Intrafraction Motion in Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer: Intensity Modulated Radiation Therapy Versus Volumetric Modulated Arc Therapy

Accepted Manuscript Intra-fraction motion in NSCLC patients treated with IMRT and VMAT based Stereotactic Body Radiotherapy: IMRT versus VMAT Maddalena M.G. Rossi, R.T.T., MSc., Heike M.U. Peulen, M.D., Josè S.A. Belderbos, M.D., PhD, Jan-Jakob Sonke, PhD. PII:

S0360-3016(16)00113-9

DOI:

10.1016/j.ijrobp.2016.01.060

Reference:

ROB 23419

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 5 August 2015 Revised Date:

27 January 2016

Accepted Date: 29 January 2016

Please cite this article as: Rossi MMG, Peulen HMU, Belderbos JSA, Sonke J-J, Intra-fraction motion in NSCLC patients treated with IMRT and VMAT based Stereotactic Body Radiotherapy: IMRT versus VMAT, International Journal of Radiation Oncology • Biology • Physics (2016), doi: 10.1016/ j.ijrobp.2016.01.060. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Intra-fraction motion in NSCLC patients treated with IMRT and VMAT based Stereotactic Body Radiotherapy: IMRT

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versus VMAT

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Maddalena M.G. Rossi R.T.T. MSc., Heike M.U. Peulen M.D., Josè S.A. Belderbos M.D. PhD, Jan-Jakob Sonke PhD.

Corresponding author: Jan-Jakob Sonke Ph.D., Department of Radiation Oncology

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The Netherlands Cancer Institute

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Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands Tel: +31-20-5121731

[email protected]

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Fax: +31-20-6691101

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Keywords: IGRT, SBRT, IMRT, VMAT, NSCLC, Intra-fraction motion. Conflict of interest: Our department licenses CBCT reconstruction and registration software to Elekta Oncology Ltd.

Short running title: Intra-fraction motion in IMRT&VMAT SBRT

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Acknowledgements This work is partially supported by a research grant from the Dutch Cancer Society (NKI

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2009-4568). The authors wish to thank Alize Scheenstra for data retrieval, and Chun Chen,

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Karolina Sikorska and Wilma Heemsbergen for their statistical assistance.

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Summary SBRT for early stage NSCLC delivers high doses that require a high precision treatment.

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Volumetric-modulated arc therapy (VMAT) is replacing intensity-modulated radiotherapy (IMRT) because of its shorter delivery time (±12min vs. ±32min respectively). CBCT scans, acquired prior- and post-dose delivery, were used to evaluate intra-fraction motion in both techniques.

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VMAT is associated with shorter treatment times and smaller intra-fraction motion (~30%

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reduction) but the influence on PTV margins is small (<0.3mm).

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Abstract Purpose

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Stereotactic Body Radiotherapy (SBRT) for early stage inoperable non-small-cell lung cancer (NSCLC) patients delivers high doses that require a high precision treatment. Typically, image guidance is used to minimize day-to-day target displacement but intra-fraction position

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variability is often not corrected. Currently, volumetric-modulated arc therapy (VMAT) is replacing intensity-modulated radiotherapy (IMRT) in many departments because of its shorter

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delivery time. This study aims to evaluate if intra-fraction variation in VMAT patients is reduced compared to patients treated with IMRT.

Material and Methods

NSCLC patients (197-IMRT and 112-VMAT), treated with a frameless SBRT technique to a

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prescribed dose of 3x18Gy, were evaluated. Image guidance for both techniques was identical: a pre-treatment CBCT (CBCTprecorr) scan for setup correction followed immediately prior to treatment by a post-correction CBCT (CBCTpostcorr) scan for verification. Then, following either

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a non-coplanar IMRT technique or a VMAT technique, a post-treatment (CBCTpostRT) scan was

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acquired. The CBCTpostRT and CBCTpostcorr scans were then used to evaluate intra-fraction motion. Treatment delivery times, systematic (Σ) and random (σ) intra-fraction variations and associated PTV-margins were calculated.

Results

Median treatment delivery time was significantly reduced by 20min (32 min to 12 min) using VMAT compared to non-coplanar IMRT. Intra-fraction tumor motion was significantly larger for IMRT in all directions up to 0.5mm systematic (Σ) and 0.7mm random (σ). The required PTV margins for IMRT and VMAT differed by less than 0.3mm. 1

ACCEPTED MANUSCRIPT Conclusion VMAT based SBRT for NSCLC was associated with significantly shorter delivery times and correspondingly smaller intra-fraction motion compared to non-coplanar IMRT. However, the

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impact on the required PTV margin, was small.

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Introduction Stereotactic Body Radiotherapy (SBRT) is the standard of care for early stage, inoperable non-

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small cell lung cancer (NSCLC), with high local control rates (88%-98% at two years) and low toxicity (1–6). Moreover, SBRT has an important role in the treatment of oligo-metastatic disease in the lung (7).

Regardless of the treatment technique used, the high fraction dose, high biologically

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effective dose and sharp dose gradients delivered with SBRT treatments necessitate image

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guidance for accurate dose delivery. Advanced in-room image-guidance systems (8–10) allow verification of the tumor position immediately prior to treatment. Whilst most image guided radiotherapy (IGRT) systems minimize inter-fraction target displacement by an online couch correction, they typically do not manage intra-fraction motion. It has been observed that intrafraction position variability correlates with the treatment delivery time (11).

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Linac based SBRT can be delivered with 3D conformal radiotherapy (3DCRT), static-gantry intensity modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT) (where the gantry rotates around the patient during irradiation).

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For IMRT multiple non-coplanar beams provide slightly better dose distributions than co-planar based plans. (12). The treatment delivery time for non-coplanar IMRT is however substantially

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longer compared to VMAT delivery (12, 13). Since 2010, double arc VMAT has gradually replaced IMRT for SBRT in our institute, thereby considerably reducing the treatment delivery time.

The reduction in treatment time associated with VMAT SBRT could potentially also reduce the intra-fraction position variability and consequently improve the accuracy of dose delivery. This study therefore aims to evaluate intra-fraction motion in NSCLC patients that have been treated with SBRT using either IMRT or VMAT. 3

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Methods Patient selection

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Patients receiving frameless SBRT to the thorax with a prescription dose of 54Gy in 3 fractions were retrospectively and consecutively selected for this study. All patients were medically inoperable or refused surgery and had peripheral T1-2 NSCLC tumors or oligometastatic disease (≤2 lesions). For 5 patients, two lesions were treated simultaneously with two

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iso-centers but only one lesion was included in this study so that these patients were not overrepresented. Patient characteristics were evaluated to distinguish possible differences between

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IMRT and VMAT patients that could influence intra-fraction motion. 4D Treatment planning

A free-breathing 4D-CT scan (24-slice Somatom Sensation Open, Siemens, Fordheim, Germany) to reduce respiration induced artefacts was acquired for all patients. A Mid-ventilation

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(MidV) or Mid-position (MidP) 3D-CT scan (14) with the tumor close to or in its time-averaged position in the respiratory cycle was derived from the 4D-CT scan. This scan was used for GTV

optimization.

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(Gross Tumor Volume) and OARs (Organs at Risk) delineation and for treatment plan

The GTV-to-PTV expansion which accounts for geometric uncertainties, including

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respiration-induced tumor motion, was calculated using the non-linear ‘van Herk’ margin recipe (15) and used population statistics combined with the patient specific tumor amplitude derived from the 4D-CT scan resulting in a patient specific anisotropic GTV-to-PTV margin (16).

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Treatment planning and delivery Patients were scanned and treated without a stereotactic frame in a supine position on a regular mattress (PI Medical Diagnostic Equipment B.V. Tijne, The Netherlands) with a knee

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and arm-support according to departmental protocol. Treatment plans for both IMRT and VMAT were optimized in Pinnacle (version 7.4-9.2; Philips Radiation Oncology Systems, Milpitas, CA, USA). In all plans, at least 95% of the PTV received the prescribed dose with a PTV maximum

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dose constraint of 165% of the prescribed dose. Patients treated with IMRT received 16 to 20 non-coplanar beams (typically ≤1.3 segments per beam, minimum segment area of 9cm2).

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Patients treated with VMAT were treated with a dual arc technique. These were arcs of 160°, 200° or 360° depending on the location of the tumor and OARs.

All patients were treated on a linac with an integrated Cone Beam CT (CBCT) scanner (Elekta Synergy 3.5/4.6; Elekta Oncology Systems Ltd., Crawley, U.K) augmented with in-house developed software for acquisition, reconstruction and registration of (4D-) CBCT.

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Patients were setup to the CT reference position using skin marks, (tattoo pinpoints and ink lines), and aligned to the treatment room lasers. The patient was then moved to the treatment

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isocentre position using table coordinates given for the treatment plan.

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Image guidance procedure

The image guidance procedure was identical for IMRT and VMAT. A 3D- or 4D-CBCT

scan was used for setup verification (17). 4D-CBCT scans were acquired when the peak-to– peak tumor amplitude in the 4D-CT was ≥0.8cm. Three CBCT’s were acquired for each fraction. After patient setup, a CBCTprecorr scan was performed for tumor alignment. Correct alignment following the image guidance derived couch correction was then validated with a CBCTpostcorr scan. Finally, a CBCTpostRT scan was acquired after dose delivery to evaluate intra-fraction motion. 5

ACCEPTED MANUSCRIPT An online dual registration to the planning CT was performed. Dual registration quantifies residual misalignment of relevant anatomy following tumor alignment in the presence of baseline shifts. Following this protocol, the bony anatomy is firstly registered to the planning CT using a local rigid registration of a rectangular region-of-interest on a representative part of

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the vertebrae. Secondly, a local rigid tumor registration (translations only) is performed using a shaped region of interest (GTV + 0.5cm margin). When a 4D-CBCT has been acquired, each phase is registered independently after which the time averaged displacement is calculated.

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Although the registration is automatic, two experienced technologists always visually check the registration. Manual adjustments were rarely performed and only when the automatic

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registration was found to be sub-optimal.

Intra-fraction motion for the bony-anatomy (IFMBA), tumor (IFMT) and baseline (IFMBL), was determined by subtraction of the CBCTpostcorr registration from the CBCTpostRT registration. The IFMBL was defined as intra-fraction position variability of the tumor corrected for

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IFMBA. Although all three IFMs have been evaluated the emphasis in the manuscript will be on IFMT. Information on the evaluation of IFMBA and IFMBL can be found in supplementary material. Treatment delivery time was measured from the start of the CBCTpostcorr to the start of the

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CBCTpostRT scan and thus includes the time required to visually evaluate the CBCTpostcorr

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scan.

Statistics

The IFMBA, IFMT and IFMBL were analyzed in SPSS v.20 and R package Ime4 (v.2.0.20)

and ImerTest (v.1.1.7). The mean and standard deviation of the IFMBA, IFMT and IFMBL were calculated for each patient. The population statistics for IFMBA, IFMT and IFMBL are described in terms of grand mean (GM: Mean per patient and the mean thereof), systematic (Σ) (standard deviation of the means per patient) and random (root mean square of the standard deviations 6

ACCEPTED MANUSCRIPT per patient) variations (σ) (18). A t-test was used to test for significant differences in GMs and random variations between the IMRT and VMAT groups for LR, CC and AP directions. Similarly, Levene’s test was used to test for significant differences in systematic variations. A t-test or Mann Whitney test evaluated differences in patient characteristics between

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the IMRT and VMAT groups. A linear mixed model approach with a backward elimination was performed to test the influence of patient characteristics on the IFMBA, IFMT and IFMBL vector length (VL). A log transformation of these vector lengths was used to achieve a normal

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distribution (table S3).

The treatment time per fraction and average time over three fractions were calculated

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per patient. P-values were calculated with linear regression to test for an effect of time on VL for IFMBA, IFMT and IFMBL.

Reported p-values have a significance level of 0.05. As IFM was expected to increase

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with time, a one-sided value has been used. P-values for all other parameters are two-sided.

To investigate the impact of potential changes in IFM, required PTV-margins were

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calculated for IMRT and VMAT based delivery as described in (16). Margins M were calculated

The

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with the non-linear ‘van Herk’ margin recipe for the 80% dose level (15).

overall

systematic

M=2.5⋅Σ+0.84⋅(√[σ2+σ2p]-σp) (Σ)

and

random

errors

Eq. 1 (σ)

were

calculated

as

Σ=√[Σ2TD+Σ2L+Σ2I] and σ=√[σ2L+σ2I+σ2R], where the subscript TD refers to target definition uncertainty, L refers to localization accuracy, I refers to intra-fraction motion, R refers to respiratory motion and σp (6.4mm) describes the width of the penumbra in lung (16). Delineation uncertainty was estimated at 1.2mm (1SD) (19), localization accuracy was estimated by the residual tumor displacement observed in the CBCTpostcorr and intra-fraction motion was derived 7

ACCEPTED MANUSCRIPT from the difference in tumor alignment between the CBCTpostcorr and CBCTpostRT as described above. As the intra-fraction motion was only known at two time points before and after treatment delivery we assumed intra-fraction displacement to change linearly with time such that the systematic component was divided by a factor 2 to obtain the average value

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amplitudes (A) using the relationship σR=0.36A(16).

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during treatment (16). Margins were evaluated for a range of peak-to-peak respiratory

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Results Patients and characteristics

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The cohort included 309 patients treated from 2006-2013 with a total of 927 analyzed CBCTs. 197 patients were treated with IMRT (181(91.8%) prior to 2010) and 112 with VMAT (6(5.4%) prior to 2010).

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The median treatment delivery times (start CBCTpostcorr, to start CBCTpostRT) were 32.0±9.1 and 12.0±4.3 minutes for IMRT and VMAT respectively (p<0.001).

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Table 1 shows patient characteristics. BMI (p=0.018), FEV1% (Normalized forced expiration value in 1 sec) (p=0.009), and WHO performance status (p=0.042) differed significantly between the IMRT and VMAT groups. The VMAT group had more patients with a better performance status. FEV1% was significantly higher in the VMAT group even though

Intra-fraction motion

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DLCO% (Diffusion capacity of the lung for carbon monoxide) and age did not differ significantly.

Intra-fraction motion was evaluated in LR, CC and AP-direction (Table 2 and S1). Group

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mean values for all directions in both techniques were ≤1.0 mm. Systematic intra-fraction variability (Σ) ranged from 1.3-1.9 mm and 1.0-1.4 mm for IMRT and VMAT respectively. IFM

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was significantly smaller in each direction for VMAT compared to IMRT (range 0.1-0.7 mm). Similarly, random variability (σ) ranged from 1.5-2.1 mm and 1.2-1.7 mm for IMRT and VMAT respectively. Figure 1 shows the cumulative distribution of the VL for IMRT and VMAT IFMT. The distribution of the VL differs significantly between the IMRT and VMAT groups (p<0.001 ). The IMRT distribution is wider confirming larger intra-fraction motion than for VMAT. Intrafraction motion of bone and baseline is reported in the supplementary material.

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ACCEPTED MANUSCRIPT Mixed model analysis The association of patient characteristics with IFMVL (intra-fraction motion vector length) was tested in a mixed model approach using backward elimination and then significant parameters were used in the final model (univariate analysis Table S2). In this final model

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(Table S3) only a few patient characteristics appeared to have a significant association with IFMVL of the tumor: BMI (p=0.032), tumor amplitude (p=0.002), WHO PS (p=0.011), and FEV1% (p=0.025). Even though these characteristics are significant, the graphs in figure 2

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indicate only a weak influence on IFM. Other patient characteristics showed no significant association with IFMVL.

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Figure 3 illustrates the effect of the treatment time on the IFMT. We found time per fraction to be a significant predictor in a linear regression model for all three IFMs (p<0.001). The R2 values from the trend-lines in the graph in figure 3 show a good fit for the data. After correcting for this time dependence, IFM differences between IMRT and VMAT were not

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statistically significant (p=0.951).

No significant difference was found in the residual tumor displacement between the two

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groups in the CBCTpostcorr scan. Therefore, GM, Σ and σ are provided for the combined IMRT and VMAT cohort (Table S4). In figure 4, the required CTV-to-PTV margins in LR, CC and AP

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are depicted as a function of the respiratory amplitude for both IMRT and VMAT based delivery techniques. Although significant differences were observed in the IFMT between the two techniques, the impact on the required margins is ≤0.3 mm for any respiratory amplitude. The limited differences in margin between IMRT and VMAT can be explained by the quadratic sum of geometrical uncertainties in equation (1) which limits the contribution of the individual components.

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Discussion We evaluated bone, tumor and baseline intra-fraction motion in patients that were treated without immobilization device, except for a knee and arm support, with either IMRT or

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VMAT SBRT for NSCLC or lung oligo-metastatic disease. We found significant differences in intra-fraction motion between the two delivery techniques which could be explained by the shorter delivery time of VMAT. However, the impact of these differences on the required PTV

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margin is small (<0.3mm). Therefore, margin reduction following the introduction of VMAT based delivery is not recommended.

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The criteria for SBRT did not change with the introduction of VMAT. The recognition of SBRT as a safe treatment with excellent local control has resulted in more patients being offered this treatment. Factors such as the inclusion of patients with oligo-metastatic disease or patients refusing surgery in favor of SBRT (10% in each group) did not significantly differ

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between VMAT and IMRT groups. The mixed model analysis showed some significant but weak associations of patient characteristics with IFM that differed between both groups. However, after correcting for time, the difference in IFM between the 2 groups was insignificant, indicating

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that the shorter delivery time of VMAT explains the observed difference in IFM. This study showed a time dependence for IFM which was in contrast to Li et al (20) and

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XXXX et al (16) where no correlation was found (p=0.23). However, in both these IMRT studies the treatment times were quite comparable ~ 25 min, whereas in our study there was a difference of 20 min between IMRT and VMAT. (A comparison of technique treatment times is shown in Table S5). Purdie et al (11) on the other hand did have a larger range in treatment times and found increased IFM when the interval between localization and repeat CBCT imaging exceeded 34 min. Note that non-coplanar IMRT requires considerable table rotations between beams which is absent in the VMAT technique. Such table rotations potentially induce secondary 11

ACCEPTED MANUSCRIPT patient motion. However, after correcting for the difference in delivery time between the two techniques, no significantly different IFM was observed. This suggests that secondary patient motion due to table movements was negligible.

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A high degree of accuracy in software and hardware is imperative for accurate treatment delivery in SBRT. Nevertheless inaccuracies may be present such as registration inaccuracies. These however have been previously measured and were found to be submillimeter (16, 21) and will thus have a minimal impact on this study.

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The IMRT patients in our present study show a similar IFMT to our previously published

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results in which fewer patients were evaluated (16), Our mean VMAT IFMT (2.5 ± 1.8mm) is similar to that found by Peguret et al (2.1± 1.2 mm) who also used frameless positioning, but with a Flattening Filter Free (FFF) technique (treatment time 3min shorter than our VMAT) (22). Li et al. (20) found a greater IFM of the tumor in poorer performance status (PS) patients, whereas our results suggest that poorer PS was associated with a reduction in IFM.

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This effect, however, could only be observed in multi-variate analysis due to correlations of PS with FEV1%, BMI, and AmpVL.

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We found a small effect of FEV1% on IFMT. . The FEV1% was significantly higher in the VMAT group, also suggesting a fitter group of patients. The pulmonary function tests for the

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VMAT group were performed in various hospitals, whereas the majority of the IMRT group were performed in one hospital. These variations could therefore be operator dependent. Nonetheless the difference of ~5% FEV1% observed between the two groups is not deemed clinically relevant. BMI had a small effect on the IFM in all directions as indicated by the shallow line in the graph of figure 2. This is comparable to Sio et al (23) who found that obese patients had a larger setup uncertainty. Many institutes use some type of immobilization device for SBRT Our frameless technique however, shows good patient compliance and our IMRT IFM results are comparable 12

ACCEPTED MANUSCRIPT with studies using immobilization devices (18, 20, 24–27). Guckenberger et al demonstrated comparable means and SDs in IFMT using a stereotactic body frame (SBF) to our results (18). Although not the aim of this study our results imply that an immobilization device is not

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necessary to achieve limited intra-fraction motion and accurate setup when using IGRT. Although the reduced IFM of VMAT compared to IMRT did not yield clinically relevant margin reduction it has the advantage of shortened treatment times which then introduces the possibility of treating >1 lesion in one treatment session. This is not only beneficial for the

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patient but also more cost effective.

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There are some possible limitations of this study. Intra-fraction motion was measured at only two time points and not during delivery itself. We therefore cannot conclusively say that intra-fraction motion occurred during the actual treatment. We defined the time between these two measurements as treatment time, but this also included the time to evaluate the CBCTpostcorr. Since this is a retrospective study we cannot exclude improved experience of

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the radiation therapy technologist (RTT) in managing intra-fraction motion. This study evaluated IFM between IMRT and VMAT using a frameless technique. The cohort included elderly patients with lower performance status (mean age 72.2 years), but

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although only PS had a significant effect on IFMT as previously mentioned, this was small. This therefore gives further credence to the fact that all patients are capable of undergoing this

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treatment without the use of immobilization devices, including elderly and frail patients. Such patients can thus benefit from SBRT as a high local tumor control is achievable with little or no toxicity (3, 27).

Strategies to further reduce intra-fraction motion and a larger potential for further reducing treatment margins can be achieved by monitoring the target during actual treatment delivery with kV planar imaging, digital tomosynthesis (28) or inline CBCT (29).

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Conclusions We have shown that intra-fraction motion for lung tumors is smaller in VMAT based delivery than in IMRT which is due to the shorter delivery times of VMAT. Nevertheless

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reduction in intra-fraction motion had limited impact on the required margins.

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5. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA.

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2010;303:1070–1076.

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18. Guckenberger M, Meyer J, Wilbert J, et al. Intra-fractional uncertainties in cone-beam CT based image-guided radiotherapy (IGRT) of pulmonary tumors. Radiother. Oncol. 2007;83:57–64.

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radiotherapy: analysis of 133 patients. Int. J. Radiat. Oncol. Biol. Phys. 2011;81:1568–75.

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20. Li W, Purdie TG, Taremi M, et al. Effect of immobilization and performance status on intrafraction motion for stereotactic lung

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22. Peguret N, Dahele M, Cuijpers JP, et al. Frameless high dose rate stereotactic lung radiotherapy: intrafraction tumor position and delivery time. Radiother. Oncol. 2013;107:419–22.

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23. Sio TT1, Jensen AR, Miller RC, Fong de los Santos LE, Hallemeier CL, Foster NR, Park SS, Bauer HJ, Chang K, Garces YI OK. Influence of patient’s physiologic factors and immobilization choice with stereotactic body radiotherapy for upper lung tumors. J Appl Clin Med Phys. 2014;15:4931.

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ACCEPTED MANUSCRIPT Figure 1: Cumulative distribution of Intra-fraction motion Vector Length in for IMRT and VMAT irradiation in lung SBRT.

Figure 2. Regression coefficients of the impact of significant patient characteristics on intra-fraction motion (IFM) for

,

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IMRT and VMAT. IFM in mm (y axis) vs patient characteristic (x axis): upper left BMI, upper right tumor amplitude (mm) (AmpV) , lower left WHO status and lower right FEV1%value. (BMI=Body Mass Index, WHO=World Health Organization performance status grades, FEV1%=Normalized forced expiration value in 1 sec)

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Figure 3 Mean vector length (VL) tumor as a function of the treatment delivery time. The blue crosses and the green starsindicate the 25 and 75 percentile values respectively.The time bin 55-59.9min contained only 2 patients.The raw

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data trendlineis shown on each graph.

Figure 4 Estimated planning target volume (PTV) margin as a function of the respiratory amplitude in the Left-Right (L-R),Cranial-Caudal (C-C) and Anterior-/posterior (A-P) directions using the non-linear margin recipe in Eq.1 The

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0.2mm (CC) and 0.3mm (AP).

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solid lines indicate IMRT, the dashed lines VMAT treatment margins. The average margin difference is 0.1mm (LR),

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Table 1 Patient characteristics in lung IMRT and VMAT groups p values

104 (52.8) 93 (47.2)

65 (58) 47 (42)

0.201

Age (yrs) Mean (range)

72.9 (42-91)

70.9 (40-89)

0.117

BMI Mean (range)

24.8 (15.2-44.8)

26.4 (13.6-38.9)

0.018

WHO PS n (%) 0 1 2 3

30 (15.2) 102 (51.8) 60 (30.5) 3 (1.5)

30 (26.8) 42 (37.5) 36 (32.1) 2 (1.8)

0.042

Tumor volume (cc) Median (range)

5.8 (0.49-62.9)

5.4 (0.22-91.6)

0..741

Tumor location n (%) Left upper lobe Left lower lobe Right upper lobe Right middle lobe Right lower lobe

62 (32) 25 (12.7) 75 (38.1) 4 (2) 30 (15.2)

33 (29.5) 15 (13.4) 33 (29.5) 4 (3.6) 26 (23.2)

Tumor Amplitude (mm) Mean Vector Length (range)

8.70 (0-39.1)

8.39 (1.0-33.1)

FEV1% Mean (range)

66.8 (21-153)

DLCO% Mean (range)

57.1 (10-103)

Treatment Times (min) 1st quartile 2nd quartile 3rd quartile

27 32 38

Surgery refused n (%)

22 (12.5%) 29 (17%)

0.082

TE D

0.628

70.1 (27-119)

0.009

59.8 (27-107)

0.317

10 12 14

<0.001

10 (10.0%)

0.525

21 (23%)

0.370

EP

AC C

Oligometastasen n (%)

M AN U

Gender n (%) Male Female

RI PT

VMAT n=112

SC

IMRT n=197

(BMI=Body Mass Index, WHO PS=World Health Organization performance status grades FEV1%=Normalized forced expiration value in 1 sec DLCO% = Diffusion capacity of the lung for carbon monoxide).

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Table 2 Intra-fraction motion, for the Tumor in Left-Right (L-R), Cranial-Caudal (C-C) and Anterior-Posterior (A-P) in mm. (GM grand mean, ∑ systematic error, σ random error)

Tumor displacement (mm)

VMAT

IMRT

VMAT

0.1

0.2

1.1

0.9

-1.1

-0.9

p=0.40

Ʃ

1.3

1.0

p=0.029 1.5

1.2

1.8

p=0.32

1.3

1.9

p=0.005 1.9

1.4

p=0.010

1.7

2.1

p=0.019

1.4

p=<0.001

EP

TE D

M AN U

p=<0.001

p=0.28

AC C

σ

A-P

IMRT

RI PT

GM

C-C

VMAT

SC

L-R IMRT

AC C

EP

TE D

M AN U

SC

RI PT

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SC

AMPV

RI PT

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BMI (kg.m2 -1)

FEV1%

AC C

EP

WHO

TE D

M AN U

AMPV (cm)

1

AC C

EP

TE D

M AN U

SC

RI PT

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9 LR CC AP

7

RI PT

6 5

5

10

15

20

TE D

M AN U

SC

Amplitude [mm]

EP

4 0

AC C

PTV margin [mm]

8

1