Range Uncertainty In Proton Therapy Research Articles

SU‐C‐204‐04: Patient Specific Proton Stopping Powers Estimation by Combining Proton Radiography and Prior‐Knowledge X‐Ray CT Information

Purpose:The material relative stopping power (RSP) uncertainty is the highest contributor to the range uncertainty in proton therapy. The purpose of this work is to develop a robust and systematic method that yields accurate, patient specific, RSP by combining 1) pre‐treatment x‐ray CT and 2) daily proton radiograph of the patient.Methods:The method is formulated as a linear least‐square optimization problem (min||Ax‐B||2). The parameter A represents the pathlength crossed by the proton in each material. The RSPs for the materials (water equivalent thickness (WET)/physical thickness) are denoted by x. B is the proton radiograph expressed as WET crossed. The problem is minimized using a convex‐conic optimization algorithm with xi<xi+1 constraint. The Gammex RMI‐465 phantom, with 13 material inserts, is used to investigate the optimal RSPs. The proton radiograph (B) is produced using Geant4 simulation. The matrix A is computed by calculating proton trajectories through the CT with the cubic‐spline approach. Geant4 RSPs are used as reference and the clinical HU‐RSP calibration curve is used as comparison. The convergence is investigated as a function of the number of angles and protons used. The radiographs angle which yield the most accurate RSPs are investigated.Results:Optimization with 9 angles and 104 protons/angle yields precise RSP (<0.75%) for all materials, except plastic lung (1.5%). Average deviation relative to Geant4 RSP is 0.5% and 3.5% using HU‐RSP. Using more than two angles or more than 4×103 proton does not further increase the RSP estimate accuracy. The insert distance to the beam initial plane is related to the RSP error for this insert material. Specific filters are applied on the proton angle and energy loss to remove nuclear interaction artefacts.Conclusion:The proposed formulation of the problem with prior knowledge x‐ray CT demonstrates serious potential to increase the accuracy of present RSP estimates.

WE‐A‐WAB‐01: New Technologies Addressing the Range Uncertainty of Proton Therapy

The role of proton therapy in radiation therapy is currently expanding. In the U.S., there are at present 11 clinical proton treatment facilities, with 10 centers operating proton gantries and 6 additional facilities under construction. One of the main challenges in proton therapy is the uncertainty in predicting proton range. Range uncertainties in proton therapy are related to ambiguity in converting x‐ray CT attenuation data to proton relative stopping power and are further compounded by organ deformation and internal motion as well as increasing relative biological effectiveness in the distal part of proton beams. Closely related to this issue is the continued development of image guidance technology in the treatment room that ideally will provide feedback for in‐room treatment plan modifications (adaptive proton therapy). Proton therapy treatment planning applies quite substantial range uncertainty margins, negating, in part, some of the advantages of the finite range. The problem of range uncertainty in proton therapy has been addressed in many ways, the ultimate goal being to reduce this uncertainty to ∼1 mm. Approaches to address this problem include Monte Carlo simulations to study the effects of different sources on proton range uncertainty, studies showing the amount of range uncertainties in patients, robust planning techniques, and various technological and calibration methods that attempt to improve the accuracy of relative proton stopping power and to detect and minimize range errors at the time of treatment, e.g., dual energy CT scanners, proton CT and radiography, prompt gamma registration and monitoring of proton radiation therapy with PET imaging. This symposium will present a broad overview of the current status of modern computational and imaging approaches to addressing the range‐uncertainty problem of proton beams in radiation therapy.Learning Objectives:1. Understand the prevailing range uncertainties in proton therapy and how they can affect clinical practice.2. Learn how the magnitude of range uncertainties has been studied with Monte Carlo simulations and in patients.3. Get an overview of new technologies addressing the range uncertainty problem in proton therapy.4. Learn about principles of proton computed tomography and radiography and how these techniques may be used for better range definition and pre‐treatment quality assurance.5. Learn about the use of prompt gamma emission for proton therapy range verification.6. Learn about the different implementations and initial clinical experience of PET verification of treatment delivery in proton and ion therapy.

Treatment planning optimisation in proton therapy

The goal of radiotherapy is to achieve uniform target coverage while sparing normal tissue. In proton therapy, the same sources of geometric uncertainty are present as in conventional radiotherapy. However, an important and fundamental difference in proton therapy is that protons have a finite range, highly dependent on the electron density of the material they are traversing, resulting in a steep dose gradient at the distal edge of the Bragg peak. Therefore, an accurate knowledge of the sources and magnitudes of the uncertainties affecting the proton range is essential for producing plans which are robust to these uncertainties. This review describes the current knowledge of the geometric uncertainties and discusses their impact on proton dose plans. The need for patient-specific validation is essential and in cases of complex intensity-modulated proton therapy plans the use of a planning target volume (PTV) may fail to ensure coverage of the target. In cases where a PTV cannot be used, other methods of quantifying plan quality have been investigated. A promising option is to incorporate uncertainties directly into the optimisation algorithm. A further development is the inclusion of robustness into a multicriteria optimisation framework, allowing a multi-objective Pareto optimisation function to balance robustness and conformity. The question remains as to whether adaptive therapy can become an integral part of a proton therapy, to allow re-optimisation during the course of a patient's treatment. The challenge of ensuring that plans are robust to range uncertainties in proton therapy remains, although these methods can provide practical solutions.

Comprehensive analysis of proton range uncertainties related to patient stopping-power-ratio estimation using the stoichiometric calibration

The purpose of this study was to analyze factors affecting proton stopping-power-ratio (SPR) estimations and range uncertainties in proton therapy planning using the standard stoichiometric calibration. The SPR uncertainties were grouped into five categories according to their origins and then estimated based on previously published reports or measurements. For the first time, the impact of tissue composition variations on SPR estimation was assessed and the uncertainty estimates of each category were determined for low-density (lung), soft, and high-density (bone) tissues. A composite, 95th percentile water-equivalent-thickness uncertainty was calculated from multiple beam directions in 15 patients with various types of cancer undergoing proton therapy. The SPR uncertainties (1σ) were quite different (ranging from 1.6% to 5.0%) in different tissue groups, although the final combined uncertainty (95th percentile) for different treatment sites was fairly consistent at 3.0–3.4%, primarily because soft tissue is the dominant tissue type in the human body. The dominant contributing factor for uncertainties in soft tissues was the degeneracy of Hounsfield numbers in the presence of tissue composition variations. To reduce the overall uncertainties in SPR estimation, the use of dual-energy computed tomography is suggested. The values recommended in this study based on typical treatment sites and a small group of patients roughly agree with the commonly referenced value (3.5%) used for margin design. By using tissue-specific range uncertainties, one could estimate the beam-specific range margin by accounting for different types and amounts of tissues along a beam, which may allow for customization of range uncertainty for each beam direction.

Range uncertainty in proton therapy due to variable biological effectiveness

Traditionally, dose in proton radiotherapy is prescribed as Gy(RBE) by scaling up the physical dose by 10%. The relative biological effectiveness (RBE) of protons is considered to vary with dose-averaged linear energy transfer (LETd), dose (d) and (α/β)x. The increase of RBE with depth causes a shift of the falloff of the beam, i.e. a change of the beam range. The magnitude of this shift will depend on dose and (α/β)x. The aim of this project was to quantify the dependence of the range shift on these parameters. Three double-scattered beams of different ranges incident on a computational phantom consisting of different regions of interest (ROIs) were used. Each ROI was assigned with (α/β)x values between 0.5 and 20 Gy. The distribution of LETd within each ROI was obtained from a Monte Carlo simulation. The LETd distribution depends on the beam energy and thus its nominal range. The RBE values within the ROIs were calculated for doses between 1 and 15 Gy using an in-house developed biophysical model. Dose-volume histograms of the RBE-weighted doses were extracted for each ROI for a ‘fixed RBE’ (RBE = 1.1) and a ‘variable RBE’ (RBE = f (d, α/β, LETd)), and the percentage difference in range was obtained from the difference of the percentage volumes at the distal 80% of the dose. Range differences in normal tissue ((α/β)x = 3 Gy) of the order of 3–2 mm were obtained, respectively, for a shallow (physical range 4.8 cm) and a deep (physical range 12.8 cm) beam, when a dose of 1 Gy normalized to the mid-SOBP was delivered. As the dose increased to 15 Gy, the variable RBE decreases below 1.1 which induces ranges of about 1 mm shorter than those obtained with an RBE of 1.1. The shift in the range of an SOBP when comparing biological dose distributions obtained with a fixed or a variable RBE was quantified as a function of dose, (α/β)x and physical range (as a surrogate of the initial beam energy). The shift increases with the physical range but decreases with increasing dose or (α/β)x. The results of our study allow a quantitative consideration of RBE-caused range uncertainties as a function of treatment site and dose in treatment planning.

SU-E-T-648: Range Uncertainty in Proton Therapy Due to Variable Biological Effectiveness

Purpose: Traditionally, dose in proton radiotherapy is prescribed as Gy(RBE) by scaling up the physical dose by 10%. This not only increases the absolute dose but also translates in a forward shift of the falloff of the beam and consequently its range. However, if the relative biological effectiveness (RBE) of protons is considered to vary with linear energy transfer (LET), dose and (alpha/beta)_x-rays, this shift will depend on these three parameters. We aim to show how much the range changes as a function of these three parametersMethods: Three beams of different ranges incident on a computational phantom consisting of different regions of interest (ROIs) were used. Each ROI was assigned with (alpha/beta)_x-rays values between 0.5Gy and 20Gy. The distribution of the dose-averaged LET within each ROI was obtained from a Monte Carlo simulation. The RBE values within the ROIs were calculated for doses between 1 and 15Gy using an in-house developed biophysical model. DVHs of the RBE weighted doses were extracted for each ROI for a ‘fixed-RBE’ (RBE=1.1) and a ‘variable-RBE’ (RBE=f(d,alpha/beta,LET)), and the percentage difference in range was obtained from the difference of the percentage volumes at 80% of the doseResults: Range shifts in normal tissue of the order of 3mm to 7mm were measured for a shallow and a deep beam respectively, when a 1Gy dose normalized to the mid-SOBP was delivered. As dose increased to 15Gy, the shifts decreased to 1mm and 5mm respectively for the same tissues and depthsConclusions: When the distal edge of the SOBP lays on normal tissue, the range shift increases with physical range but decreases with increasing dose or (alpha/beta)_x-rays. The results of our study allow a quantitative consideration of RBE-caused range uncertainties as a function of treatment site and dose in treatment planning

SU-GG-T-434: A Joint Research Investigation Comparing MCNPX and Geant4 Monte Carlo Codes to Reduce the Range Uncertainties in Proton Therapy

Purpose: Advanced technology may help control the depth of the dose delivered to anatomical regions in the patient with a accuracy close to 1 mm. Monte Carlo methods are able to precisely model the transport of protons within the patient offering the potential to assist in achieving this level of accuracy. Both MCNPX and Geant4 Monte Carlo codes have been used for proton beam therapy simulations. However, to our knowledge very little has been done to compare the inherent differences in the handling of proton transport between the two codes. Methods: A detailed comparison of proton dose distributions within a variety of phantoms was performed between MCNPX and Geant4. Simulations were done using a generic water phantom, a complex phantom with bone and lung components, and a patient phantom produced from CT data. A spread‐out Bragg peak proton beam with a range of 17.3 cm and a modulation width of 5 cm was considered. A qualitative comparison investigating the differences between dose distributions together with quantitative comparisons using gamma analysis was completed. Results: The MCNPX and Geant4 dose distributions agreed very well for most cases. For all curves considered the gamma analysis yielded at least 90% of the points within the 2% and 2 mm criteria. There appears to be a slight disagreement in the uniformity of SOBPs in the water and complex phantom. Conclusion: This study improves our understanding of the differences in the proton dose deposition predicted from MCNPX and Geant4 Monte Carlo codes.

SU‐GG‐J‐156: Optimizing a 3‐Stage Compton Camera for Imaging Prompt Gammas during Proton Irradiation

Purpose: Due to the intrinsic range uncertainties in proton therapy and its potential impact on the dose delivery, secondary prompt gamma ray emitted during proton treatment delivery is being explored as a dose verification tool. In this work, we investigate the use of a 3‐stage Compton camera to measure secondary prompt gamma emission. The purpose of this study was: (1) to develop an optimal 3‐stage Compton camera specifically designed to measure prompt gamma rays from tissue and (2) to determine the feasibility of using this 3‐stage Compton camera to measure and image prompt gammas emitted from irradiated tissues during proton beam irradiation. Method and Materials: The 3‐stage Compton camera was modeled in Geant4 as three high‐purity germanium detectors arranged in parallel‐plane geometry. Initially, an isotropic gamma source ranging from 0.1 to 15 MeV was used to determine the detector dimensions (width and thickness) that provided the optimal detection efficiency. Then, the gamma source was replaced by a proton beam irradiating a tissue phantom to calculate the overall efficiency of the optimized camera during proton beam irradiation. Results: Using the isotropic gamma source, the optimal dimensions chosen for the 3‐stage Compton camera were 3 cm thick by 10 cm wide for the first detector, 3 cm thick by 10 cm wide for the second, and 10 cm thick by 10 cm wide for the third. The overall efficiency of the 3‐stage Compton camera varied from 2.4 to 10.5 × 10−6 prompt gammas detected per starting proton over the range of proton energies. Conclusion: Based on the overall efficiency results and the typical number of protons emitted during a treatment (about 1 × 1011 protons), the 3‐stage Compton camera should detect a sufficient number of prompt gammas to allow for image reconstruction of the dose deposition within the tissue phantom.

WE-A-BRA-03: Considerations of Inter-Observer and Inter-Fractional Anatomical Variability in Estimating the Beam Range Uncertainty in Proton Therapy of Prostate Cancer

Purpose: For estimates of proton range, conversion of CT Hounsfield units (HU) to stopping powers is complicated due to limited knowledge of atomic composition of tissue, and ionization potentials. Historically, the overall range uncertainty of 3.5% is stipulated, regardless of tumor site. We evaluate the variation in CT anatomy traversed by proton beam in transit to the prostate, and evaluate the range uncertainty specific to that site. Method: CT scans were analyzed for 10 patients, representing a range of body constitution: body-mass index (BMI) between 22–39 kg/m2. Proton range compensators were designed following standard planning protocol. The distribution of HU was histogrammed for various raytraces (beam paths through 5×5 mm2 compensator elements). Based on HU, voxels were stratified into 3 categories: adipose, “soft” (muscle, skin, connective, hematopoietic), and bony tissue. From literature, maximum range uncertainties were taken to be 1.8% in bone, and 1.1% in soft tissue. Amounts of different tissue types per raytrace, and accumulated uncertainty in proton range, were estimated for individual patients. Inter-fractional variations were evaluated with serial CT data. Results: Although the HU frequency histograms differ substantially between raytraces for the same patient, the inter-fractional variability (assuming image-guided set-up) was found to be insignificant. Across the patient selection, the relative share of adipose tissue in the beam path correlated with BMI, however, the share of bony tissue was stable. Relative range uncertainty averaged across the compensator was within 1.20–1.27% for all 10 patients, and the maximum among all patients' raytraces was 1.43%. Conclusion: Estimated range uncertainty resulting from CT conversion was under 1.5% for all patients. Combined with scanner calibration errors (∼1%), the overall range uncertainty in prostate treatments is below 2.5%. This may allow for a safe range margin reduction by 2–3 mm, leading to 1–1.5 Gy drop in dose to skin and proximal tissue.

SU-FF-T-227: A Method for Intra-Fractional Beam Range Control in Proton Therapy Treatment

Purpose: Range uncertainty in proton therapy is a recognized concern. For some treatment sites, e.g., prostate, liver/pancreas, beam range in patient may change daily due to variations in patient setup and anatomical configurations. We propose a strategy for intra‐fractional range control based on in‐vivo range verification and retroactive correction. Method and Materials: A protontreatment field contains a series of spread‐out Bragg peaks (SOBP) weighted to produce a dose distribution uniform in depth over the target volume. While the convention is to deliver all the peaks with their full weights in a single sequence, we want to split the delivery into two or more subsequences each containing only part of the weight for each peak. The first one or two subsequences can be used to detect the beam range in patient, and the remaining subsequences will be delivered with, if necessary, adjusted beam energies and weights to retroactively correct the overall beam range so that the total dose distribution for the treatment session is as prescribed for the target volume and critical organs nearby. Range detection can be achieved by point dose measurements and by manipulating the partial weights of the subsequences to “encode” the beam range information into the dose distributions. Specifically, “sloped” SOBP depth dose distributions were created and dose ratios between oppositely “sloped” subsequences were used to determine the water equivalent pathlengths to the dosimeter locations. Results: “Sloped” SOBP distributions were produced with sufficient accuracy in a passive‐scattering beam delivery system. Phantom tests with ion chamber showed millimeter accuracy in range determination. Treatment planning exercises were performed for prostate cases to illustrate the range control strategy. Conclusion: A method for intra‐fractional beam range control in protontreatment has been explored with encouraging results.

MO‐D‐BRC‐01: Introduction: Challenges of Post‐Treatment and Real‐Time Imaging of Dose Deposition in Proton Therapy

The finite range of protons is the primary physical advantage leading to the potentially greatly improved dose distributions in proton radiation therapy. The other side of the coin is that it takes extra care to make sure that the protons actually stop at the right location. Fortunately, proton therapy provides unique opportunities to visualize interactions of the therapeutic beam with the patient. These interactions are more or less closely related to the delivered dose distribution, and can therefore be used as a dose surrogate for treatment verification. In this symposium we will highlight three examples of such interaction mechanisms, as well as their potential to provide clinically useful information about the in‐vivo dose distribution either post‐treatment or even in real‐time. Some of the methods are applicable to photon therapy as well.In this short introduction we will discuss various reasons that lead to uncertainties in the proton range and will show estimates of the magnitude of the range uncertainties. We will then go over techniques to deal with range uncertainties in treatment planning, and will finally discuss what could be gained if we could reduce or eliminate range uncertainties.Learning Objectives:1. Name three reasons for range uncertainties in proton therapy.2. Quantify the magnitude of range uncertainties.3. Name at least one method that reduces the impact of range uncertainties.

A point dose method for in vivo range verification in proton therapy

Range uncertainty in proton therapy is a recognized concern. For certain treatment sites, less optimal beam directions are used to avoid the potential risk, but also with reduced benefit. In vivo dosimetry, with implanted or intra-cavity dosimeters, has been widely used for treatment verification in photon/electron therapy. The method cannot, however, verify the beam range for proton treatment, unless we deliver the treatment in a different manner. Specifically, we split the spread-out Bragg peaks in a proton field into two separate fields, each delivering a ‘sloped’ depth–dose distribution, rather than the usual plateau in a typical proton field. The two fields are ‘sloped’ in opposite directions so that the total depth–dose distribution retains the constant dose plateau covering the target volume. By measuring the doses received from both fields and calculating the ratio, the water-equivalent path length to the location of the implanted dosimeter can be verified, thus limiting range uncertainty to only the remaining part of the beam path. Production of such subfields has been experimented with a passive scattering beam delivery system. Phantom measurements have been performed to illustrate the application for in vivo beam range verification.

WE‐E‐AUD C‐04: Effect of CT Calibration Phantom Size On the Range in Proton Radiation Therapy

Purpose: The range of a proton beam in the patient is estimated using the relationship between CT numbers (HU) and relative linear stopping powers (RLSP). The purpose of this study is to assess the range uncertainties introduced by the size of the phantom used for determining the calibration curve. Method and Materials: CT scans were performed on tissue equivalent inserts placed at the center of two phantoms of different sizes representing human head and body with a GE Lightspeed 16‐slice CT scanner. The HU to RLSP calibration curve was established for each phantom based on a stoichiometric calibration technique. For each planning CT image data set, two plans were generated using head and body calibration curves, respectively. The range difference between two corresponding fields was evaluated using distance‐to‐agreement (DTA) along the beam direction in a homogenous water phantom in water equivalent thickness (WET). The DTAs were calculated with a threshold of percent dose difference of 3%. Plans for four prostate and four lung patients were investigate. Results: The measured CT number for the same insert placed in two phantoms of different sizes could differ up to 200 HU for the bone equivalent materials. The maximum dose difference between two proton plans generated with head and body calibration curves could be up to 33%. The difference in DTA was up to 2.4 mm WET for prostate patients and 5.4 mm WET for lung patients. Conclusion: The calibration phantom size could contribute up to 5.4 mm WET range uncertainties for the lung patients in our study. The current practice is to use average calibration curve to minimize the uncertainty. Advanced imaging techniques such as dual‐energy CT scans could be utilized to reduce the uncertainty in CT numbers. Other factors that introduce range uncertainty in proton therapy will be investigated in future.