Radiotherapy and Oncology 121 (2016) 281–287

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Radiotherapy and Oncology

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Liver proton therapy

An evaluation of rescanning technique for liver tumour treatments using

a commercial PBS proton therapy system
Ye Zhang a,b,⇑, Isabel Huth b, Martin Wegner b, Damien Charles Weber a,c, Antony John Lomax a,d
a
Center for Proton Therapy, Paul Scherrer Institut, Villigen-PSI, Switzerland; b Varian Medical Systems – Particle Therapy GmbH, Troisdorf, Germany; c Radiation Oncology Department,
University Hospital Zurich; and d Department of Physics, ETH Zurich, Switzerland

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: The treatment quality of pencil beam scanned (PBS) proton therapy to mobile
Received 25 June 2016 tumour treatments can be compromised due to interplay effects. The aim of this work is to systematically
Received in revised form 12 September evaluate the effectiveness of rescanning for liver tumour treatments for a commercial PBS delivery sys-
2016
tem.
Accepted 25 September 2016
Available online 7 October 2016
Materials and methods: Plans were calculated to patient specific ITV’s (2GyRBE), using spot spacings of 4
and 8 mm for 1- and 3-field plans. 4D dose calculations were performed using regular and irregular
motion extracted from nine 4DCT(MRI) liver datasets with 4 different starting phases. Up to 19 times
Keywords:
Scanned proton therapy
adaptive-scaled layered and volumetric rescanning were simulated using beam profiles and delivery
Moving targets dynamics of a commercial proton therapy system.
4D dose calculation Results: For small (10 mm) motions, 3-field plans achieved CTV HI’s (D5–D95) to within 8.5% (80th per-
Interplay effect centile) of the static case without rescanning. For larger motions, volumetric rescanning resulted in 4.5%
Rescanning improved HI in comparison to layered, but requires 5 times longer treatment times and is more sensitive
4DMRI to detailed plan characteristics and delivery dynamics. Increased spot spacings were found to reduce sen-
sitivity to interplay and reduce delivery times by 60%, whilst reduced energy switching times decreased
treatment time by up to 75% for volumetric rescanning without however improving plan quality.
Conclusion: For the investigated proton therapy system, rescanning can help recover dose homogeneity
under conditions of motion but, particularly for motions over 10 mm, should be combined with addi-
tional motion mitigation techniques.
Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 121 (2016) 281–287

Pencil Beam Scanned proton therapy (PBS) is becoming one of
the most attractive radiotherapy techniques, with promising clini-
cal outcomes being demonstrated for various indications [1–3].
However, its efficacy for the treatment of moving tumours (e.g.
lung, liver and other tumour sites in the upper abdomen or pelvic
region) is still a matter of concern, mainly due to the interplay
effects [4]. In addition to motion induced dose blurring effects at
the edge of the target volume, which can be efficiently addressed
using an internal target volume (ITV) [5], additional over- and
under-dosage within the target volume, due to the interplay of
delivery dynamics and anatomical motion, cannot be compensated
by margins only. Therefore, selecting and implementing additional
motion mitigation approaches for PBS are essential for assuring the
advantages of this technique in terms of delivery quality.
Various strategies have been proposed to mitigate motion
effects for PBS based treatments [6,7]. For instance, interplay can
⇑ Corresponding author at: WBBA/014, Paul Scherrer Institut, 5232 Villigen-PSI,
Switzerland.
E-mail address: ye.zhang@psi.ch (Y. Zhang).
be reduced if motion amplitude is controlled, such as by breath-
hold [8] or beam gating [9–12] strategies or, at the other end of
the spectrum of complexity, by tumour tracking [13–15].
Alternatively, rescanning [16,17] can be regarded as a relatively
straightforward way to deal with the interplay effect, since it is
only dependent on statistical averaging and is independent of
any extra equipment, implementation or active cooperation from
the patient.
Although the effectiveness of rescanning for mobile tumours
has been demonstrated in a number of simulations and experi-
ments [18–23], its performance is highly machine-specific, simply
due to its sensitivity to small variations in the relative timelines of
beam delivery and respiratory tumour motion [18]. In addition,
beam size, as well as machine specific scanning parameters, spot
distance, dose rate, lateral position switching time, energy layer
switching time etc., all have a significant impact on the timeline
of each delivered spot and can therefore result in substantial differ-
ences in the final dose distribution and motion mitigation efficacy.
Consequently, it is important to study such effects using as accu-
rate a simulation of the actual delivery conditions as possible, so

http://dx.doi.org/10.1016/j.radonc.2016.09.011
0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
282 PBS proton rescanning for liver tumour
as to be able to obtain a meaningful quantification of the interplay
effects, as well as to investigate the optimal parameters for apply-
ing a robust plan.
In this study, we have systematically evaluated the effective-
ness of different liver tumour treatments using the delivery charac-
teristics of the Varian ProBeam PBS system, through the use of
dedicated 4D dose calculations (4DDC) which consider the specific
parameters of this system (raster scanning with variable dose rate),
together with a comprehensive motion database which not only
takes into account realistic patient geometries and deformable
motion, but also includes inter-cycle breathing variability. In par-
ticular, we have compared the efficacy of different rescanning
approaches and treatment plan scenarios, as well as the dosimetric
effects of motion irregularity.
Materials and methods
Patient and motion data
Nine 4DCT(MRI) datasets [24] have been used in this study,
generated from three 4DCT data sets of three liver patients
(denoted as I, II and III respectively), each additionally modulated
by three different motion scenarios (denoted as A, B and C)
extracted from a 4DMRI motion library of liver motion using
dynamic image fusion [24]. In order to produce these datasets,
the mechanical correspondence of liver meshes in MRI and CT were
firstly determined by defining landmarks which move similarly
across different livers. Then, the simulated 4DCT(MRI) are created
by warping these deformation fields, extracted from 4DMRI, to a
static 3DCT data set. The tumour locations and characteristics of
each patient are shown in Fig. 1. CTV volumes at End-of-
Exhalation (EE, the reference phase) were 403, 264 and 122 cc
for Patients I, II and III respectively. The extracted liver motions
(with respect to the reference EE phase of the first breathing cycle)
have also been shown in Fig. 1, as acquired from 4DMRI with a
Fig. 1. Components used for generating 4DCT(MRI) datasets for 4D dose calculations.
temporal resolution of 2–3 Hz. The mean, inter-cycle averaged
motion magnitudes for motion A, B and C were of the order of
10, 15 and 20 mm with mean/range periods, calculated using
Fourier analysis of the breathing signals, of 3.3(2.9–4.0),
6.3(5.2–7.2), 5.3(4.7–6.3) seconds respectively.
4D dose calculation
The beam profiles and scanning parameters used for all 4DDC’s
are those of the Varian ProBeam PBS system. As such, proton pencil
beams have been modelled using an energy dependent parameter-
isation of integral depth dose curves in water and a two-
dimensional Gaussian representation of lateral profiles with beams
sizes (sigma) in air of 4–5.5 mm at isocentre (depending on the
energy). For each field, pencil beam separations orthogonal to the
beam direction of either 4 or 8 mm have been used, together with
energy switching times (for 3.5 MeV, corresponding to range steps
of 3.9–8.6 mm (75–245 MeV) in water)) of 700, 500, 200 and
100 ms. The faster energy switching times have been included in
this analysis in order to analyse the potential impact of energy
switching time on interplay effects, rescanning efficiency and
treatment duration. For lateral motion of pencil beams, raster scan-
ning has been modelled by including the magnetic scanning time
in the delivery timeline calculation. Raster scanning speeds are
20 mm/ms and 5 mm/ms for the two directions respectively, with
maximum dose rates being set to be around 2  1010 protons/s
(energy dependent). For consecutive pencil beams spaced by more
than 10 mm, the beam is switched-off in between. In addition, the
duration of each spot irradiation depends on the fluence (number
of protons per spot resulting from the field specific optimisation
process) and the dose rate (protons/s) of the proton beam at the
given energy, as the ProBeam system varies dose rate on an energy
layer-by-layer basis, such that the pencil beam with the smallest
weight in the layer can be delivered with a duration of at least
3 ms.
 Y. Zhang et al. / Radiotherapy and Oncology 121 (2016) 281–287
Rescanning
Two rescanning strategies have been implemented in this study
– layered and volumetric rescanning (LS and VS). For layered res-
canning, spots within one iso-energy layer are visited several times
until the planned fluences per pencil beam are completely deliv-
ered, before the energy is changed for the next layer. In contrast,
for volumetric rescanning, instead of repeating the scanning pat-
tern within one energy layer, the whole target volume (all energy
layers) is visited in each rescan.
For both approaches, the division of beam weight (protons
delivered for each spot per rescan) is based on a scaling model in
which all spot weights are divided uniformly by a given factor,
with this scaled beam weight being applied in each rescan. How-
ever, it should be noted that within any one energy layer, opti-
mised PBS fields can have a large dynamic range of pencil beam
weights [25], and thus when multiple rescans are applied, there
is an increasing number of low weighted pencil beams which can
be difficult to apply. For this reason, an adaptive-scaling algorithm
has been used, which can compensate this by comparing the scaled
beam weight with a pre-defined threshold (3.5 million protons)
to assure that all beam weights are above threshold and are deliv-
erable. Pencil beams are not further visited once their defined
beam weight has been fully achieved in previous rescanning.
4D treatment planning and plan evaluation
In order to differentiate the dose inhomogeneity induced by
interplay effects from those of dose blurring at the field edges, a
geometric Internal Target Volume (gITV) was calculated for each
patient from the 4DCT(MRI) datasets by the Clinical Target Volume
(CTV) from each phase of the first breathing cycle of each motion
scenario (see Fig. 1). PTV was assumed to be equal to CTV without
considering patient setup error. Three single-field-plans (using the
field directions depicted in Fig. 1) and a three-field-plan were cal-
culated for each of the nine cases, using the reference CT at the EE
phase. For all fields and plans, the Single Field Uniform Dose
(SFUD) approach was used [26], ensuring a homogenous coverage
of the target from all individual fields and a prescription dose of
2GyRBE to the case specific gITV was defined for all plans. Layered
and volumetric rescanning with 1–19 times (1 rescan is equal
to no rescan) have then been simulated in the 4DDC using the
above mentioned parameters of the ProBeam system. The 4DDCs
have also been performed for both regular (repeated motion of
the first breathing cycle) and irregular motion (based on multiple
breathing cycles), and have been simulated each with four differ-
ent starting phases: end exhalation (0%), middle inhalation (25%),
end inhalation (50%) and middle exhalation (75%).
Dose Volume Histograms (DVHs) were calculated for each 4D
plan, from which the homogeneity index (HI) of the dose within
the CTV was measured in terms of the difference between the D5
and D95 (D5–D95). Since a relatively large gITV has been used
which covers the range of tumour motion, any deterioration in
the HI value will be mainly due to over- and under-dosages result-
ing from residual interplay effects. Furthermore, in order to obtain
statistical significance, a two-sided Wilcoxon rank sum test (signif-
icance level = 5%, paired) has been performed between the result-
ing HI values from the different rescanning approaches, plan
configurations, delivery starting phases, motion patterns and
energy switching times. Additionally, we have used a normalised
quantification of the variation of HI, defined as the difference
between maximum and minimum HI divided by the mean HI, to
quantify the influence of starting phase and energy switching time.
The higher this variation, the higher the impact expected for the
analysed parameter.
283
Results
The effectiveness of rescanning
Due to differences in tumour geometry and location, this 4D
analysis has considered a large variation of plan characteristics.
The calculated fields contained between 775 and 2138 individually
weighted proton pencil beams, between 14 and 26 energy layers
(ranging between 77 and 178.5 MeV), and between 4 and
12  1010 protons-per-field to deliver 2GyRBE to the gITV. Without
rescanning (Fig. 2), three-field plans achieved HI’s within
7.2/8.5/12.0% (median/80th percentile/maximum) of the static case
for all three investigated patients with the 10 mm motion trace
(scenario A), independent of motion irregularities. In contrast, for
the larger motions (scenarios B and C), HI’s for the three-field plans
were 15.8/18.1/20.2 worse than the static case when rescanning is
not employed. In addition, by taking into account the four different
starting phases of beam delivery, statistically significant differences
(P  0.01) between LS and VS were found. For the same motions
and three-field plans, volumetric rescanning (VS) provided mean
improvements of 4.5% in HI in comparison to layered rescanning
(LS). LS could at best achieve HI to within only 9.2/10.9/13.5%
(median/80th/max) of the static case, whilst VS could reduce fur-
ther to within 5.1/6.6/10.3% (median/80th/max). However, this
comes at a cost of, on average, 5 times longer treatment times for
VS. For the smaller motion (A), LS and VS were able to achieve com-
parable plan homogeneity. However, for the larger motions (B and
C), increased variation in HI, as a function of patient and increasing
scan number, was found for VS.
The impact of spot spacing and plan configuration
When spot spacing was enlarged from 4 mm to 8 mm, treat-
ment times for a single scan could be reduced by 60%, mainly
due to the higher dose rates which were achieved as a result of
the higher average weight per pencil beam for the 8 mm plans.
In addition, without rescanning, there was also an around 20%
reduction of the interplay effect when using the larger spot spac-
ing. Compared to the three-field-plans, the single-field-plans have
almost double the magnitude of interplay effect if no motion mit-
igation is applied, especially for larger motion, with HI’s as high as
80% being calculated. Moreover, the uncertainty bands (20th–80th
percentile) for these single-field plans were generally larger than
for the three-field-plans, indicating a higher sensitivity of single-
field plans to field direction, patient and motion irregularity. Sig-
nificant differences (P  0.01) between LS and VS have been found
for all cases, being however less pronounced for the smaller
motion. The different results indicate the sensitivity of 4D treat-
ments on the details of the delivery dynamics.
The impact of motion starting phase
Our statistical analysis indicates significant differences
(P  0.01) between 4D plans calculated with different starting
phases. However, there was no direct correlation between nor-
malised HI variation and rescan number for either LS or VS. As
shown by boxplots in Fig. 3(c) and (d), the dosimetric impact
was generally more pronounced and varied for VS than LS. The
median value of the normalised variation of up to 30% were
observed for individual subjects and specific rescan number. This
indicated that LS tends to be more predictable, whilst not quite
so effective as VS.
The impact of motion irregularity
As shown in Fig. 4, both LS and VS yielded statistically signifi-
cant (P  0.01) higher HI values (1% in mean over all scenarios)
284
Fig. 2. HI of 4D plans (in CTV) using layered (red) or volumetric (blue) rescanning with a function of scan number, motion scenarios and plan configurations. Colour-bands
represent the 20th–80th percentile of HIs from 3 different patient subjects, 4 different starting phases, 2 types of motion pattern, and 3 field directions (for single-field-plan).
Dots in red and blue show data of each 4D plan.
for irregular motion than regular motion, indicating that an under-
estimation of motion effects could be obtained if motion is mod-
elled as a perfectly repeatable pattern (e.g. the 4DCT approach).
This disparity (shown by uncertainty bands of 20th–80th per-
centile) can even reach ±5% for individual patients or rescanning
scenarios, without however a clear correlation with rescan num-
ber. This effect seems to be more pronounced for VS than LS and
maybe due to the longer treatment times which may increase
the probability of encountering more substantial motion
variations.
Impact of energy switching time
As shown in Fig. 5(c) and (d) for the three-field-plan, by adjust-
ing the energy switching time (dE) from 700 ms successively down
to 500, 200 and 100 ms, the median treatment time could be
reduced by 25%, 63% and 75% respectively for volumetric rescan-
ning. Delivery time reductions were less pronounced for layered-
rescanning (<10%). However, no evidence could be found to indi-
cate systematic improvements in plan homogeneity for either LS
or VS (Fig. 5(a) and (b)) when shorter energy switching times were
employed. Similar results have also been found for the two single-
field-plan scenarios, as shown in Suppl. 3. On the contrary,
statistical analysis indicated a significant (P  0.01) increase of
HI values for VS when dE was reduced from 700 ms to 500 or
200 ms, with the median normalised variation of HI values being
30% for VS, but only around 10% for LS, indicating that reducing
PBS proton rescanning for liver tumour
the energy switching time could have a larger impact on treatment
quality on VS than LS. These results are also visible in Fig. 5(b),
where HI variations can be seen to be more pronounced for VS
when energy switching time was reduced to 100 ms (red).
Discussion
We have performed a comprehensive 4D treatment planning
study to quantify interplay effects, and the effectiveness of rescan-
ning, for PBS proton liver treatments using the Varian ProBeam
system. In total, more than 100,000 4D dose calculations have been
performed, analysing 10 different variables that could affect the 4D
results, including patient geometry, tumour motion, motion pat-
tern, spot spacing, plan configuration, field direction, starting
phase, rescan approach, scan number and energy switching time.
In addition, in contrast to the conventional 4DCT approach, by
using 4DCT(MRI) datasets, breathing irregularity has also been
taken into account, providing a unique opportunity to evaluate
the effects of organ motion on PBS proton therapy as a function
of different 4D delivery parameters and for realistic motion
scenarios.
Our results show that the effects of the interplay effect, and res-
canning as a mitigation approach, are both patient specific and
highly dependent on tumour geometry and motion amplitude, as
well as plan and delivery parameters. For the 10 mm motion (sce-
nario A) without rescanning, the 80th-percentile of HI’s (HI80) were
 Y. Zhang et al. / Radiotherapy and Oncology 121 (2016) 281–287 285

Fig. 3. (a and b) HI in CTV (three-field-plan) and (c and d) its normalized variation (the ratio of range and mean), as a function of scan number, rescan mode and starting
phases. Colour-bands present the 20th–80th percentile of HIs from the 9 cases, each with 2 types of motion pattern (regular and irregular).

Fig. 4. Dosimetric difference of HIs from 4D plans (three-field-plans) with regular and irregular motion pattern. Colour-bands present the 20th–80th percentile of the
differences from the 9 cases, each with 4 different starting phases.

within 8.5% of the HI for the static case for the three-field-plans,
but were only within 16.5% for single-field-plans. However, for sin-
gle field plans, using rescanning with an appropriate rescan factor
(>10) could improve HI80 to within 6.1% of the static case for lay-
ered rescanning (LS) and to within 1.9% for volumetric rescanning
(VS). Combining three-field plans with x10 rescanning can further
improve HI80 to within 5.2% of the static case for LS, and within
1.8% for VS. These findings indicate the importance of applying res-
canning and/or multiple-field-plans (cf. [27]) to increase plan
robustness to motion. For the larger motions however (scenarios
B and C), interplay can only be partially mitigated using rescanning
or multiple fields alone. For the three-field-plans without rescan-
ning, HI80 increased by 18.1% compared to the static case, and by
31.8% for single-field plans. Even though these can be reduced with
x10 rescanning, single-field HI80 values were still 14.3% higher
than the respective static cases for LS, and 9.1% higher for VS. By
combining three-field-plans with 10 rescanning however, HI80
can get to within 10.9% of the static case for LS and 6.6% for VS.
286 PBS proton rescanning for liver tumour
Fig. 5. (a and b) HIs in CTV, (c and d) treatment time (three-field-plan) and (e and f) the normalized variation (the ratio of range and mean) of HIs with a function of rescan
numbers, rescan mode and energy switching times. Colour-bands present the 20th–80th percentile of 4D plans from the 9 cases, each with 2 types of motion pattern and 4
different starting phases (only for HI).
Moreover, variations in HI (shown by 20th–80th percentile colour
bands) also increase as a function of patient geometry and starting
phase, indicating the necessity for combining rescanning with
other motion mitigation strategies (eg. gating) [27] in order to
obtain reliable or predictable mitigation for large motions. Never-
theless, for the larger motions, VS on average achieves a 4.5%
improved HI in comparison to LS, but requires 5 times longer to
deliver the same plan, with its efficacy to mitigate interplay also
being less predictable as a function of rescan number. Besides HI,
V95 (shown by Suppl. 1) shows a similar tendency, whilst the
mean dose in the CTV (Suppl. 2) stays within ±2% (without rescan-
ning) and ±1% (with rescanning) of the static reference. This obser-
vation is in good agreement with the results from previous studies
based on the machine parameters of other centres [12,19,20,22].
Using different plan configurations can change the time struc-
ture of each spot delivery. Although the spot position and energy
of the single-field plans are the same as the corresponding field
from the three-field plan, spot fluences are 3 times higher, and
are thus associated with a longer beam-on time. As such, the dosi-
metric impacts will be different with respect to motion. Moreover,
using different spot spacing also ultimately changes the time struc-
ture of the delivery, and is therefore expected to have an impact on
the sensitivity of a plan to the interplay effect. For example, a smal-
ler spot spacing requires a larger number of spots but a lower num-
ber of protons per spot, thus increasing the scanning time by
decreasing the effective dose rate for the system studied in this
work. However, with raster scanning, there is only very little differ-
ence in in-layer scanning time as a function of pencil beam spacing,
so that higher effective dose rates and shorter treatment times are
expected for the plan with larger spot spacing. On the other hand,
when more rescans are applied, the dose rate is nevertheless lim-
ited by the pre-defined threshold of the spot weight within one
energy layer (3.5 million protons in the relevant energy range),
so that differences in treatment time between plans with different
spot spacing become less and less pronounced. Interestingly, in
this work, we have found that the combination of three field plans
and 4 mm spot spacings under conditions of rescanning may be
difficult to deliver on the ProBeam system, due to the resulting
number of spots that fall below minimally deliverable spot fluence.
As such, this scenario has not been investigated further here.
Motion irregularity has also been found to have a noticeable influ-
ence on all patient scenarios, but is especially pronounced for lar-
ger motions (scenarios B and C), and generally has more influence
on volumetric rescanning than layered rescanning, due to the
longer treatment times which increase the possibility of encoun-
tering larger motion variations. However, this could also be due
to the gITV being defined from only a single breathing cycle from
the original planning 4DCT, which therefore does not include such
motion variations. More work needs to be performed in this
direction.
Moreover, shortening energy switching time would certainly
decrease treatment delivery time (particularly for VS), but there
is no evidence from this work to show that plan quality would
actually be improved. In contrast, more pronounced fluctuations
in dose homogeneity have been observed for volumetric rescan-
ning when energy switching time was reduced to 100 ms. In addi-
tion, one should note that we have here considered a conventional
fractionation scheme (2 Gy/fraction) and the 4DDC’s have been
performed for one fraction only. However, fractionation helps to
mitigate motion effects, at least if it is assumed that the starting
phase for delivery of each fraction is randomly distributed over
the breathing cycle. This effect though will become progressively
less effective if hypo-fractionation schedules are used.
Furthermore, we need to mention that our 4D dose calculation
simulated a continuous plan delivery, which means for a given res-
can plan, there is no waiting time to synchronise each scan and
each breathing cycle. Changing the scan number will completely
change the timeline of each spot with respect to the motion pat-
tern. Therefore, there is no absolute guarantee that more rescan-
ning will always provide an improved quality. As we have tried
to show here, there are many factors affecting the homogeneity
and conformity of the delivered dose under conditions of motion,
and it is not a surprise to us that rescanning cannot mitigate all.
It is also worth mentioning that there is a limited scan number that
 Y. Zhang et al. / Radiotherapy and Oncology 121 (2016) 281–287
can be applied, due to restrictions of the smallest deliverable pencil
beam weight (fluence), as shown in Suppl. 4. Since the ProBeam
system currently uses raster scanning, for layered rescanning, the
increased delivery time is mainly due to the reduced effective dose
rate and, depending on the prescription dose per field, there is
therefore a limit to how many re-scans can be applied (e.g. 19
in this study). Consequently, the delivery time for 19 rescanning
is only a factor 2 longer than for a single scan, which may not be
sufficient to completely average out the interplay effects. This is
the reason why the effectiveness of layered rescanning reported
in this study is not quite as good as for previously reported results
[19]. Nevertheless, this limitation can be compensated in further
developments by either introducing an extra spot settling time
during the in-layer scanning, or by using variable paths for the
scanning of each layer, which may enhance the statistical averag-
ing effect of rescanning.
Finally, although a large number of 4D dose calculations have
been performed in this work, the number of simulations within a
specific group is still limited (3 patient geometries each simulated
with 3 different motion patterns), and it is a fundamental problem
of the number of degrees of freedom in the 4D problem. Neverthe-
less, expanding the study to include more patients and motion data
in the future would definitely be helpful to confirm the findings
obtained here. However, in practice, patient specific 4D dose calcu-
lations and evaluations may be necessary for assessing the sensi-
tivity of PBS proton therapy with higher degrees of confidence.
Furthermore, the more complex IMPT approach (Intensity Modu-
lated Proton Therapy) has not been considered here as clinically
acceptable plans for these liver cases could be achieved using the
more robust SFUD approach. We also need to mention that the
conclusions drawn here are based on evaluations of liver tumour
treatments only. As such, it is difficult to make any direct inference
about other indications. For example, the use of protons for lung
cancers is additionally challenging due to significant density vari-
ations, which are highly dependent on the tumour location and
size. This is an on-going area of research at our centre.
In summary, for 10 mm motion, both LS and VS appear to be
equally effective rescanning approaches, particularly if multiple
fields are used. For motions larger than 10 mm, layered rescanning
has been shown to be the most time efficient method of motion
mitigation for the Varian ProBeam system, even if volumetric res-
canning is more effective for retrieving dose homogeneity (4.5%).
For current energy switching times however, volumetric rescan-
ning would take up to 5 times longer to deliver. Taking into
account the realistic beam and scanning parameters of the
ProBeam system, and the use of realistic and variable breathing
patterns in different liver cases, our results indicate that rescan-
ning could be a viable and efficient motion mitigation technique
to mitigate moderate motion effects (10 mm) on the ProBeam
system, but should be combined with additional techniques for lar-
ger motions.
Conflict of interest
This work was supported by the research grant from Varian
Medical Systems – Particle Therapy, Germany.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.radonc.2016.09.
011.
287
References
[1] Weber DC, Schneider R, Goitein G, Koch T, Ares C, Geismar JH, et al. Spot
scanning-based proton therapy for intracranial meningioma: long-term results
from the Paul Scherrer Institute. Int J Radiat Oncol Biol Phys 2012;83:865–71.
[2] Rutz HP, Weber DC, Goitein G, Ares C, Bolsi A, Lomax AJ, et al. Postoperative
spot-scanning proton radiation therapy for chordoma and chondrosarcoma in
children and adolescents: initial experience at Paul Scherrer Institute. Int J
Radiat Oncol Biol Phys 2008;71:220–5.
[3] Ares C, Hug EB, Lomax AJ, Bolsi A, Timmermann B, Rutz HP, et al. Effectiveness
and safety of spot scanning proton radiation therapy for chordomas and
chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol
Biol Phys 2009;75:1111–8.
[4] Phillips MH, Pedroni E, Blattmann H, Boehringer T, Coray A, Scheib S. Effects of
respiratory motion on dose uniformity with a charged particle scanning
method. Phys Med Biol 1992;37:223–34.
[5] ICRU. Prescribing, recording and reporting proton-beam therapy. J ICRU 2007.
[6] Bert C, Durante M. Motion in radiotherapy: particle therapy. Phys Med Biol
2011;56:R113.
[7] Knopf A, Bert C, Heath E, Nill S, Kraus K, Richter D, et al. Special report:
workshop on 4D-treatment planning in actively scanned particle therapy–
recommendations, technical challenges, and future research directions. Med
Phys 2010;37:4608–14.
[8] Wong VY, Tung SY, Ng AW, Li FA, Leung JO. Real-time monitoring and control
on deep inspiration breath-hold for lung cancer radiotherapy—combination of
ABC and external marker tracking. Med Phys 2010;37:4673.
[9] Bert C, Gemmel A, Saito N, Rietzel E. Gated irradiation with scanned particle
beams. Int J Radiat Oncol Biol Phys 2009;73:1270–5.
[10] Schätti A, Zakova M, Meer D, Lomax AJ. The effectiveness of combined gating
and rescanning for treating mobile targets with proton spot scanning. An
experimental and simulation-based investigation. Phys Med Biol
2014;59:3813.
[11] Furukawa T, Inaniwa T, Sato S, Shirai T, Mori S, Takeshita E, et al. Moving target
irradiation with fast rescanning and gating in particle therapy. Med Phys
2010;37:4874–9.
[12] Mori S, Zenklusen S, Inaniwa T, Furukawa T, Imada H, Shirai T, et al. Conformity
and robustness of gated rescanned carbon ion pencil beam scanning of liver
tumors at NIRS. Radiother Oncol 2014;111:431–6.
[13] Bert C, Saito N, Schmidt A, Chaudhri N, Schardt D, Rietzel E. Target motion
tracking with a scanned particle beam. Med Phys 2007;34:4768–71.
[14] Luchtenborg R, Saito N, Durante M, Bert C. Experimental verification of a real-
time compensation functionality for dose changes due to target motion in
scanned particle therapy. Med Phys 2011;38:5448–58.
[15] Zhang Y, Knopf A, Tanner C, Lomax AJ. Online image guided tumour tracking
with scanned proton beams: a comprehensive simulation study. Phys Med Biol
2014;59:7793.
[16] Zenklusen SM, Pedroni E, Meer D. A study on repainting strategies for treating
moderately moving targets with proton pencil beam scanning at the new
Gantry 2 at PSI. Phys Med Biol 2010;55:5103.
[17] Knopf A-C, Hong TS, Lomax A. Scanned proton radiotherapy for mobile
targets—the effectiveness of rescanning in the context of different treatment
planning approaches and for different motion characteristics. Phys Med Biol
2011;56:7257.
[18] Dowdell S, Grassberger C, Sharp GC, Paganetti H. Interplay effects in proton
scanning for lung: a 4D Monte Carlo study assessing the impact of tumor and
beam delivery parameters. Phys Med Biol 2013;58:4137.
[19] Bernatowicz K, Lomax AJ, Knopf A. Comparative study of layered and
volumetric rescanning for different scanning speeds of proton beam therapy
in liver patients. Phys Med Biol 2013;58:7905–20.
[20] Grassberger C, Dowdell S, Lomax A, Sharp G, Shackleford J, Choi N, et al. Motion
interplay as a function of patient parameters and spot size in spot scanning
proton therapy for lung cancer. Int J Radiat Oncol Biol Phys 2013;86:380–6.
[21] Li Y, Kardar L, Li X, Li H, Cao W, Chang JY, et al. On the interplay effects with
proton scanning beams in stage III lung cancer. Med Phys 2014;41:021721.
[22] Schätti A, Zakova M, Meer D, Lomax AJ. Experimental verification of motion
mitigation of discrete proton spot scanning by rescanning. Phys Med Biol
2013;58:8555.
[23] Bert C, Grözinger SO, Rietzel E. Quantification of interplay effects of scanned
particle beams and moving targets. Phys Med Biol 2008;53:2253.
[24] Boye D, Lomax AJ, Knopf A. Mapping motion from 4D-MRI to 3D-CT for use in
4D dose calculations: a technical feasibility study. Med Phys 2013;40:061702.
[25] Lomax AJ, Böhringer T, Bolsi A, Coray D, Emert F, Goitein G, et al. Treatment
planning and verification of proton therapy using spot scanning: initial
experiences. Med Phys 2004;31:3150.
[26] Lomax A. Intensity modulated proton therapy. In: Delaney T, Kooy H, editors.
Proton and charged particle radiotherapy. Boston, Lippincott: Williams and
Wilkins; 2008.
[27] Zhang Y, Knopf A, Weber DC, Lomax AJ. Improving 4D plan quality for PBS-
based liver tumour treatments by combining online image guided beam gating
with rescanning. Phys Med Biol 2015;60:8141.