A.J. Lomax

Is it necessary to plan with safety margins for actively scanned proton therapy

In radiation therapy, a plan is robust if the calculated and the delivered dose are in agreement, even in the case of different uncertainties. The current practice is to use safety margins, expanding the clinical target volume sufficiently enough to account for treatment uncertainties. This, however, might not be ideal for proton therapy and in particular when using intensity modulated proton therapy (IMPT) plans as degradation in the dose conformity could also be found in the middle of the target resulting from misalignments of highly in-field dose gradients. Single field uniform dose (SFUD) and IMPT plans have been calculated for different anatomical sites and the need for margins has been assessed by analyzing plan robustness to set-up and range uncertainties. We found that the use of safety margins is a good way to improve plan robustness for SFUD and IMPT plans with low in-field dose gradients but not necessarily for highly modulated IMPT plans for which only a marginal improvement in plan robustness could be detected through the definition of a planning target volume.

Emerging technologies in proton therapy

Abstract An increasing number of proton therapy facilities are being planned and built at hospital based centers. Most facilities are employing traditional dose delivery methods. A second generation of dose application techniques, based on pencil beam scanning, is slowly being introduced into the commercially available proton therapy systems. New developments in accelerator physics are needed to accommodate and fully exploit these new techniques. At the same time new developments such as the development of small cyclotrons, Dielectric Wall Accelerator (DWA) and laser driven systems, aim for smaller, single room treatment units. In general the benefits of proton therapy could be exploited optimally when achieving a higher level in accuracy, beam energy, beam intensity, safety and system reliability. In this review an overview of the current developments will be given followed by a discussion of upcoming new technologies and needs, like increase of energy, on-line MRI and proton beam splitting for independent uses of treatment rooms.

Respiratory liver motion estimation and its effect on scanned proton beam therapy.

Proton therapy with active scanning beam delivery has significant advantages compared to conventional radiotherapy. However, so far only static targets have been treated in this way, since moving targets potentially lead to interplay effects. For 4D treatment planning, information on the target motion is needed to calculate time-resolved dose distributions. In this study, respiratory liver motion has been extracted from 4D CT data using two deformable image registration algorithms. In moderately moving patient cases (mean motion range around 6 mm), the registration error was no more than 3 mm, while it reached 7 mm for larger motions (range around 13 mm). The obtained deformation fields have then been used to calculate different time-resolved 4D treatment plans. Averaged over both motion estimations, interplay effects can increase the D₅-D₉₅ value for the clinical target volume (CTV) from 8.8% in a static plan to 23.4% when motion is considered. It has also been found that the different deformable registration algorithms can provide different motion estimations despite performing similarly for the selected landmarks, which in turn can lead to differing 4D dose distributions. Especially for single-field treatments where no motion mitigation is used, a maximum (mean) dose difference (averaged over three cases) of 32.8% (2.9%) can be observed. However, this registration ambiguity-induced uncertainty can be reduced if rescanning is applied or if the treatment plan consists of multiple fields, where the maximum (mean) difference can decrease to 15.2% (0.57%). Our results indicate the necessity to interpret 4D dose distributions for scanned proton therapy with some caution or with error bars to reflect the uncertainties resulting from the motion estimation. On the other hand, rescanning has been found to be an appropriate motion mitigation technique and, furthermore, has been shown to be a robust approach to also deal with these motion estimation uncertainties.

Long term outcomes of patients with skull-base low-grade chondrosarcoma and chordoma patients treated with pencil beam scanning proton therapy

PURPOSEnTo evaluate the long term tumor control and toxicity of skull base tumors treated with pencil beam scanning proton therapy (PT).nnnMATERIALS AND METHODSnPT was delivered to 151 (68%) and 71 (32%) chordoma and chondrosarcoma (ChSa) patients, respectively. Mean age of patients was 40.8±18.4years and the male to female ratio was 0.53. The postoperative tumor was abutting the brainstem or optic apparatus in 71 (32.0%) patients. The postoperative mean gross tumor volume (GTV) was 35.7±29.1cm(3). The delivered mean PT dose was 72.5±2.2GyRBE.nnnRESULTSnAfter a mean follow-up of 50 (range, 4-176) months, 35 local (15.8%) failures were observed between 10.9 and 85.4months. The estimated 7-year LC rate for chordoma (70.9%; CI95% 61.5-81.8) was significantly lower compared to the LC rate for ChSa patients (93.6%; 95%CI 87.8-99.9; P=0.014). The estimated 7-year distant metastasis-free- and overall survival rate was 91.6% (95%CI 91.6-98.6) and 81.7% (95%CI 74.7-89.5), respectively. On multivariate analysis, optic apparatus and/or brainstem compression, histology and GTV were independent prognostic factors for LC and OS. The 7-year high grade toxicity-free survival was 87.2 (95%CI 82.4-92.3).nnnCONCLUSIONSnPBS PT is an effective treatment for skull base tumors with acceptable late toxicity. Optic apparatus and/or brainstem compression, histology and GTV allow independent prediction of the risk of local failure and death in skull base tumor patients.

Comparative study of layered and volumetric rescanning for different scanning speeds of proton beam in liver patients

In recent years, particle therapy has become a widely accepted form of cancer treatment and technological advances in beam delivery technology (i.e. pencil beam scanning (PBS)) have enabled the application of highly conformal dose distributions to static targets. Current research focuses on the possibilities for the treatment of mobile targets with these techniques. Of different motion mitigation methods being investigated, rescanning is perhaps the easiest to apply clinically. In general however, different PBS delivery systems exhibit a different temporal parameter space between delivery and target motions, due to the system specific beam position adjustment times (BPATs). Depending on these BPATs, dosimetric effects appearing during irradiation of moving targets vary significantly. In this work, volumetric and layered rescanning were compared for four different scenarios--a combination of fast and slow BPATs laterally (4 ms and 10 ms) and in depth (80 ms and 1 s); and nine different treatment plan arrangements for two clinical liver cases. 4D dose calculations were performed assuming regular, sinusoidal rigid motion as a worst-case motion scenario to model interplay effects. Calculations were sampled over three different starting phases resulting in a total of 432 dose distributions. It was found that layered rescanning is the method of choice for slow scanning systems, both in terms of dose homogeneity (D5-95 values are lower by up to 16% with layered rescanning) and in the estimated treatment delivery times (reduction of up to 300 s with layered rescanning). Analysis of dose homogeneity showed that layered rescanning leads to a smoother decrease in dose inhomogeneity as a function of the number of rescans than volumetric rescanning, which shows larger fluctuations. However, layered rescanning appears to be more sensitive to the starting phase. When analyzing the performance of both approaches and different scanning speeds as a function of delivery time, layered rescanning appears to be the only viable approach for slow energy changing systems, even approaching the performance of fast energy changing systems, as long as lateral scanning speeds are kept high. Similar results were found for multiple field plans and when analyzing different field directions.

Experimental verification of IMPT treatment plans in an anthropomorphic phantom in the presence of delivery uncertainties

Clinically relevant intensity modulated proton therapy (IMPT) treatment plans were measured in a newly developed anthropomorphic phantom (i) to assess plan accuracy in the presence of high heterogeneity and (ii) to measure plan robustness in the case of treatment uncertainties (range and spatial). The new phantom consists of five different tissue substitute materials simulating different tissue types and was cut into sagittal planes so as to facilitate the verification of co-planar proton fields. GafChromic films were positioned in the different planes of the phantom, and 3D-IMPT and distal edge tracking (DET) plans were delivered to a volume simulating a skull base chordoma. In addition, treatments planned on CTs of the phantom with HU units modified were delivered to simulate systematic range uncertainties (range-error treatments). Finally, plans were delivered with the phantom rotated to simulate spatial errors. Results show excellent agreement between the calculated and the measured dose distribution: >99% and 98% of points with a gamma value <1 (3%/3 mm) for the 3D-IMPT and the DET plan, respectively. For both range and spatial errors, the 3D-IMPT plan was more robust than the DET plan. Both plans were more robust to range than to the spatial uncertainties. Finally, for range error treatments, measured distributions were compared to a model for predicting delivery errors in the treatment planning system. Good agreement has been found between the model and the measurements for both types of IMPT plan.

The influence of the optimization starting conditions on the robustness of intensity-modulated proton therapy plans

In this paper the influence of varying the starting conditions on intensity-modulated proton therapy (IMPT) plans has been studied. In particular IMPT plans have been optimized based on four different starting conditions of initial beamlet fluences: (a) all beamlets with an initial constant weight, delivering a gradient from the proximal to the distal edge of the target (forward wedge approach); (b) beamlet weights reduced from the distal to the proximal aspect of the target such as to deliver a flat spread-out-Bragg-peak (SOBP approach); (c) beamlet weights calculated to deliver a gradient from the distal (maximal dose) to the proximal edge (inverse wedge); (d) beamlet weights set universally to zero except the most distal one, for each given lateral direction (i.e. distal-edge-tracking, DET). An analysis of robustness to range errors has been performed by recalculating plans, assuming a systematic 3% error in CT values. Results showed that IMPT plans optimized with the forward wedge approach were very sensitive to range errors, since organs-at-risk (OAR) were spared by patching single-field lateral and distal fall-offs, the last ones being strongly sensitive to range errors. In addition a plan robust to range errors can be achieved by starting the optimization process in the case of low-dose constraints to OAR, with the initial flat SOBP approach, and with either the DET or the inverse wedge approaches, in the case of stringent dose-volume constraints to OAR. Starting condition-based optimization as proposed here can therefore provide a tool to transparently steer the optimization outcome to solutions more robust to uncertainties.

Improving 4D plan quality for PBS-based liver tumour treatments by combining online image guided beam gating with rescanning

Pencil beam scanned (PBS) proton therapy has many advantages over conventional radiotherapy, but its effectiveness for treating mobile tumours remains questionable. Gating dose delivery to the breathing pattern is a well-developed method in conventional radiotherapy for mitigating tumour-motion, but its clinical efficiency for PBS proton therapy is not yet well documented. In this study, the dosimetric benefits and the treatment efficiency of beam gating for PBS proton therapy has been comprehensively evaluated. A series of dedicated 4D dose calculations (4DDC) have been performed on 9 different 4DCT(MRI) liver data sets, which give realistic 4DCT extracting motion information from 4DMRI. The value of 4DCT(MRI) is its capability of providing not only patient geometries and deformable breathing characteristics, but also includes variations in the breathing patterns between breathing cycles. In order to monitor target motion and derive a gating signal, we simulate time-resolved beams eye view (BEV) x-ray images as an online motion surrogate. 4DDCs have been performed using three amplitude-based gating window sizes (10/5/3u2009mm) with motion surrogates derived from either pre-implanted fiducial markers or the diaphragm. In addition, gating has also been simulated in combination with up to 19 times rescanning using either volumetric or layered approaches. The quality of the resulting 4DDC plans has been quantified in terms of the plan homogeneity index (HI), total treatment time and duty cycle. Results show that neither beam gating nor rescanning alone can fully retrieve the plan homogeneity of the static reference plan. Especially for variable breathing patterns, reductions of the effective duty cycle to as low as 10% have been observed with the smallest gating rescanning window (3u2009mm), implying that gating on its own for such cases would result in much longer treatment times. In addition, when rescanning is applied on its own, large differences between volumetric and layered rescanning have been observed as a function of increasing number of re-scans. However, once gating and rescanning is combined, HI to within 2% of the static plan could be achieved in the clinical target volume, with only moderately prolonged treatment times, irrespective of the rescanning strategy used. Moreover, these results are independent of the motion surrogate used. In conclusion, our results suggest image guided beam gating, combined with rescanning, is a feasible, effective and efficient motion mitigation approach for PBS-based liver tumour treatments.

Advantages and limitations of the ‘worst case scenario’ approach in IMPT treatment planning

The worst case scenario (also known as the minimax approach in optimization terms) is a common approach to model the effect of delivery uncertainties in proton treatment planning. Using the dose-error-bar distribution previously reported by our group as an example, we have investigated in more detail one of the underlying assumptions of this method. That is, the dose distributions calculated for a limited number of worst case patient positioning scenarios (i.e. limited number of shifts sampled on a spherical surface) represent the worst dose distributions that can occur during the patient treatment under setup uncertainties. By uniformly sampling patient shifts from anywhere within a spherical error-space, a number of treatment scenarios have been simulated and dose deviations from the nominal dose distribution have been computed. The dose errors from these simulations (comprehensive approach) have then been compared to the dose-error-bar approach previously reported (surface approximation) using both point-by-point and dose- and error-volume-histogram analysis (DVH/EVHs). This comparison has been performed for two different clinical cases treated using intensity modulated proton therapy (IMPT): a skull-base and a spinal-axis tumor. Point-by-point evaluation shows that the surface approximation leads to a correct estimation (95% accuracy) of the potential dose errors for the 96% and 85% of the irradiated voxels, for the two investigated cases respectively. We also found that the voxels for which the surface approximation fails are generally localized close to sharp soft tissue-bone interfaces and air cavities. Moreover, analysis of EVHs and DVHs for the two cases shows that the percentage of voxels of a given volume of interest potentially affected by a certain maximum dose error is correctly estimated using the surface approximation and that this approach also accurately predicts the upper and lower bounds of the DVH curves that can occur under positioning uncertainties. In conclusion, the assumption that the larger the patient shift the worse the dose error does not always hold on a point-by-point basis. Nevertheless, when performing a volumetric analysis, a limited set of worst case error scenarios correctly represents the worst quality of the plan in presence of setup errors. As a consequence of these results, we believe that the worst case scenario approach can be used in the IMPT planning procedure for estimating plan robustness provided that the possible limitations of this approach are known.

An evaluation of rescanning technique for liver tumour treatments using a commercial PBS proton therapy system.

BACKGROUND AND PURPOSEnThe treatment quality of pencil beam scanned (PBS) proton therapy to mobile tumour treatments can be compromised due to interplay effects. The aim of this work is to systematically evaluate the effectiveness of rescanning for liver tumour treatments for a commercial PBS delivery system.nnnMATERIALS AND METHODSnPlans were calculated to patient specific ITVs (2GyRBE), using spot spacings of 4 and 8mm 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 adaptive-scaled layered and volumetric rescanning were simulated using beam profiles and delivery dynamics of a commercial proton therapy system.nnnRESULTSnFor small (∼10mm) motions, 3-field plans achieved CTV HIs (D5-D95) to within 8.5% (80th percentile) of the static case without rescanning. For larger motions, volumetric rescanning resulted in 4.5% improved HI in comparison to layered, but requires 5 times longer treatment times and is more sensitive to detailed plan characteristics and delivery dynamics. Increased spot spacings were found to reduce sensitivity 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.nnnCONCLUSIONnFor the investigated proton therapy system, rescanning can help recover dose homogeneity under conditions of motion but, particularly for motions over 10mm, should be combined with additional motion mitigation techniques.