Preliminary tests of dosimetric quality and projected therapeutic outcomes of multi-phase 4D radiotherapy with proton and carbon ion beams.

Objective. The purpose of this study was to perform preliminary pre-clinical tests to compare the dosimetric quality of two approaches to treating moving tumors with ion beams: synchronously delivering the beam with the motion of a moving planning target volume (PTV) using the recently developed multi-phase 4D dose delivery (MP4D) approach, and asynchronously delivering the ion beam to a motion-encompassing internal tumor volume (ITV) combined with rescanning.Approach. We created 4D optimized treatment plans with proton and carbon ion beams for two patients who had previously received treatment for non-small cell lung cancer. For each patient, we created several treatment plans, using approaches with and without motion mitigation: MP4D, ITV with rescanning, static deliveries to a stationary PTV, and deliveries to a moving tumor without motion compensation. Two sets of plans were optimized with margins or robust uncertainty scenarios. Each treatment plan was delivered using a recently-developed motion-synchronized dose delivery system (M-DDS); dose distributions in water were compared to measurements using gamma index analysis to confirm the accuracy of the calculations. Reconstructed dose distributions on the patient CT were analyzed to assess the dosimetric quality of the deliveries (conformity, uniformity, tumor coverage, and extent of hotspots).Main results. Gamma index analysis pass rates confirmed the accuracy of dose calculations. Dose coverage was >95% for all static and MP4D treatments. The best conformity and the lowest lung doses were achieved with MP4D deliveries. Robust optimization led to higher lung doses compared to conventional optimization for ITV deliveries, but not for MP4D deliveries.Significance. We compared dosimetric quality for two approaches to treating moving tumors with ion beams. Our findings suggest that the MP4D approach, using an M-DDS, provides conformal motion mitigation, with full target coverage and lower OAR doses.

Compensating for beam modulation due to microscopic lung heterogeneities in carbon ion therapy treatment planning.

PURPOSE: To predict and mitigate for the degradation in physical and biologically effective dose distributions of particle beams caused by microscopic heterogeneities in lung tissue. MATERIALS AND METHODS: The TRiP98 treatment planning system was adapted to account for the beam-modulating effect of heterogeneous lung tissue in physical and biological inverse treatment planning. The implementation employs an analytical model that derives the degradation from the established "modulation power" parameter P mod and the total water-equivalent thickness of lung parenchyma traversed by the beam. Beam modulation was reproduced through an on-the-fly convolution of the reference Bragg curve with Gaussian kernels depending on the modulation power of lung tissue (upstream). For biological doses, the degradation was determined by modulating dose-averaged α , ß , and LET distributions. Carbon SOBP measurements behind lung substitute material were performed to validate the code. The implementation was then applied to a phantom and patient case. RESULTS: Experimental results show the passage through a 20-cm Gammex LN300 slab led to a decrease in target coverage and broadening of the SOBP distal fall-off. However, dose coverage was regained through optimization. A good agreement between calculated and measured SOBPs was also found. In addition, a patient case study revealed a 3.2% decrease in D 95 from degradation ( P mod = 450 µ m), which was reduced to a 0.4% difference after optimization. Furthermore, widening of the RBE distribution beyond the target distal edge was observed. This implies an increased degradation in the biological dose, which could be harmful to healthy tissues distal to the target. CONCLUSIONS: This is the first implementation capable of compensating for lung dose perturbations, which is more effective than margin extensions. A larger patient study is needed to examine the observed modulation in the RBE distribution and judge the clinical relevance also in IMPT, where margins might prove insufficient to recover target coverage.

Extension of RBE-weighted 4D particle dose calculation for non-periodic motion.

PURPOSE: Highly conformal scanned Carbon Ion Radiotherapy (CIRT) might permit dose escalation and improved local control in advanced stage thoracic tumors, but is challenged by target motion. Dose calculation algorithms typically assume a periodically repeating, regular motion. To assess the effect of realistic, irregular motion, new algorithms of validated accuracy are needed. METHODS: We extended an in-house treatment planning system to calculate RBE-weighted dose distributions in CIRT on non-periodic CT image sequences. Dosimetric accuracy was validated experimentally on a moving, time-resolved ionization chamber array. Log-file based dose reconstructions were compared by gamma analysis and correlation to measurements at every intermediate detector frame during delivery. The impact of irregular motion on treatment quality was simulated on a virtual 4DCT thorax phantom. Periodic motion was compared to motion with varying amplitude and period ± baseline drift. Rescanning as a mitigation strategy was assessed on all scenarios. RESULTS: In experimental validation, average gamma pass rates were 99.89+-0.30% for 3%/3 mm and 88.2+-2.2% for 2%/2 mm criteria. Average correlation for integral dose distributions was 0.990±0.002. Median correlation for single 200 ms frames was 0.947±0.006. In the simulations, irregular motion deteriorated V95 target coverage to 81.2%, 76.6% and 79.0% for regular, irregular motion and irregular motion with base-line drift, respectively. Rescanning restored V95 to >98% for both scenarios without baseline drift, but not with additional baseline drift at 83.7%. CONCLUSIONS: The validated algorithm permits to study the effects of irregular motion and to develop and adapt appropriate motion mitigation techniques.

Dosimetric Validation of a System to Treat Moving Tumors Using Scanned Ion Beams That Are Synchronized With Anatomical Motion.

PURPOSE: The purpose of this study was to validate the dosimetric performance of scanned ion beam deliveries with motion-synchronization to heterogenous targets. METHODS: A 4D library of treatment plans, comprised of up to 10 3D sub-plans, was created with robust and conventional 4D optimization methods. Each sub-plan corresponded to one phase of periodic target motion. The plan libraries were delivered to a test phantom, comprising plastic slabs, dosimeters, and heterogenous phantoms. This phantom emulated range changes that occur when treating moving tumors. Similar treatment plans, but without motion synchronization, were also delivered to a test phantom with a stationary target and to a moving target; these were used to assess how the target motion degrades the quality of dose distributions and the extent to which motion synchronization can improve dosimetric quality. The accuracy of calculated dose distributions was verified by comparison with corresponding measurements. Comparisons utilized the gamma index analysis method. Plan quality was assessed based on conformity, dose coverage, overdose, and homogeneity values, each extracted from calculated dose distributions. RESULTS: High pass rates for the gamma index analysis confirmed that the methods used to calculate and reconstruct dose distributions were sufficiently accurate for the purposes of this study. Calculated and reconstructed dose distributions revealed that the motion-synchronized and static deliveries exhibited similar quality in terms of dose coverage, overdose, and homogeneity for all deliveries considered. Motion-synchronization substantially improved conformity in deliveries with moving targets. Importantly, measurements at multiple locations within the target also confirmed that the motion-synchronized delivery system satisfactorily compensated for changes in beam range caused by the phantom motion. Specifically, the overall planning and delivery approach achieved the desired dose distribution by avoiding range undershoots and overshoots caused by tumor motion. CONCLUSIONS: We validated a dose delivery system that synchronizes the movement of the ion beam to that of a moving target in a test phantom. Measured and calculated dose distributions revealed that this system satisfactorily compensated for target motion in the presence of beam range changes due to target motion. The implication of this finding is that the prototype system is suitable for additional preclinical research studies, such as irregular anatomic motion.

A Modular System for Treating Moving Anatomical Targets With Scanned Ion Beams at Multiple Facilities: Pre-Clinical Testing for Quality and Safety of Beam Delivery.

BACKGROUND: Quality management and safety are integral to modern radiotherapy. New radiotherapy technologies require new consensus guidelines on quality and safety. Established analysis strategies, such as the failure modes and effects analysis (FMEA) and incident learning systems have been developed as tools to assess the safety of several types of radiation therapies. An extensive literature documents the widespread application of risk analysis methods to photon radiation therapy. Relatively little attention has been paid to performing risk analyses of nascent radiation therapy systems to treat moving tumors with scanned heavy ion beams. The purpose of this study was to apply a comprehensive safety analysis strategy to a motion-synchronized dose delivery system (M-DDS) for ion therapy. METHODS: We applied a risk analysis method to new treatment planning and treatment delivery processes with scanned heavy ion beams. The processes utilize a prototype, modular dose delivery system, currently undergoing preclinical testing, that provides new capabilities for treating moving anatomy. Each step in the treatment process was listed in a process map, potential errors for each step were identified and scored using the risk probability number in an FMEA, and the possible causes of each error were described in a fault tree analysis. Solutions were identified to mitigate the risk of these errors, including permanent corrective actions, periodic quality assurance (QA) tests, and patient specific QA (PSQA) tests. Each solution was tested experimentally. RESULTS: The analysis revealed 58 potential errors that could compromise beam delivery quality or safety. Each of the 14 binary (pass-or-fail) tests passed. Each of the nine QA and four PSQA tests were within anticipated clinical specifications. The modular M-DDS was modified accordingly, and was found to function at two centers. CONCLUSION: We have applied a comprehensive risk analysis strategy to the M-DDS and shown that it is a clinically viable motion mitigation strategy. The described strategy can be utilized at any ion therapy center that operates with the modular M-DDS. The approach can also be adapted for use at other facilities and can be combined with existing safety analysis systems.

Four-dimensional carbon-ion pencil beam treatment planning comparison between robust optimization and range-adapted internal target volume for respiratory-gated liver and lung treatment.

We investigated the dose differences between robust optimization-based treatment planning (4DRO) and range-adapted internal target volume (rITV). We used 4DCT dataset of 20 lung cancer and 20 liver cancer patients, respectively, who had been treated with respiratory-gated carbon-ion pencil beam scanning therapy. 4DRO and rITV plans were created with the same clinical target volume (CTV) and organs at risk (OAR) contours. Four-dimensional dose distribution was calculated using deformable image registration. Dose metrics (e.g. D95, V20) were analyzed. Statistical significance was assessed by the Wilcoxon signed-rank test. For the lung cases, the mean CTV-D95 value for the rITV plan (=98.5%) was same as that for the 4DRO plan (=98.5%, P = 0.106), while the mean D95 value for the CTV + setup margin contour for the rITV plan (=98.2%) was higher than that for the 4DRO plan (95.2%, P < 0.001). For the liver cases, the mean CTV-D95 value for the rITV plan (=98.1%) was slightly lower than that for the 4DRO plan (=98.5%, P < 0.01), while the mean D95 value for the CTV + setup margin contour for the rITV plan (=98.0%) was higher than that for the 4DRO plan (94.1%, P < 0.001). For the doses to the organs at risk (OARs), the ipsilateral lung-V20/liver-V20 values for the rITV plan (=10.1%/19.7%) was significantly higher than that for the 4DRO plan (=8.6%/17.6, P < 0.001). Although the target coverage for 4DRO plan may be worse than that for rITV plan in the presence of the setup error, the 4DRO plan can improve OAR dose while preserving acceptable target dose coverage.

Tumor Control Probability Analysis for Single-Fraction Carbon-Ion Radiation Therapy of Early-Stage Non-small Cell Lung Cancer.

PURPOSE: To investigate the suitability of the linear-quadratic (LQ) and universal survival curve (USC) models in describing the 3-year tumor control probability data of patients with stage I non-small cell lung cancer treated with carbon-ion radiation therapy. Carbon-ion radiation therapy was given at a total dose of 59.4 to 95.4 Gy (relative biological effectiveness [RBE]) in 18 fractions, at 72 Gy[RBE] in 9 fractions, at 52.8 to 60 Gy[RBE] in 4 fractions, and at 28 to 50 Gy[RBE] in a single fraction. METHODS AND MATERIALS: A meta-analysis of published clinical data from 394 patients presenting with early-stage non-small cell lung cancer was conducted. Tumor control probability modeling based on the LQ and USC models was performed by simultaneously fitting the clinical data obtained from the different fractionation schedules while considering several spread-out Bragg peak (SOBP) sizes. Radiobiological parameters were derived from the fit. On the basis of the results, a novel SOBP was created for the single-fraction regimen that was optimized with respect to the USC model and aimed at achieving a 95% local control. RESULTS: The USC model gave a better fit to the 3-year local control data than the LQ model did. The fit using various SOBP sizes yielded transition doses between 5.6 and 7.0 Gy. The results also revealed α/ß ratios between 7.4 and 9.1 Gy for the LQ model and between 7.4 and 9.4 Gy for the USC model. CONCLUSIONS: The USC model provided a better estimate of the local control rate for the single-fraction course. For the schemes with a greater number of fractions, the local control rate estimates from the LQ and USC models were comparable. A USC-based SOBP design was then created for the single-fraction schedule. The updated design resulted in a flatter RBE profile compared with the conventional SOBP design. It also gave a better clinical dose prediction to optimize the tumor control rate.

Effects of Charged Particles on Human Tumor Cells.

The use of charged particle therapy in cancer treatment is growing rapidly, in large part because the exquisite dose localization of charged particles allows for higher radiation doses to be given to tumor tissue while normal tissues are exposed to lower doses and decreased volumes of normal tissues are irradiated. In addition, charged particles heavier than protons have substantial potential clinical advantages because of their additional biological effects, including greater cell killing effectiveness, decreased radiation resistance of hypoxic cells in tumors, and reduced cell cycle dependence of radiation response. These biological advantages depend on many factors, such as endpoint, cell or tissue type, dose, dose rate or fractionation, charged particle type and energy, and oxygen concentration. This review summarizes the unique biological advantages of charged particle therapy and highlights recent research and areas of particular research needs, such as quantification of relative biological effectiveness (RBE) for various tumor types and radiation qualities, role of genetic background of tumor cells in determining response to charged particles, sensitivity of cancer stem-like cells to charged particles, role of charged particles in tumors with hypoxic fractions, and importance of fractionation, including use of hypofractionation, with charged particles.