Uncertainties in ocular proton planning and their impact on required margins.

PURPOSE: To review required margins in ocular proton therapy (OPT) based on an uncertainty estimation and to compare them with widely used values. Further, uncertainties when using registered funduscopy images in the 3D model is investigated. METHODS: An uncertainty budget in planning and delivery was defined to determine required aperture and range margins. Setup uncertainties were considered for a cohort of treated patients and tested in a worst-case estimation. Other uncertainties were based on a best-guess and knowledge of institutional specifics, e.g. range reproducibility. Margins for funduscopy registration were defined resulting from scaling, rotation and translation of the image. Image formation for a wide-field fundus camera was reviewed and compared to the projection employed in treatment planning systems. RESULTS: Values for aperture and range with margins of 2.5 mm as reported in literature could be determined. Aperture margins appear appropriate for setup uncertainties below 0.5 mm, but depend on lateral penumbra. Range margins depend on depth and associated density uncertainty in tissue. Registration of funduscopy images may require margins of >2 mm, increasing towards the equator. Difference in the projection may lead to discrepancies of several mm. CONCLUSIONS: The commonly used 2.5 mm aperture margin was validated as an appropriate choice, while range margins could be reduced for lower ranges. Margins may however not include uncertainties in contouring and possible microscopic spread. If a target base is contoured on registered funduscopy images care must be taken as they are subject to larger uncertainties. Multimodal imaging approach in OPT remains advisable.

Consistency of Faraday cup and ionization chamber dosimetry of proton fields and the role of nuclear interactions.

BACKGROUND: A Faraday cup (FC) facilitates a quite clean measurement of the proton fluence emerging from clinical spot-scanning nozzles with narrow pencil-beams. The utilization of FCs appears to be an attractive option for high dose rate delivery modes and the source models of Monte-Carlo (MC) dose engines. However, previous studies revealed discrepancies of 3%-6% between reference dosimetry with ionization chambers (ICs) and FC-based dosimetry. This has prevented the widespread use of FCs for dosimetry in proton therapy. PURPOSE: The current study aims at bridging the gap between FC dosimetry and IC dosimetry of proton fields delivered with spot-scanning treatment heads. Particularly, a novel method to evaluate FC measurements is introduced. METHODS: A consistency check is formulated, which makes use of the energy balance and the reciprocity theorem. The measurement data comprise central-axis depth distributions of the absorbed dose of quasi-monochromatic fields with a width of about 28.5 cm and FC measurements of the reciprocal fields with a single spot. These data are complemented by a look-up of energy-range tables, the average Q-value of transmutations, and the escape energy carried away by neutrons and photons. The latter data are computed by MC simulations, which in turn are validated with measurements of the distal dose tail and neutron out-of-field doses. For comparison, the conventional approach of FC evaluation is performed, which computes absorbed dose from the product of fluence and stopping power. The results from the FC measurements are compared with the standard dosimetry protocols and improved reference dosimetry methods. RESULTS: The deviation between the conventional FC-based dosimetry and the IC-based one according to standard dosimetry protocols was -4.7 (± 3.3)% for a 100 MeV field and -3.6 (±3.5)% for 200 MeV, thereby agreeing within the reported uncertainties. The deviations could be reduced to -4.0 (± 2.9)% and -3.0 (± 3.1)% by adopting state-of-the-art reference dosimetry methods. The alternative approach using the energy balance gave deviations of only -1.9% (100 MeV) and -2.6% (200 MeV) using state-of-the-art dosimetry. The standard uncertainty of this novel approach was estimated to be about 2%. CONCLUSIONS: An alternative concept has been established to determine the absorbed dose of monoenergetic proton fields with an FC. It eliminates the strong dependence of the conventional FC-based approach on the MC simulation of the stopping-power and of the secondary ions, which according to the study at hand is the major contributor to the underestimation of the absorbed dose. Some contributions to the uncertainty of the novel approach could potentially be reduced in future studies. This would allow for accurate consistency tests of conventional dosimetry procedures.

Comprehensive investigation of lateral dose profile and output factor measurements in small proton fields from different delivery techniques.

BACKGROUND AND PURPOSE: As a part of the commissioning and quality assurance in proton beam therapy, lateral dose profiles and output factors have to be acquired. Such measurements can be performed with point detectors and are especially challenging in small fields or steep lateral penumbra regions as the detector's volume effect may lead to perturbations. To address this issue, this work aims to quantify and correct for such perturbations of six point detectors in small proton fields created via three different delivery techniques. METHODS: Lateral dose profile and output measurements of three proton beam delivery techniques (pencil beam scanning, pencil beam scanning combined with collimators, passive scattering with collimators) were performed using high-resolution EBT3 films, a PinPoint 3D 31022 ionization chamber, a microSilicon diode 60023 and a microDiamond detector 60019 (all PTW Freiburg, Germany). Detector specific lateral dose response functions K(x,y) acting as the convolution kernel transforming the undisturbed dose distribution D(x,y) into the measured signal profiles M(x,y) were applied to quantify perturbations of the six investigated detectors in the proton fields and correct the measurements. A signal theoretical analysis in Fourier space of the dose distributions and detector's K(x,y) was performed to aid the understanding of the measurement process with regard to the combination of detector choice and delivery technique. RESULTS: Quantification of the lateral penumbra broadening and signal reduction at the fields center revealed that measurements in the pencil beam scanning fields are only compromised slightly even by large volume ionization chambers with maximum differences in the lateral penumbra of 0.25 mm and 4% signal reduction at the field center. In contrast, radiation techniques with collimation are not accurately represented by the investigated detectors as indicated by a penumbra broadening up to 1.6 mm for passive scattering with collimators and 2.2 mm for pencil beam scanning with collimators. For a 3 mm diameter collimator field, a signal reduction at field center between 7.6% and 60.7% was asserted. Lateral dose profile measurements have been corrected via deconvolution with the corresponding K(x,y) to obtain the undisturbed D(x,y). Corrected output ratios of the passively scattered collimated fields obtained for the microDiamond, microSilicon and PinPoint 3D show agreement better than 0.9% (one standard deviation) for the smallest field size of 3 mm. CONCLUSION: Point detector perturbations in small proton fields created with three delivery techniques were quantified and found to be especially pronounced for collimated small proton fields with steep dose gradients. Among all investigated detectors, the microSilicon diode showed the smallest perturbations. The correction strategies based on detector's K(x,y) were found suitable for obtaining unperturbed lateral dose profiles and output factors. Approximation of K(x,y) by considering only the geometrical averaging effect has been shown to provide reasonable prediction of the detector's volume effect. The findings of this work may be used to guide the choice of point detectors in various proton fields and to contribute toward the development of a code of practice for small field proton dosimetry.

Commissioning and validation of a novel commercial TPS for ocular proton therapy.

BACKGROUND: Until today, the majority of ocular proton treatments worldwide were planned with the EYEPLAN treatment planning system (TPS). Recently, the commercial, computed tomography (CT)-based TPS for ocular proton therapy RayOcular was released, which follows the general concepts of model-based treatment planning approach in conjunction with a pencil-beam-type dose algorithm (PBA). PURPOSE: To validate RayOcular with respect to two main features: accurate geometrical representation of the eye model and accuracy of its dose calculation algorithm in combination with an Ion Beam Applications (IBA) eye treatment delivery system. METHODS: Different 3D-printed eye-ball-phantoms were fabricated to test the geometrical representation of the corresponding CT-based model, both in orthogonal 2D images for X-ray image overlay and in fundus view overlaid with a funduscopy. For the latter, the phantom was equipped with a lens matching refraction of the human eye. Funduscopy was acquired in a Zeiss Claus 500 camera. Tantalum clips and fiducials attached to the phantoms were localized in the TPS model, and residual deviations to the actual position in X-ray images for various orientations of the phantom were determined, after the nominal eye orientation was corrected in RayOcular to obtain a best overall fit. In the fundus view, deviations between known and displayed distances were measured. Dose calculation accuracy of the PBA on a 0.2 mm grid was investigated by comparing between measured lateral and depth-dose profiles in water for various combinations of range, modulation, and field-size. Ultimately, the modeling of dose distributions behind wedges was tested. A 1D gamma-test was applied, and the lateral and distal penumbra were further compared. RESULTS: Average residuals between model clips and visible clips/fiducials in orthogonal X-ray images were within 0.3 mm, including different orientations of the phantom. The differences between measured distances on the registered funduscopy image in the RayOcular fundus view and the known ground-truth were within 1 mm up to 10.5 mm distance from the posterior pole. No clear benefit projection of either polar mode or camera mode could be identified, the latter mimicking camera properties. Measured dose distributions were reproduced with gamma-test pass-rates of >95% with 2%/0.3 mm for depth and lateral profiles in the middle of spread-out Bragg-peaks. Distal falloff and lateral penumbra were within 0.2 mm for fields without a wedge. For shallow depths, the agreement was worse, reaching pass-rates down to 80% with 5%/0.3 mm when comparing lateral profiles in air. This is caused by low-energy protons from a scatter source in the IBA system not modeled by RayOcular. Dose distributions modified by wedges were reproduced, matching the wedge-induced broadening of the lateral penumbra to within 0.4 mm for the investigated cases and showing the excess dose within the field due to wedge scatter. CONCLUSION: RayOcular was validated for its use with an IBA single scattering delivery nozzle. Geometric modeling of the eye and representation of 2D projections fulfill clinical requirements. The PBA dose calculation reproduces measured distributions and allows explicit handling of wedges, overcoming approximations of simpler dose calculation algorithms used in other systems.

CD9- and CD81-positive extracellular vesicles provide a marker to monitor glioblastoma cell response to photon-based and proton-based radiotherapy.

Glioblastoma multiforme (GBM) is the most aggressive tumor of the central nervous system with a poor prognosis. In the treatment of GBM tumors, radiotherapy plays a major role. Typically, GBM tumors cannot be cured by irradiation because of intrinsic resistance machanisms. An escalation of the irradiation dose in the GBM tumor is difficult due to the high risk of severe side effects in the brain. In the last decade, the development of new irradiation techniques, including proton-based irradiation, promised new chances in the treatment of brain tumors. In contrast to conventional radiotherapy, irradiation with protons allows a dosimetrically more confined dose deposition in the tumor while better sparing the normal tissue surrounding the tumor. A systematic comparison of both irradiation techniques on glioblastoma cells has not been performed so far. Despite the improvements in radiotherapy, it remains challenging to predict the therapeutical response of GBM tumors. Recent publications suggest extracellular vesicles (EVs) as promising markers predicting tumor response. Being part of an ancient intercellular communication system, virtually all cells release specifically composed EVs. The assembly of EVs varies between cell types and depends on environmental parameters. Here, we compared the impact of photon-based with proton-based radiotherapy on cell viability and phenotype of four different glioblastoma cell lines. Furthermore, we characterized EVs released by different glioblastoma cells and correlated released EVs with the cellular response to radiotherapy. Our results demonstrated that glioblastoma cells reacted more sensitive to irradiation with protons than photons, while radiation-induced cell death 72 h after single dose irradiation was independent of the irradiation modality. Moreover, we detected CD9 and CD81-positive EVs in the supernatant of all glioblastoma cells, although at different concentrations. The amount of released CD9 and CD81-positive EVs increased after irradiation when cells became apoptotic. Although secreted EVs of non-irradiated cells were not predictive for radiosensitivity, their increased EV release after irradiation correlated with the cytotoxic response to radiotherapy 72 h after irradiation. Thus, our data suggest a novel application of EVs in the surveillance of anti-cancer therapies.

Technical note: Impact of beam properties for uveal melanoma proton therapy-An in silico planning study.

PURPOSE: To evaluate the impact of beam quality in terms of distal fall-off (DFO, 90%-10%) and lateral penumbra (LP, 80%-20%) of single beam ocular proton therapy (OPT) and to derive resulting ideal requirements for future systems. METHODS: Nine different beam models with DFO varying between 1 and 4 mm and LP between 1 and 4 mm were created. Beam models were incorporated into the RayStation with RayOcular treatment planning system version 10 B (RaySearch Laboratories, Stockholm, Sweden). Each beam model was applied for eight typical clinical cases, covering different sizes and locations of uveal melanoma. Plans with and without an additional wedge were created, resulting in 117 plans with a total prescribed median dose of 60 Gy(RBE) to the clinical target volume. Treatment plans were analyzed in terms of V20-V80 penumbra volume, D1 (dose to 1% of the volume) for optic disc and macula, optic nerve V30 (volume receiving 30 Gy(RBE), i.e., 50% of prescription), as well as average dose to lens and ciliary body. An LP-dependent aperture margin was based on estimated uncertainties, ranging from 1.7 to 4.0 mm. RESULTS: V20-V80 showed a strong influence by LP, while DFO was less relevant. The optic disc D1 reached an extra dose of up to 3000 cGy(RBE), comparing the defined technical limit of DFO = LP = 1 mm with DFO = 3 mm/LP = 4 mm. The latter may result from a pencil-beam scanning (PBS) system with static apertures. Plans employing a wedge showed an improvement for organs at risk sparing. CONCLUSION: Plan quality is strongly influenced by initial beam parameters. The impact of LP is more pronounced when compared to DFO. The latter becomes important in the treatment of posterior tumors near the macula, optic disc or optic nerve. The plan quality achieved by dedicated OPT nozzles in single- or double-scattering design might not be achievable with modified PBS systems.

Results of an independent dosimetry audit for scanned proton beam therapy facilities.

PURPOSE: An independent dosimetry audit based on end-to-end testing of the entire chain of radiation therapy delivery is highly recommended to ensure consistent treatments among proton therapy centers. This study presents an auditing methodology developed by the MedAustron Ion Beam Therapy Center (Austria) in collaboration with the National Physical Laboratory (UK) and audit results for five scanned proton beam therapy facilities in Europe. METHODS: The audit procedure used a homogeneous and an anthropomorphic head phantom. The phantoms were loaded either with an ionization chamber or with alanine pellets and radiochromic films. Homogeneously planned doses of 10Gy were delivered to a box-like target volume in the homogeneous phantom and to two clinical scenarios with increasing complexity in the head phantom. RESULTS: For all tests the mean of the local differences of the absolute dose to water determined with the alanine pellets compared to the predicted dose from the treatment planning system installed at the audited institution was determined. The mean value taken over all tests performed was -0.1±1.0%. The measurements carried out with the ionization chamber were consistent with the dose determined by the alanine pellets with a mean deviation of -0.5±0.6%. CONCLUSION: The developed dosimetry audit method was successfully applied at five proton centers including various "turn-key" Cyclotron solutions by IBA, Varian and Mevion. This independent audit with extension to other tumour sites and use of the correspondent anthropomorphic phantoms may be proposed as part of a credentialing procedure for future clinical trials in proton beam therapy.

Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining.

Technical improvements in clinical radiotherapy for maximizing cytotoxicity to the tumor while limiting negative impact on co-irradiated healthy tissues include the increasing use of particle therapy (e.g., proton therapy) worldwide. Yet potential differences in the biology of DNA damage induction and repair between irradiation with X-ray photons and protons remain elusive. We compared the differences in DNA double strand break (DSB) repair and survival of cells compromised in non-homologous end joining (NHEJ), homologous recombination repair (HRR) or both, after irradiation with an equal dose of X-ray photons, entrance plateau (EP) protons, and mid spread-out Bragg peak (SOBP) protons. We used super-resolution microscopy to investigate potential differences in spatial distribution of DNA damage foci upon irradiation. While DNA damage foci were equally distributed throughout the nucleus after X-ray photon irradiation, we observed more clustered DNA damage foci upon proton irradiation. Furthermore, deficiency in essential NHEJ proteins delayed DNA repair kinetics and sensitized cells to both, X-ray photon and proton irradiation, whereas deficiency in HRR proteins sensitized cells only to proton irradiation. We assume that NHEJ is indispensable for processing DNA DSB independent of the irradiation source, whereas the importance of HRR rises with increasing energy of applied irradiation.

Relating Linear Energy Transfer to the Formation and Resolution of DNA Repair Foci After Irradiation with Equal Doses of X-ray Photons, Plateau, or Bragg-Peak Protons.

Proton beam therapy is increasingly applied for the treatment of human cancer, as it promises to reduce normal tissue damage. However, little is known about the relationship between linear energy transfer (LET), the type of DNA damage, and cellular repair mechanisms, particularly for cells irradiated with protons. We irradiated cultured cells delivering equal doses of X-ray photons, Bragg-peak protons, or plateau protons and used this set-up to quantitate initial DNA damage (mainly DNA double strand breaks (DSBs)), and to analyze kinetics of repair by detecting γH2A.X or 53BP1 using immunofluorescence. The results obtained validate the reliability of our set-up in delivering equal radiation doses under all conditions employed. Although the initial numbers of γH2A.X and 53BP1 foci scored were similar under the different irradiation conditions, it was notable that the maximum foci level was reached at 60 min after irradiation with Bragg-peak protons, as compared to 30 min for plateau protons and photons. Interestingly, Bragg-peak protons induced larger and irregularly shaped γH2A.X and 53BP1 foci. Additionally, the resolution of these foci was delayed. These results suggest that Bragg-peak protons induce DNA damage of increased complexity which is difficult to process by the cellular repair apparatus.

Dosimetry intercomparison of four proton therapy institutions in Germany employing spot scanning.

AIM: To verify the consistency of dose and range measurement in an interinstitution comparison among proton therapy institutions in Germany which use the pencil-beam scanning technique. METHODS: Following a peer-to-peer approach absorbed dose and range have been intercompared in several missions at two hosting centers with two or three visiting physics teams of participating institutions using their own dosimetry equipment. A meta-analysis has been performed integrating the results of the individual missions. Dose has been determined with ionization chambers according to the dosimetry protocol IAEA TRS-398. For determination of the depth of the distal 80% dose the teams used either a scanning water phantom, a variable water column or a multi-layer ionization chamber. RESULTS: The systematic deviation between measured doses of the participating institutions is less than 1%. Ranges differ systematically less than 0.4mm. CONCLUSIONS: The match of measured dose and range is better than expected from the respective uncertainties. As all physics teams agree on the assessment of absorbed dose and range, an important prerequisite for a start of joint clinical studies is fulfilled.

Evaluation of detectors for acquisition of pristine depth-dose curves in pencil beam scanning.

Acquisition of quasi-monoenergetic ("pristine") depth-dose curves is an essential task in the frame of commissioning and quality assurance of a proton therapy treatment head. For pencil beam scanning delivery modes this is often accomplished by measuring the integral ionization in a plane perpendicular to the axis of an unscanned beam. We focus on the evaluation of three integral detectors: two of them are plane-parallel ionization chambers with an effective radius of 4.1 cm and 6.0 cm, respectively, mounted in a scanning water phantom. The third integral detector is a 6.0 cm radius multilayer ionization chamber. The experimental results are compared with the corresponding measurements under broad field conditions, which are performed with a small radius plane-parallel chamber and a small radius multilayer ionization chamber. We study how a measured depth-dose curve of a pristine proton field depends on the detection device, by evaluating the shape of the depth-dose curve, the relative charge collection efficiency, and intercomparing measured ranges. Our results show that increasing the radius of an integral chamber from 4.1 cm to 6.0 cm increases the collection efficiency by 0%-3.5% depending on beam energy and depth. Ranges can be determined by the large electrode multilayer ionization chamber with a typical uncertainty of 0.4 mm on a routine basis. The large electrode multilayer ionization chamber exhibits a small distortion in the Bragg Peak region. This prohibits its use for acquisition of base data, but is tolerable for quality assurance. The good range accuracy and the peak distortion are characteristics of the multilayer ionization chamber design, as shown by the direct comparison with the small electrode counterpart.

Daily QA in proton therapy using a single commercially available detector.

We present here a novel method for using a single device in the daily quality assur- ance (QA) of pencil beam scanning (PBS) proton beams and an improved method for uniform scanning (US). The device can be used to measure the spot position, spot sigma, range, output, collinearity of the X-ray system and proton beam, and to QA the first scatterers and a number of other imaging and mechanical checks. We have performed the daily QA according to this procedure for more than six months in both a PBS gantry and a US gantry. All of the tests were found to be sensitive and accurate enough to determine if the property being tested is within the tolerance. The output has remained within the ± 2% tolerance, with the majority of measurements within ± 1%, and the range was within ± 0.5 mm. The collinearity of the proton beam in both gantries is within the ± 1 mm tolerance in both X and Y directions for all measurements. A novel procedure to measure the functionality of the first scatterers in the US gantry is included in the QA procedure. It was found to be sensitive enough to pick up the thinnest scatterer of 0.6 mm in both possible failure methods - when it always remains in the beam or in the case when it never goes into the beam. The daily QA procedure presented here can be implemented at PBS or US proton therapy centers with a minimal outlay for equipment and setup time. The procedure can be performed in less than 30 min, and has been found to be accurate and reliable enough for the QA of a proton therapy gantry before patient treatment every day.