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Dosimetric consequences of pencil beam width variations in scanned beam particle therapy

This article has been downloaded from IOPscience. Please scroll down to see the full text article. 2013 Phys. Med. Biol. 58 3979 (http://iopscience.iop.org/0031-9155/58/12/3979) View the table of contents for this issue, or go to the journal homepage for more

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IOP PUBLISHING Phys. Med. Biol. 58 (2013) 39793993

PHYSICS IN MEDICINE AND BIOLOGY

doi:10.1088/0031-9155/58/12/3979

Dosimetric consequences of pencil beam width variations in scanned beam particle therapy
M A Chanrion 1,2 , F Ammazzalorso 1 , A Wittig 1 , R Engenhart-Cabillic 1 and U Jelen 1
1 Department of Radiotherapy and Radiation Oncology, University of Marburg, Marburg, Germany 2 Universit e Claude Bernard Lyon 1, Lyon, France

E-mail: Urszula.Jelen@med.uni-marburg.de

Received 4 December 2012, in nal form 21 April 2013 Published 17 May 2013 Online at stacks.iop.org/PMB/58/3979 Abstract Scanned ion beam delivery enables the highest degree of target dose conformation attainable in external beam radiotherapy. Nominal pencil beam widths (spot sizes) are recorded during treatment planning system commissioning. Due to changes in the beam-line optics, the actual spot sizes may differ from these commissioning values, leading to differences between planned and delivered dose. The purpose of this study was to analyse the dosimetric consequences of spot size variations in particle therapy treatment plans. For 12 patients with skull base tumours and 12 patients with prostate carcinoma, scanned-beam carbon ion and proton treatment plans were prepared and recomputed simulating spot size changes of (1) 10% to simulate the typical magnitude of uctuations, (2) 25% representing the worst-case scenario and (3) 50% as a part of a risk analysis in case of fault conditions. The primary effect of the spot size variation was a dose deterioration affecting the target edge: loss of target coverage and broadening of the lateral penumbra (increased spot size) or overdosage and contraction of the lateral penumbra (reduced spot size). For changes 25%, the resulting planning target volume mean 95%-isodose line coverage (CI-95%) deterioration was ranging from negligible to moderate. In some cases changes in the dose to adjoining critical structures were observed. (Some gures may appear in colour only in the online journal)

1. Introduction The rationale behind the use of ion beams in high-precision radiation therapy lies in their physical property of depositing most of the dose at a well-dened depth, the Bragg peak. Additionally, for carbon ion beams, the enhanced biological effectiveness around their tracks (Amaldi and Kraft 2005) has to be considered. In order to irradiate an extended target volume,
0031-9155/13/123979+15$33.00 2013 Institute of Physics and Engineering in Medicine Printed in the UK & the USA 3979

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multiple individual Bragg peaks of single narrow mono-energetic beams need to be juxtaposed. To achieve the highest possible degree of target conformation, scanning delivery systems have been developed (Haberer et al 1993, Pedroni et al 1995, Furukawa et al 2010). In such systems the ion beam is deected by magnetic elds to paint the tumour transversely in a raster fashion, while in-depth Bragg peak placing is achieved by either active energy variation at the accelerator level or passive energy variation with range shifter plates. In treatment planning systems (TPS), the lateral proles of particle pencil beams are typically described with a (single or double) 2D Gaussian function, characterized by its full width at half maximum (FWHM), referred to in the following as a beam spot size. Energydependent multiple scattering in the treatment nozzle makes available spot sizes a function of energy. During the commissioning phase, spot sizes measured in air are recorded in the TPS. In synchrotron-based facilities, libraries of several focus settings are typically predened (Kr amer et al 2000, Parodi et al 2012). Spot size and spot spacing (raster pitch) determine the levels of dose homogeneity and inuence the steepness of lateral dose fall-off (Weber 1996, B aumer and Farr 2011). In practice, the homogeneity of dose deposition from overlapping carbon ion pencil beams can be ensured by rule of thumb that the raster pitch should be in the order of one-third of the beam spot size (Haberer et al 1993, Weber 1996, Kr amer et al 2000), while optimal spot size and raster grid settings for protons have been recently investigated by Widesott et al (2012). Fluctuations in the beam transport and extraction systems may result in deviations of the actual spot sizes from the nominal values (Parodi et al 2010) and potentially lead to differences between planned and delivered dose, including compromised target coverage or overdosage of abutting critical structures. Such variations may exist among the treatment rooms, as well as be occurring over time. For instance, during the irradiation blocks at the GSI Helmholtzzentrum f ur Schwerionenforschung, in the framework of the German ion beam therapy pilot project, typical spot size variations within 1020% with incidental maximum discrepancies of up to 40% were observed for carbon ion beams (Schardt and Weber 2012). A similar range has been recently reported by Mirandola et al (2012) for proton beams at the CNAO (Centro Nazionale di Adroterapia Oncologica) synchrotron-based facility. At the Particle Therapy Centre in Marburg, which is not yet in clinical operation, these variations have not been analysed so far, but are expected to be in the same range owing to the similar design of the accelerators. The purpose of this study was to analyse the dosimetric consequences of spot size variations on the delivery of typical scanned beam particle therapy treatment plans.

2. Materials and methods 2.1. Patient data Twelve patients with skull base tumours and 12 patients with prostate tumours were selected for this study. For both patient groups the clinical target volume (CTV), planning target volume (PTV) and the relevant organs at risk were delineated on the Pinnacle3 TPS (Philips Healthcare, Best, The Netherlands). In the patient group with skull base tumours, cases were selected with tumour localization typical for established particle therapy indications (chordoma, chondrosarcoma, adenocystic carcinoma). The planning computed tomographies (CT) had an in-slice pixel size and a slice thickness of respectively 0.98 and 3 mm for two patients, 0.59 and 3 mm for two patients and 0.59 and 2.5 mm for the remaining eight patients. The mean CTV volume was 49.9 24.1 cc (range: 15.690.7 cc). The PTV was dened by uniform 3D CTV expansion of 2 mm.

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In the patient group with prostate tumours, the planning CTs were acquired with a pixel size of 0.98 and 3 mm slice thickness. The mean CTV volume was 67.8 25.7 cc (range: 30.9108.0 cc). The PTV was dened by uniform 3D CTV expansion of 5 mm. 2.2. Treatment planning For both patient groups, scanned beam proton treatment plans and biologically optimized carbon ion treatment plans were prepared using the TRiP98 TPS (Kr amer et al 2000) which employs the local effect model (LEM) (Kr amer and Scholz 2000). The conversion program dcm2trip, developed at our institution and distributed with TRiP98, was used to convert the DICOM data (CT images and structure sets) to the VOXELPLAN format used by TRiP98 (Kr amer 2011, TRiP online documentation). For carbon ion plans, the relative biological effectiveness (RBE) of carbon ions was computed through the LEM I ( / = 2 Gy, = 0.1 Gy1 , = 0.05 Gy2 , threshold dose Dt = 30 Gy and nucleus radius r = 5 m) (Karger et al 2006, Schulz-Ertner et al 2007), employing the low-dose approximation (Kr amer and Scholz 2006). In proton plans, a constant RBE factor of 1.1 was used. All plans used a two-lateral-opposed-beam setup, reecting the geometry typically available at xed-nozzle combined proton-carbon ion facilities. Isocentric table rotations were used in some skull base cases, where deemed benecial. For skull base treatment plans the prescription dose was set to 6063 Gy (RBE) delivered in 2021 fractions for carbon ion plans and 6674 Gy (RBE) in 3337 fractions for proton plans similarly to Nikoghosyan et al (2010a, 2010b) and Ares et al (2009). Also maximum dose constraints were derived from the protocols adopted in the above mentioned studies. The prostate carbon ion treatment plans were optimized for a total dose of 60 Gy (RBE) delivered in 20 fractions similarly to Akakura et al (2004) and the proton plans were optimized to 74 Gy (RBE) in 37 fractions. Treatment planning contained no formal constraints for the rectum, however the resulting plans were checked for V90% < 10%. For both tumour localizations, the minimum satisfactory planning objective was the delivery of at least 95% of the prescription dose to >95% of the PTV volume. Realistic, clinically relevant optimization approaches were chosen for this planning study: for skull base cases, with the necessity of complex planning constraints coupled with the possibility of accurate patient positioning, intensity modulation (IMPT) was used (Gemmel et al 2008), whereas for prostate cases, for which safety against intra-fraction movement is of concern, single eld uniform dose optimization (SFUD) was employed. For all plans a minimum reference beam width of 5 mm was requested from the planning system, which selected effective sizes (in air, at isocentre) available in a synchrotron library compatible with the GSI facility during the German ion beam therapy pilot project and representative of modern combined-beam facilities, like the Particle Therapy Centre in Marburg. This resulted in carbon ion beam widths of 5.07.5 mm for skull base cases and 5.45.7 mm for prostate cases (similarly to Kosaki et al 2012, Jelen et al 2012). For protons the respective values were 6.113.5 mm and 7.310.5 mm (in air, at isocentre) and were enabled by treatment planning and delivery with shorter nozzle-to-patient distance than for carbon ions (Bubula et al 2012). These planning settings enabled comparability of some effects, as they resulted in proton spot sizes, measured at patient surface, as close as possible to the corresponding ones of carbon ions. The irradiation raster pitch was set to 2 mm for carbon ion plans and to 3 mm for proton plans. Approximately equal values were used for the so-called lateral target extension, a tolerance allowing the TPS to place additional spots outside the target volume projection, transversely to the beam, to ensure PTV coverage without the need for spots with excessive

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uence at the target border. The in-depth peak positioning step was set to 3 mm for carbon ion plans, through use of a ripple lter (Kr amer et al 2000), and to 2 mm for proton plans. For dose calculation, the multiplescatter (ms) algorithm was used, which employs a double-Gaussian pencil beam parametrization, taking into account the angular distribution of fragments after nuclear interactions and multiple Coulomb scattering of charged particles through matter (Kr amer et al 2000, Iancu et al 2009). The dose grid resolution was the same as the planning CT. 2.3. Simulation of spot size variations The characteristics of all scanned pencil beams in an optimized plan (spot size and pitch, energy, particle count) are recorded by the TPS. These data were edited and the FWHM of each spot modied by (1) 10% to simulate the typical magnitude of uctuations, (2) 25% to simulate the worst-case scenario and (3) 50% as a part of treatment risk analysis in case of fault conditions and to verify suitability of interlock thresholds. The modied plans were fed back into the planning system and the dose distributions recomputed without re-optimization. 2.4. Evaluation The treatment plans were compared in terms of dose distribution and dosevolume histograms (DVH). For a quantitative assessment the mean dose (Dmean ), coverage index (CI), conformity index (CN), homogeneity index (HI) and near-maximum/near-minimum dose (Dnear-max , Dnear-min ) were used. The CI was dened as the volume percentage encompassed by a selected isodose line. The CN index was calculated as proposed by Paddick (2000). The Dnear-min and Dnear-max were dened at the 98% and 2% volume levels respectively (ICRU 2007) and the HI index was calculated as the difference Dnear-max Dnear-min normalized to the prescription dose. For statistical comparison of selected indices, a non-parametric, paired-sample sign test was performed with a signicance level of 0.05 using the R statistical environment (R Core Team 2012). A 3 pp (percentage point) deviation from the clinical objective was deemed clinically relevant. 3. Results 3.1. Dosimetric quality of the optimized treatment plans For the original plans, with no FWHM modications, the mean PTV and CTV coverage was adequate for both groups of patients as presented in tables 1 and 2 for skull base cases and tables 3 and 4 for prostate cases (denoted as nominal). For skull base cases the constraints dened for critical structures were fullled to a clinically satisfactory level in all plans. Instead, in 1 of 12 prostate cases rectum dose exceeded the planning constraint (V90% = 17.5% for both ion species), but was deemed acceptable in consideration of a complex anatomical situation. 3.2. Dosimetric effects of spot size variations The primary effect of the spot size variations was a dose deterioration around the target edge. For larger deviations, visible loss of coverage and broadening of the lateral penumbra (increased spot size) or overdosage and contraction of the lateral penumbra (reduced spot size) occurred.

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Table 1. Mean (1 sd) of selected dosimetric indices of the original (nominal FWHM) and recomputed (modied FWHM) carbon ion skull base treatment plans.

CTV FWMH 50% 25% 10% Nominal +10% +25% +50%

a b c

PTV CI-95%a 98.7 0.5 99.3 0.3b 99.0 0.4b 98.2 0.4 96.8 0.6b 92.3 1.7b,c 81.9 3.4b,c CN-95% 77.3 3.6 82.6 2.9 85.2 2.7 86.6 2.6 87.1 2.6 85.0 2.8 77.2 4.2 Dmean (%) 101.7 0.3 101.1 0.2 100.5 0.1 100.1 0.2 99.7 0.2 99.0 0.3 97.7 0.5 Dnear-min (%) Dnear-max (%) HI (%) 95.9 0.9 97.0 0.5 96.5 0.7 95.3 0.7 93.8 0.6 91.1 0.8 86.8 1.2 112.0 2.6 106.9 1.3 104.3 0.7 103.1 0.4 102.3 0.3 101.7 0.3 101.3 0.3 16.1 3.4 9.9 1.4 7.7 0.9 7.8 0.9 8.6 0.8 10.6 0.9 14.5 1.1

CI-98%a 91.7 4.5b,c 96.6 1.6b 98.1 0.7b 98.0 0.9 96.5 1.5b 91.0 2.3b,c 77.2 4.9b,c

Differences tested statistically (sign test). Statistically signicant (p < 0.05) difference with respect to the nominal plan. Clinically relevant (3 pp) deviation from the clinical objective. Table 2. Mean (1 sd) of selected dosimetric indices of the original (nominal FWHM) and recomputed (modied FWHM) proton skull base treatment plans.

CTV FWMH 50% 25% 10% Nominal +10% +25% +50%

a b c

PTV CI-95%a 97.8 0.8b 97.7 0.7b 96.7 0.7b 95.5 0.7 93.9 0.9b 90.3 1.5b,c 80.6 6.2b,c CN-95% 75.7 5.2 77.5 5.2 78.6 5.1 79.0 4.9 78.9 4.8 77.7 4.5 71.5 7.6 Dmean (%) 101.3 0.4 101.3 0.3 100.8 0.2 100.5 0.2 100.1 0.2 99.4 0.2 95.8 8.2 Dnear-min (%) Dnear-max (%) HI (%) 94.8 0.8 94.6 0.9 93.4 0.8 92.3 0.7 91.1 0.8 89.1 0.9 78.2 24.7 109.2 1.8 107.7 1.2 106.5 0.9 105.7 0.7 105.0 0.5 104.2 0.5 103.2 0.5 14.4 1.5 13.1 1.0 13.1 0.9 13.4 0.9 13.9 0.9 15.0 1.0 25.0 24.5

CI-98%a 87.6 3.8b,c 94.1 2.1b 94.7 2.0b 94.2 2.1 93.3 2.2b 90.2 2.5b,c 78.0 7.1b,c

Differences tested statistically (sign test). Statistically signicant (p < 0.05) difference with respect to the nominal plan. Clinically relevant (3 pp) deviation from the clinical objective. Table 3. Mean (1 sd) of selected dosimetric indices of the original (nominal FWHM) and recomputed (modied FWHM) carbon ion prostate treatment plans.

CTV FWMH 50% 25% 10% Nominal +10% +25% +50%

a b c

PTV CI-95%
b,c a b

CI-98%

CN-95% 85.0 3.0 88.7 2.0 90.5 1.7 91.6 1.5 92.6 1.3 92.6 1.3 84.7 3.9

Dmean (%) 100.2 0.2 100.5 0.1 100.4 0.1 100.2 0.1 100.0 0.2 99.6 0.2 98.8 0.4

Dnear-min (%) Dnear-max (%) HI (%) 95.0 0.7 97.4 0.4 98.1 0.3 97.9 0.5 96.7 0.7 94.3 0.7 90.5 0.9 109.5 0.9 105.5 0.4 103.4 0.2 102.5 0.3 102.0 0.2 101.6 0.2 101.3 0.2 14.6 1.5 8.1 0.7 5.3 0.5 4.6 0.6 5.3 0.7 7.2 0.7 10.8 0.8

81.7 9.4 96.3 1.8 99.0 0.6b 99.7 0.2 99.9 0.1b 99.9 0.1b 99.6 0.6b

98.0 1.1 99.8 0.1b 99.8 0.1b 99.6 0.3 99.2 0.4b 97.3 0.8b 87.5 4.0b,c

Differences tested statistically (sign test). Statistically signicant (p < 0.05) difference with respect to the nominal plan. Clinically relevant (3 pp) deviation from the clinical objective.

3.2.1. Skull base cases. For a selected patient, the exemplary dose distributions of the original plan and of recomputations with beam spot size modications, are presented in gure 1 for carbon ion plans and in gure 2 for proton plans. The corresponding dose proles, demonstrating the inuence of spot size modications on dose homogeneity and lateral penumbra, are shown in gure 3. These effects are noticeable in the prolonged tails and the shallower shoulders of the PTV and CTV DVHs (gure 4).

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Figure 1. Carbon ion dose distributions of an exemplary skull base case with original (nominal) and modied spot FWHM, in the transversal (T), coronal (C) and sagittal (S) planes. In transversal view: PTVwhite, brainstemblue. Table 4. Mean (1 sd) of selected dosimetric indices of the original (nominal FWHM) and recomputed (modied FWHM) proton prostate treatment plans.

CTV FWMH 50% 25% 10% nominal +10% +25% +50%

a b c

PTV CI-95%
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CI-98%

CN-95% 86.4 3.0 88.5 2.4 89.5 2.0 89.7 1.9 89.3 1.8 86.3 2.1 81.4 3.8

Dmean (%) 101.4 0.3 101.2 0.2 100.8 0.1 100.4 0.1 100.1 0.2 99.6 0.2 98.5 0.3

Dnear-min (%) Dnear-max (%) HI (%) 95.4 0.5 95.9 0.6 95.3 1.0 94.4 1.0 93.2 1.0 91.3 0.9 87.8 0.8 109.0 0.7 107.3 0.7 106.1 0.6 105.2 0.6 104.4 0.6 103.4 0.5 102.2 0.4 13.6 1.1 11.4 1.2 10.7 1.5 10.8 1.5 11.2 1.5 12.1 1.3 14.4 1.1

78.3 5.6b,c 88.1 4.4b,c 92.0 3.5 94.6 2.9 96.7 2.1b 98.7 1.1b 98.9 1.1b

98.6 0.8b 98.9 0.5b 98.3 0.8b 97.4 1.0 95.9 1.3b 91.6 2.0b,c 85.0 3.5b,c

Differences tested statistically (sign test). Statistically signicant (p < 0.05) difference with respect to the nominal plan. Clinically relevant (3 pp) deviation from the clinical objective.

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Figure 2. Proton dose distributions of an exemplary skull base case with original (nominal) and modied spot FWHM, in the transversal (T), coronal (C) and sagittal (S) planes. In transversal view: PTVwhite, brainstemblue.

The mean dosimetric indices of treatment plans, both with nominal and modied FWHM values, are presented in table 1 for carbon ion and table 2 for proton plans. Spot size variations did not induce relevant change in mean target dose. In terms of PTV coverage, for both particle species, the plans recomputed with reduced spot sizes or with spot size increase of 10% showed only minor changes and continued to fulll the initial clinical objectives, while a FWHM increase by 25% and 50% resulted in a statistically signicant and clinically relevant reduction of the mean CIPTV -95%. This was reduced respectively to 92.3 1.7% and 81.9 3.4% in carbon ion plans and to 90.3 1.5% and 80.6 6.2% in proton plans. In the CTV, for FWHM modications of +25%, +50% and 50%, a statistically signicant and clinically relevant CICTV -98% reduction to respectively 91.0 2.3%, 77.2 4.9% and 91.7 4.5% was observed for carbon ion plans. Consistently, for proton plans, a mean CICTV -98% reduction to 90.2 2.5%, 78.0 7.1% and 87.6 3.8% was observed for the same FWHM modications. The appearance of overdosed and underdosed

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Figure 3. Exemplary dose cross-proles for a skull base case, at the isocentre along the mediolateral (left), superoinferior (middle) and anteroposterior (right) directions, of the original (nominal FWHM) and recomputed (modied FWHM) plans. Plans prepared with: (a) with carbon ions (b) with protons. Shaded area represents the extension of the PTV.

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Figure 4. DVH for PTV (left), CTV (middle) and brainstem (right) for an exemplary skull base case. Plans prepared with: (a) with carbon ions (b) with protons.

regions was reected by changes in the Dnear-max and Dnear-min and, consequently, by increase (i.e. worsening) of the HI. A modication of the lateral beam gradients, visible in the prole plots in gure 3 lead, in some cases, to a change in the dose delivered to the critical structures in close proximity of the target. An example of this effect is shown in one patient in gure 4, where the low-to-medium-dose and high-dose regions of the brainstem DVH are affected by the FWHM variations.

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Figure 5. Carbon ion dose distributions of an exemplary prostate case with original (nominal) and modied spot FWHM, in the transversal (T), coronal (C) and sagittal (S) planes. In transversal view: PTVwhite, rectumblue.

Over the entire patient cohort and for both ion species, the Dnear-max to the brainstem increased with the decrease of the spot size. For carbon ion plans the maximum increase of Dnear-max to the brainstem, observed in an individual patient, was 1.0 pp for 10%, 2.5 for 25% and 5.4 pp for 50% spot size reduction. For proton plans, respectively for the same spot size modications, brainstem Dnear-max increases by 1.1, 2.6 and 4.4 pp were observed, also in an individual patient.

3.2.2. Prostate cases. The dose distributions of the original and recomputed plans of an exemplary prostate patient are shown in gure 5 for carbon ion and in gure 6 for proton plans, while the corresponding dose cross-proles are presented in gure 7. For both carbon ions and protons, plans behaved in general similarly to those of skull base cases: with a decreasing spot FWHM, overdosage areas appeared in the dose distributions, while an increasing spot

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Figure 6. Proton dose distributions of an exemplary prostate case with original (nominal) and modied spot FWHM, in the transversal (T), coronal (C) and sagittal (S) planes. In transversal view: PTVwhite, rectumblue.

size led to underdosage effects, also reected in the prolonged tails and shallower shoulders of the DVH of the PTV (gure 8). The mean dosimetric indices for prostate treatment plans, both original and recomputed, are presented in tables 3 and 4 for carbon ion plans and proton plans respectively. No clinically relevant changes were observed in the mean PTV doses. Dose distribution deteriorations visible in gures 5 and 6 were reected in homogeneity and coverage indices. In carbon ion plans, changes of the spot size by 10% and 25% did not induce a clinically relevant deterioration of the CTV and PTV coverage. For a beam spot size variation of +50%, the mean CIPTV -95% was reduced signicantly to 87.5 4.0%, while for a spot size reduction by 50% the CICTV -98% was reduced to 81.7 9.4%. Similarly, in proton plans, all tested spot size reductions, together with the spot size increase by 10%, did not induce a clinically relevant deterioration of the PTV coverage. Instead further spot size increase affected the PTV coverage, reducing it to 91.6 2.0% and to 85.0 3.5%. Contrary to carbon ion plans, the spot size decrease always resulted in

Dosimetric consequences of pencil beam width variations in particle therapy

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Figure 7. Dose cross-proles for an exemplary prostate case, at the isocentre along the mediolateral (left), superoinferior (middle) and anteroposterior (right) directions, of the original (nominal FWHM) and recomputed (modied FWHM) plans. Plans prepared with: (a) with carbon ions (b) with protons. Shaded area represents the extension of the PTV.

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Figure 8. DVH for the PTV (left), CTV (middle) and rectum (right) for an exemplary prostate case. Plans prepared with: (a) with carbon ions (b) with protons.

pronounced reduction of CICTV -98% to 92.0 3.5%, 88.1 4.4% and 78.3 5.6% for 10, 25% and 50%. The spot size increase caused instead a slight CICTV -98% enhancement. As in the skull base cases, dose modications in structures abutting the target volume were observed for both particle species, as shown by the DVH (gure 8). In carbon ion plans, the maximum increase of Dnear-max observed in one patient was 1.8, 4.8 and 10.4 pp, for spot size reduction by 10%, 25% and 50% respectively, while for proton plans the maximum increase was respectively 1.1, 2.5 and 4.1 pp.

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4. Discussion The consequences of variations in the delivered spot sizes, with respect to the nominal values used for planning, on target coverage and on sparing of abutting critical structures were investigated, for scanned beam particle therapy with protons and carbon ions. In the only published study known to the authors addressing this topic, Parodi et al (2010) simulated for proton and carbon ion beams, horizontal prole width changes of 50%, 100% and 150%, as well as extreme situations of narrow rectangular or truncated proles, on treatment plans prepared for a spherical target of 50 mm in diameter, placed at a 50 mm depth in water, with no contiguous critical structures. Such geometry represents a worst-case scenario, where indepth beam broadening and the compensating effects of numerous overlapping pencil beams unlikely manage to counteract the effects of spot size deviations. Additionally, as the focus of this work was risk assessment and denition of threshold settings for the beam monitoring system, the FWHM variations that were tested all fall in the upper range of expected values. Instead in our study spot size variations were simulated on realistic clinical treatment plans. The simulated values of the FWHM deviations, 10, 25 and 50%, reect respectively typical uctuations, peak uctuations and fault conditions, for synchrotron-based particle therapy facilities (Schardt and Weber 2012, Mirandola et al 2012). Moreover, the patient cohorts represent realistic clinical scenarios: extent and localization of target volumes are consistent with typical particle therapy indications, treatment plans were prepared according to clinical guidelines (e.g. use of planning constraints, IMPT for skull base cases) and RBE of carbon ions, as calculated by the LEM model, was taken into account. The primary effect of the spot size variations on both particle species was a loss of conformity and homogeneity in the delivered dose mainly in proximity of the target edges. For larger deviations, visible dose deterioration occurred, with loss of coverage and broadening of the lateral penumbra (increased spot size) or overdosage and contraction of the lateral penumbra (reduced spot size) (gures 3 and 7). In the rst approximation, the differing patient geometries (tumour volume and location, tissue inhomogeneity), within each patient cohort, did not introduce signicant variability in the dosimetric results. Instead, these appeared more dependent on the indication and optimization approach of choice: the skull base cases, with shallower penetration depths and more modulated original rasters (IMPT), were more affected by spot size changes as compared to the prostatic tumour cases, with deeper localization and smoother original uences (SFUD-optimization on a regular volume). For decreasing spot sizes, an overdosage trend appeared with both carbon ions and protons, compatible with the delivery of the uence planned for each pencil beam to a smaller area. The narrowing of the lateral penumbra, combined with the unmodied raster pitch, qualitatively resulted in a modulation or rippling of the delivered dose, visible in the notched cross-proles (gures 3 and 7), especially nearby the edge and for larger variations (50%). The rippling effect introduced dose minima below the clinical CTV reference dose (98% of the prescription) causing decrease of mean CICTV -98%, both in skull base and prostatic tumour localization. No relevant change on either the mean PTV dose or the CIPTV -95% was associated with it, as the dose oscillations remained above 95% and cancelled out. On the target edges the uence boost caused by spot reduction is the dominating effect, with the appearance of overdosages. The spot size increase resulted in dose smearing and gradient softening induced by the delivery, by each pencil beam, of the same uence over a larger surface. With larger spot size deviations ( 25%), this phenomenon affected the PTV coverage and the underdosage involved almost the entire inner PTV rim (gures 1 and 2). For the head cases, where a CTV-to-PTV margin of 2 mm was employed, the edge underdosage affected even the CTV coverage with a decrease of the CICTV -98%, which can potentially be clinically relevant. For the largest spot

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size increase (50%) applied on skull base cases, the underdosage affected such a large relative volume (by expanding from the edge inside the target) to induce a reduction of the mean PTV dose, a parameter else virtually unaffected in all other scenarios considered in this study. In prostate cases, with a CTV-to-PTV margin of 5 mm, the CTV coverage was not affected. Furthermore, dose increase caused by spot size reduction can occur partially outside of the target volume and involve abutting critical structures. In our study, for carbon ion plans, this resulted in an increase of the Dnear-max by up to 2.5 pp in the brainstem for skull base cases and 4.8 pp in the rectum for prostate cases, for spot size reduction by 25%, and respectively by 5.4 pp and 10.4 pp, for spot size reduction by 50%. For proton plans, the corresponding values were: 2.6 pp and 2.5 pp for spot size reduction by 25% and 4.4 pp and 4.1 pp for spot size reduction by 50%. An attempt at a direct comparison between carbon ions and protons based on the dosimetric response of treatment plans in the presence of spot size modications, is confounded by inherent differences in the dose conformity the two species enable. However, some qualitative observations can be made considering the dosimetric indexes obtained in case of extreme spot size modications (50%) relatively to the original values for each species. While the changes in CI were comparable, some distinct patterns could be observed for the HI. For skull base cases the HI was affected more by spot size reduction in carbon ion plans and more by spot size increase in proton plans. This observation can be easily explained by the reduced compensating effect from scattering in carbon ion plans as compared with proton plans, especially for very narrow spot sizes. In contrary, the effects of beam spot size increase are more severe for protons, as they accumulate with the more pronounced scattering in tissue. For prostate cases, a stronger homogeneity degradation in carbon ion plans with reduced spot sizes was also present, while the effects of spot size increase were similar for both ion species. The latter demonstrates how, at depths corresponding to prostate localization, scattering becomes relevant also for carbon ions, making the effects comparable. When assessing the potential impact of these results on patient treatment, some simplications potentially affecting the interpretation of this study should not be neglected. In our investigation identical modications were simulated for all energy layers of each plan and along both transversal beam axes. In practice, uctuations of variable magnitude should be expected at each extraction cycle and with one transversal direction (horizontal) larger than the other, as a consequence of the extraction septum construction (Parodi et al 2010), presumably reducing the total effect on dose distributions. Furthermore, as previously mentioned, according to the technical data of different facilities, a variation of 25% should be considered as the worst-case scenario under normal operation conditions. Excessive deviations could be prevented, employing the beam monitoring system coupled with an interlock, strongly limiting, in practice, possible dose distribution deterioration. Finally, the application of the total therapeutic dose is often divided into fractions, typically over the course of several weeks, causing delivery uncertainties, like spot size discrepancies, to be statistically smoothed, provided that they are not systematic. Still, it is advisable that, for a thorough clinical assessment, a similar study be repeated in the future, employing e.g. the on-line beam monitoring system log as input, in order to consider the real number of particles delivered per spot, spot size and spot position, which are all subject to delivery-time uctuations. 5. Conclusion In actively scanned particle beam radiotherapy, differences in the width of pencil beams between commissioning data and actual beam extraction have dosimetric inuence on

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treatment plans. Although for realistic spot size variation ( 25% FWHM), the observed target coverage deterioration was ranging from negligible to moderate, this should be considered with caution. In particular, in some cases spot size variations are associated with relevant changes in the dose to adjoining critical structures. Some of the negative effects can be mitigated e.g. with the application of treatment planning margins. Finally, spot size variations are only one of many potential delivery-time uncertainties that can affect the nal dose distribution, like positioning errors, anatomy changes, range uncertainties etc. For novel techniques, like carbon ion scanned-beam radiotherapy, the relevance of such uncertainties and of their interplay remain mostly to be quantied. Acknowledgments This work has been supported by a Research Grant of the University Medical Center Giessen and Marburg (UKGM) 35/2010 MR. The development of the data conversion and visualisation tools was supported by the ULICE project co-funded by the European Commission under FP7 grant agreement number 228436. The authors are grateful to Dr M Kr amer for enabling the TRiP98 computations, to Dr G Iancu and Dr U Weber for providing the proton base data and to Dr U Weber for providing technical information on the beam spot size variations and his valuable comments on the manuscript. References
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