherapy, Orange City, Iowa, USA). Plans were created on the average intensity projection data set from all 10 phases of a full lung 4DCT cine scan, which was reviewed and approved by a physicist prior to planning. All patients were treated with coplanar VMAT with 2 or 3 partial (200°) arcs, with pre- and post-treatment CBCTs.

A graphical overview of our margin analysis workflow is shown in Figure 1. Deformable registration of the original planning CT (average intensity projection from 4DCT) and IGTV contour to the post-treatment CBCT was completed for each fraction using SmartAdapt v13 (Varian Medical Systems, Palo Alto, California, USA) deformable registration algorithm. This simultaneously captures the intrafraction translation and rotation of the IGTV and any volume changes. The volume of interest for deformation was set to enclose the original PTV plus a 1-2 cm margin in order to encompass tissues surrounding the PTV but exclude (and therefore preserve the integrity of) the external body contour. The CBCT and initial IGTV contour were used as references to review each deformed IGTV (d-IGTV) to ensure a high-quality registration and minimize deformation errors. Each d-IGTV contour was independently reviewed by a clinician and medical physicist.

Fig. 1A stepwise overview to margin analysis using deformable registration. The planning CT (a) IGTV contour for each case is deformed onto the post-treatment cone-beam CT (CBCT) for every fraction (b). The deformed IGTVs (d-IGTV) are reviewed and edited if necessary to ensure consistency (c). The initial planning CT PTV expansion (a) is changed from 5 mm to 3 mm (d) and the case is replanned (e). Both 5 mm and 3 mm PTV plans are recalculated on the deformed planning CTs (f). Coverage of the d-IGTV contour is analyzed for every fraction (f).

All plans were retrospectively replanned with 3 mm PTV margins using identical optimization and calculation parameters (Varian Eclipse Progressive Resolution Optimizer (PRO) and Anisotropic Analytical Algorithm (AAA) v11 with dose grid resolution of 2.5 mm) and normalized to match the coverage of the original plan (PTV V100%=95%). Dose was recalculated on each deformed CT to assess d-IGTV coverage for both 5 mm and 3 mm PTV plans. The percent of the d-IGTV receiving ≥100% of the prescription dose (V100%) and the minimum dose covering 99.9% of the d-IGTV volume (D99.9%) were used to assess d-IGTV coverage.

To study the difference in normal tissue treated, several metrics were compared between the 5 mm and 3 mm PTV plans calculated on the original (non-deformed) CT sets. The volume of the body receiving ≥50% and ≥80% of the prescription dose (V50% and V80%) was determined. For analysis of OARs the volume of the lung receiving ≥20 Gy (V20Gy) and the mean lung dose (MLD) were calculated, and for those patients with any overlap of the 5 mm PTV with the chest wall (N=22) the dose to 0.035 cm3 (D0.035cc) and 30 cm3 (D30cc) of chest wall (including ribs) was determined.

To analyze normal tissue complication probability (NTCP) for radiation pneumonitis the MLD was converted to MLD(3Gy) using the following equation calculated by Borst et al. (derived from the linear quadratic model):
where α/β=3 and the slope of the line of best fit (regression coefficient of 0.92) for 12 Gy per fraction SABR treatments was 1.8.19Borst GR Ishikawa M Nijkamp J et al.Radiation pneumonitis after hypofractionated radiotherapy: Evaluation of the LQ(L) model and different dose parameters. Normal tissue complication probability (NTCP) for radiation pneumonitis was then calculated using the following equation:
where t=MLD(3Gy)−TD50m*TD50, TD50 = 20.8 Gy (the dose for a 50% NTCP), and m = 0.45 (steepness parameter in the Lyman model).19Borst GR Ishikawa M Nijkamp J et al.Radiation pneumonitis after hypofractionated radiotherapy: Evaluation of the LQ(L) model and different dose parameters.,20Complication probability as assessed from dose-volume histograms.Tumor control probability (TCP), used to predict 2-year LC, was determined by using the average d-IGTV D99.9% from each patient's 5 mm and 3 mm plan to calculate the size-adjusted BED (sBED):
where BED10 is the biologically effective SABR dose using average d-IGTV D99.9% and an α/β of 10 Gy, c is a constant (10 Gy/cm), and L is the tumor diameter (calculated assuming a spherical IGTV, i.e. L=2*[3IGTVvolume4π]1/3), then by using the following formula validated by Ohri et al.:

TCP=e[sBED−−TCD50]/k/(1+e[sBED−−TCD50]/k)

(5)

where TCD50 and k are parameters that define the shape of the TCP curve.21Ohri N Werner-Wasik M Grills IS et al.Modeling local control after hypofractionated stereotactic body radiation therapy for stage I non-small cell lung cancer: A report from the Elekta Collaborative Lung Research Group. Size-adjusted BED is used due to the approximate linear reduction in effective dose with increasing tumour diameter, consistent with reported local control rates decreasing with tumour size.21Ohri N Werner-Wasik M Grills IS et al.Modeling local control after hypofractionated stereotactic body radiation therapy for stage I non-small cell lung cancer: A report from the Elekta Collaborative Lung Research Group.

This study was approved by the XXX Research Ethics Board (REB number XXX).

ResultsAnalysis of intrafractional shifts from 173 post-treatment CBCTs from 33 patients using Eq. 1, showed a PTV margin requirement of 2.3 mm to achieve ≥95% of the prescription dose delivered to the IGTV in 90% of patients (2.21 mm anterior-posterior, 1.60 mm superior-inferior, and 1.05 mm left-right). For the same coverage in 99% of patients a PTV margin of 3.0 mm was found sufficient (2.95 mm anterior-posterior, 2.14 mm superior-inferior, and 1.40 mm left-right).Dosimetric analysis included 144 fractions from 36 consecutively treated lung SABR patients. Median time from initial CBCT to post-treatment CBCT was 7.48 min (interquartile range 6.72-8.84 min, average 7.9 ± 1.9 min). The average IGTV volume was 8.97 cc (range 0.17-52.2 cc). With 5 mm PTV margins, all 144 fractions had d-IGTV V100%>95% (Table 1) and D99.9%>95% (Figure 2). With 3 mm PTV margins d-IGTV V100%>95% in 99.3% of fractions (143/144). Only 3 of 144 fractions had d-IGTV V100%95% in 98.6% of fractions (142/144). The average d-IGTV coverage (V100% and D99.9%) over all 4 fractions for each patient was >95% for all patients with both margins. Although Wilcoxon signed-rank tests revealed statistical differences in both d-IGTV V100% and D99.9% between the PTV margins (p98% of all fractions and 100% of patients (averaged over 4 fractions), thus surpassing generally accepted criteria for PTV margin size.14van Herk M Remeijer P Lebesque J V The probability of correct target dosage: Dose-population histograms for deriving treatment margins in radiotherapy.

Table 1d-IGTV V100% by PTV margin size

Abbreviations: d-IGTV, deformed internal gross tumor volume, V100%, percent of the d-IGTV receiving at least 100% of the prescription dose, PTV, planning target volume

Note: acceptable d-IGTV coverage was defined as V100%>95%

Fig. 2The minimum percentage of the prescription dose covering 99.9% of the deformed internal gross tumor volume (d-IGTV) for each fraction with 5 mm versus 3 mm planning target volume (PTV) margins. Acceptable coverage was defined as d-IGTV D99.9%>95%.

Body V50% and V80% data by PTV margin size can be seen in Supplemental Figure S1 and Table 2. For each patient's treatment course the decrease in body V50% and V80% with 3 mm PTV margins was calculated. The average volume reduction for the study population was 28 cc and 12 cc with an average relative reduction of 28% and 31% respectively. Using paired t-tests significant reductions in total lung V20Gy and MLD over patients’ treatment courses with 3 mm PTV margins was also observed. The average absolute reduction in lung V20Gy was 0.7% (range 0.2-1.4%) while the average relative reduction was 25% (14-42%). Average MLD over patients’ treatment courses was reduced by an absolute 0.2-0.7 Gy (average relative reduction 12-25%). NTCPMLD(3Gy), calculated using Eq. 2 and Eq. 3 (with a TD50 of 20.8 Gy and m of 0.45), showed a 0.8% average decrease in radiation pneumonitis risk with 3 mm PTV margins (range 0.1-2.7%) (Figure 3). For the subset of patients with overlap of the chest wall and the 5 mm margin PTV, use of a 3 mm PTV margin significantly reduced both the median chest wall D0.035cc and D30cc (Table 2).

Table 2Organ at risk parameters by PTV margin size

Abbreviations: PTV, planning target volume, body Vx%, volume of the body receiving at least x% of the prescription dose, lung V20Gy , percent of lung receiving at least 20 Gy, MLD, mean lung dose, NTCPMLD(3Gy) = normal tissue complication probability for radiation pneumonitis calculated utilizing mean lung dose in 2 Gy equivalents with an α/β of 3, DXcc, the dose to X cm3 of the chest wall (including ribs).

*Only patients for which the 5 mm margin PTV overlaps with the chest wall (N = 22) included.

Fig. 3Normal tissue complication probability (NTCP) reduction for radiation pneumonitis when planning target volume (PTV) margins are reduced from 5 mm to 3 mm compared to internal gross tumor volume (IGTV). MLD(3Gy) is the mean lung dose in 2 Gy equivalents calculated using an α/β ratio of 3 Gy. The dotted line represents the linear best fit line with R2 representing the regression coefficient.

Using our average d-IGTV D99.9% values with Eq. 4 and Eq. 5 the average TCP with 5 mm PTV margins was 96.1% with an average sBED of 104.5 Gy (range 63.1-138.7 Gy) (Figure 4). For 3 mm PTV margins the average TCP was 95.2% with an average sBED of 95.5 Gy (range 63.0-120.4 Gy). We estimate the uncertainty on these TCP calculations to be comparable to the standard deviations of the mean d-IGTV D99.9% values we obtained for each margin size, which are 7% and 5% for 5 mm and 3 mm PTV margins, respectively.

Fig. 4Two-year tumor control probability (TCP) calculated from average deformed internal gross tumor volume (d-IGTV) D99.9% achieved with 5 mm and 3 mm planning target volume (PTV) margins versus prescribed size-adjusted biological equivalent dose (sBED). sBED is defined as the biological equivalent dose minus 10 times the tumor diameter in cm (using the linear quadratic model with α/β ratio of 10 Gy). Power trendlines for each PTV margin are represented by dotted lines with r2 representing the regression coefficient.

DiscussionInnovations in image guidance, planning, immobilization, and delivery techniques have allowed SABR to become an excellent treatment option in early-stage lung cancer. Success relies on adequate target coverage and avoidance of geometrical misses. PTV margins of 5 mm are generally accepted as the current standard for lung SABR and are being used in modern trial design.4Swaminath A Wierzbicki M Parpia S et al.Canadian phase III randomized trial of stereotactic body radiotherapy versus conventionally hypofractionated radiotherapy for stage I, medically inoperable non–small-cell lung cancer – rationale and protocol design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial. Our study is the first we are aware of to validate PTV margin reduction to 3 mm. The most significant difference when compared to prior studies is our reduction in treatment time, which can primarily be attributed to the use of VMAT and FFF beams.13Wierzbicki M Mathew L Swaminath A. A method for optimizing planning target volume margins for patients receiving lung stereotactic body radiotherapy.,16Yan Y Yadav P Bassetti M et al.Dosimetric differences in flattened and flattening filter-free beam treatment plans. Wierzbicki et al. calculated that a 5 mm PTV margin covered ≥95% of the target volume ≥95% of the time; however, their average treatment time was 17.8 min.13Wierzbicki M Mathew L Swaminath A. A method for optimizing planning target volume margins for patients receiving lung stereotactic body radiotherapy. Grills et al. demonstrated that 5 mm PTV margins were required to adequately account for intrafractional drift observed with treatment times (not reported) required by 6X non-coplanar IMRT.8Grills IS Hugo G Kestin LL et al.Image-guided radiotherapy via daily online cone-beam CT substantially reduces margin requirements for stereotactic lung radiotherapy. Purdie et al. showed that mean intrafractional movement was significantly decreased when the interval between localization and repeat CBCT was shorter with a mean time between localization and repeat CBCT of 34 minutes.9Purdie TG Bissonnette J-P Franks K et al.Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: Localization, verification, and intrafraction tumor position. However, the same group did not reproduce this result in a subsequent study with a mean time of 25.9 minutes.15Li W Purdie TG Taremi M et al.Effect of immobilization and performance status on intrafraction motion for stereotactic lung radiotherapy: Analysis of 133 patients. Vloet et al. investigated 6X non-coplanar VMAT versus 6X non-coplanar IMRT for potential margin reduction and reported an average treatment time of 22 ± 6 min for the VMAT cohort.17Vloet A Li W Giuliani M et al.Comparison of residual geometric errors obtained for lung SBRT under static beams and VMAT techniques: Implications for PTV margins. They recommended a 3 mm PTV margin only if a mid-treatment CBCT and re-positioning could be performed.17Vloet A Li W Giuliani M et al.Comparison of residual geometric errors obtained for lung SBRT under static beams and VMAT techniques: Implications for PTV margins. Although the current evidence for correlating intrafraction motion and treatment time is still inconclusive, we hypothesise that our significantly shorter average treatment time of 7.9 min allows for acceptable IGTV coverage with 3 mm PTV margins (V100%>95% in 99.3% of fractions) without the requirement for repeat imaging and repositioning, which would increase overall treatment time.The original van Herk formalism assumes infinite fraction number and a non-deformed target, therefore is applicable for conventional non-hypofractionated schedules.14van Herk M Remeijer P Lebesque J V The probability of correct target dosage: Dose-population histograms for deriving treatment margins in radiotherapy. The robustness of the formalism has been experimentally validated for such large fraction number and non-deformed target scenarios.22Ecclestone G Bissonnette JP Heath E. Experimental validation of the van Herk margin formula for lung radiation therapy. The modified formalism we employed for our lung SABR PTV margin calculation (Eq. 1) has been validated for lung SABR fractionation.15Li W Purdie TG Taremi M et al.Effect of immobilization and performance status on intrafraction motion for stereotactic lung radiotherapy: Analysis of 133 patients.,18Sonke J-J Rossi M Wolthaus J van Herk M Damen E Belderbos J. Frameless Stereotactic Body Radiotherapy for Lung Cancer Using Four-Dimensional Cone Beam CT Guidance. However, for very small fraction numbers the formalism may underestimate the required margin.23