Treatment-planning approaches to intensity modulated proton therapy and the impact on dose-weighted linear energy transfer.

PURPOSE: We quantified the effect of various forward-based treatment-planning strategies in proton therapy on dose-weighted linear energy transfer (LETd). By maintaining the dosimetric quality at a clinically acceptable level, we aimed to evaluate the differences in LETd among various treatment-planning approaches and their practicality in minimizing biologic uncertainties associated with LETd. METHOD: Eight treatment-planning strategies that are achievable in commercial treatment-planning systems were applied on a cylindrical water phantom and four pediatric brain tumor cases. Each planning strategy was compared to either an opposed lateral plan (phantom study) or original clinical plan (patient study). Deviations in mean and maximum LETd from clinically acceptable dose distributions were compared. RESULTS: In the phantom study, using a range shifter and altering the robust scenarios during optimization had the largest effect on the mean clinical target volume LETd, which was reduced from 4.5 to 3.9 keV/µm in both cases. Variations in the intersection angle between beams had the largest effect on LETd in a ring defined 3 to 5 mm outside the target. When beam intersection angles were reduced from opposed laterals (180°) to 120°, 90°, and 60°, corresponding maximum LETd increased from 7.9 to 8.9, 10.9, and 12.2 keV/µm, respectively. A clear trend in mean and maximum LETd variations in the clinical cases could not be established, though spatial distribution of LETd suggested a strong dependence on patient anatomy and treatment geometry. CONCLUSION: Changes in LETd from treatment-plan setup follow intuitive trends in a controlled phantom experiment. Anatomical and other patient-specific considerations, however, can preclude generalizable strategies in clinical cases. For pediatric cranial radiation therapy, we recommend using opposed lateral treatment fields to treat midline targets.

Three-dimensional dose and LETD prediction in proton therapy using artificial neural networks.

PURPOSE: Challenges in proton therapy include identifying patients most likely to benefit; ensuring consistent, high-quality plans as its adoption becomes more widespread; and recognizing biological uncertainties that may be related to increased relative biologic effectiveness driven by linear energy transfer (LET). Knowledge-based planning (KBP) is a domain that may help to address all three. METHODS: Artificial neural networks were trained using 117 unique treatment plans and associated dose and dose-weighted LET (LETD ) distributions. The data set was split into training (n = 82), validation (n = 17), and test (n = 18) sets. Model performance was evaluated on the test set using dose- and LETD -volume metrics in the clinical target volume (CTV) and nearby organs at risk and Dice similarity coefficients (DSC) comparing predicted and planned isodose lines at 50%, 75%, and 95% of the prescription dose. RESULTS: Dose-volume metrics significantly differed (α = 0.05) between predicted and planned dose distributions in only one dose-volume metric, D2% to the CTV. The maximum observed root mean square (RMS) difference between corresponding metrics was 4.3 GyRBE (8% of prescription) for D1cc to optic chiasm. DSC were 0.90, 0.93, and 0.88 for the 50%, 75%, and 95% isodose lines, respectively. LETD -volume metrics significantly differed in all but one metric, L0.1cc of the brainstem. The maximum observed difference in RMS differences for LETD metrics was 1.0 keV/µm for L0.1cc to brainstem. CONCLUSIONS: We have devised the first three-dimensional dose and LETD -prediction model for cranial proton radiation therapy has been developed. Dose accuracy compared favorably with that of previously published models in other treatment sites. The agreement in LETD supports future investigations with biological doses in mind to enable the full potential of KBP in proton therapy.

Pre- and Posttherapy Risk Factors for Vasculopathy in Pediatric Patients With Craniopharyngioma Treated With Surgery and Proton Radiation Therapy.

PURPOSE: Vasculopathy (VAS) is a significant complication associated with radiation therapy in patients treated for brain tumors. We studied the type, location, severity, timing, and resolution of VAS in children with craniopharyngioma treated with proton radiation therapy (PRT) and evaluated predictors of stenosis (STN) using a novel patient and imaging-based modeling approach. METHODS AND MATERIALS: Children with craniopharyngioma (n = 94) were treated with 54 Gy relative biological effectiveness PRT in a clinical trial, NCT01419067. We evaluated VAS type, location, severity, and resolution. VAS events were segmented and related to their location, operative corridor, PRT dose, and vascular territory to facilitate mixed effect logistic regression modeling of spatial predictors of STN events. RESULTS: Forty-five (47.9%) patients had 111 instances of confirmed VAS (pre-PRT n = 37, 33.3%). The median time to post-PRT VAS was 3.41 years (95% confidence interval, 1.86-6.11). STN events were observed post-PRT in 23.4% (n = 22) of patients. Post-PRT VAS was detected by cerebral angiogram in 9.6% (n = 9), severe in 4.3% (n = 4), and compensated on perfusion in 2.1% (n = 2). Revascularization was required for 5 (5.3%) patients. Postsurgical, pre-PRT VAS, and PRT dose to unperturbed vessels were predictive of STN. The effect of PRT on STN was negligible within the surgical corridor. CONCLUSIONS: VAS often precedes PRT and was the strongest predictor of post-PRT STN. The adverse effect of PRT on STN was only apparent in unperturbed vasculature beyond the operative corridor.

Monte Carlo framework for commissioning a synchrotron-based discrete spot scanning proton beam system and treatment plan verification.

This study aimed to develop a Monte Carlo (MC) framework for commissioning the narrow proton beams (spot size sigma, 5.2 mm 2 mm at isocenter for 69.4 MeV-221.3 MeV for the main beam option and 4.1 mm 1.3 mm for the minibeam option respectively) of a synchrotron-based proton therapy system and design an independent absolute dose calculation engine for intensity-modulated proton treatments. A proton therapy system (Hitachi PROBEAT-V) was simulated using divergent and convergent beam models at the nozzle entrance. The innovative source weighting scheme for the MC simulation with TOPAS (TOol for PArticle Simulations) was implemented using dose output data for the absolute dose calculations. The results of the MC simulation were compared to the experimental data, analyzed and used to commission the treatment planning system. Two MC models, divergent and convergent beams were implemented. The convergent beam model produced a high level of agreement when MC and measurements were analyzed. The beam ellipticity did not result in significant differences between MC simulated and treatment planning system calculated doses. A model of a synchrotron-based spot scanning proton therapy system has been developed and implemented in the TOPAS MC transport code framework. The dose computation engine is useful for treatment plan verification with primary and minibeam beam option.

Dose perturbation caused by metallic port in breast tissue expander in proton beam therapy.

Proton beam treatment is being looked favourably now in breast treatment. Tissue expanders are often placed after mastectomy that contains metallic port for saline injection which produces dose perturbations in proton beam therapy with uncertain dosimetry. Dose perturbation for a stainless-steel injection port from a breast implant is investigated in this study. Measurements, Monte-Carlo simulation, and calculated dose distribution of plans based on kVCT and MVCT images are compared. Treatment plans are performed on kVCT and MVCT images to observe the effect of metal artifact from the breast implant. The kVCT based plan underestimates the beam range due to the overestimated water equivalent thickness of the metal ports as a result of image degradation. Compared to the measurement with metal port in the proton beam, the MVCT-based treatment planning provides more accurate dose calculation than the kVCT-based results. The dose perturbation factor calculated from MVCT planning is within 10% of the measurement results while HU corrected kVCT plan still shows dose difference as large as 100% due to the incorrect range pull back calculation caused by the misrepresentation of the volume between the plastic cap and the stainless-steel base. The dose enhancement observed at the metal and solid water interface is as large as 15%, which needs to be accounted for in the planning process if there is a clinical concern. Dose reduction as large as 16% is observed with depth from 1 cm to 4 cm underneath the thickest part of the metallic port whereas lateral dose perturbation is also seen up to 7 mm. The measurement data are supported by the Monte-Carlo simulated results with a maximum dose difference of 6%. It is concluded that if proton beam is used with metallic port, MVCT imaging data is recommended. In lieu of MVCT, DECT, CT scanner with metal artifact reduction software or in the very least, extended HU range should be used to reduce the streaking artifact as well as to produce a more accurate image of the metallic port.

Systemic mechanisms and effects of ionizing radiation: A new 'old' paradigm of how the bystanders and distant can become the players.

Exposure of cells to any form of ionizing radiation (IR) is expected to induce a variety of DNA lesions, including double strand breaks (DSBs), single strand breaks (SSBs) and oxidized bases, as well as loss of bases, i.e., abasic sites. The damaging potential of IR is primarily related to the generation of electrons, which through their interaction with water produce free radicals. In their turn, free radicals attack DNA, proteins and lipids. Damage is induced also through direct deposition of energy. These types of IR interactions with biological materials are collectively called 'targeted effects', since they refer only to the irradiated cells. Earlier and sometimes 'anecdotal' findings were pointing to the possibility of IR actions unrelated to the irradiated cells or area, i.e., a type of systemic response with unknown mechanistic basis. Over the last years, significant experimental evidence has accumulated, showing a variety of radiation effects for 'out-of-field' areas (non-targeted effects-NTE). The NTE involve the release of chemical and biological mediators from the 'in-field' area and thus the communication of the radiation insult via the so called 'danger' signals. The NTE can be separated in two major groups: bystander and distant (systemic). In this review, we have collected a detailed list of proteins implicated in either bystander or systemic effects, including the clinically relevant abscopal phenomenon, using improved text-mining and bioinformatics tools from the literature. We have identified which of these genes belong to the DNA damage response and repair pathway (DDR/R) and made protein-protein interaction (PPi) networks. Our analysis supports that the apoptosis, TLR-like and NOD-like receptor signaling pathways are the main pathways participating in NTE. Based on this analysis, we formulate a biophysical hypothesis for the regulation of NTE, based on DNA damage and apoptosis gradients between the irradiation point and various distances corresponding to bystander (5mm) or distant effects (5cm). Last but not least, in order to provide a more realistic support for our model, we calculate the expected DSB and non-DSB clusters along the central axis of a representative 200.6MeV pencil beam calculated using Monte Carlo DNA damage simulation software (MCDS) based on the actual beam energy-to-depth curves used in therapy.

Effect of Scanning Beam for Superficial Dose in Proton Therapy.

Proton beam delivery technology is under development to minimize the scanning spot size for uniform dose to target, but it is also known that the superficial dose could be as high as the dose at Bragg peak for narrow and small proton beams. The objective of this study is to explore the characteristics of dose distribution at shallow depths using Monte Carlo simulation with the FLUKA code for uniform scanning (US) and discrete spot scanning (DSS) proton beams. The results show that the superficial dose for DSS is relatively high compared to US. Additionally, DSS delivers a highly heterogeneous dose to the irradiated surface for comparable doses at Bragg peak. Our simulation shows that the superficial dose can become as high as the Bragg peak when the diameter of the proton beam is reduced. This may compromise the advantage of proton beam therapy for sparing normal tissue, making skin dose a limiting factor for the clinical use of DSS. Finally, the clinical advantage of DSS may not be essential for treating uniform dose across a large target, as in craniospinal irradiation (CSI).

Proton Therapy Facility Planning From a Clinical and Operational Model.

This paper provides a model for planning a new proton therapy center based on clinical data, referral pattern, beam utilization and technical considerations. The patient-specific data for the depth of targets from skin in each beam angle were reviewed at our center providing megavoltage photon external beam and proton beam therapy respectively. Further, data on insurance providers, disease sites, treatment depths, snout size and the beam angle utilization from the patients treated at our proton facility were collected and analyzed for their utilization and their impact on the facility cost. The most common disease sites treated at our center are head and neck, brain, sarcoma and pediatric malignancies. From this analysis, it is shown that the tumor depth from skin surface has a bimodal distribution (peak at 12 and 26 cm) that has significant impact on the maximum proton energy, requiring the energy in the range of 130-230 MeV. The choice of beam angles also showed a distinct pattern: mainly at 90° and 270°; this indicates that the number of gantries may be minimized. Snout usage data showed that 70% of the patients are treated with 10 cm snouts. The cost of proton beam therapy depends largely on the type of machine, maximum beam energy and the choice of gantry versus fixed beam line. Our study indicates that for a 4-room center, only two gantry rooms could be needed at the present pattern of the patient cohorts, thus significantly reducing the initial capital cost. In the USA, 95% and 100% of patients can be treated with 200 and 230 MeV proton beam respectively. Use of multi-leaf collimators and pencil beam scanning may further reduce the operational cost of the facility.

Lung cancer radiation therapy: Monte Carlo investigation of "under dose" by high energy photons.

Loss of electronic equilibrium in lung tissue causes a build-up region in the tumor. Increasing the photon energy increases the depth at which electronic equilibrium is reestablished within the lung tumor. This study uses the Monte Carlo code PENELOPE for simulations of radiation treatment of tumor surrounded by lung. Six MV photons were compared to 15 MV photons using four beam arrangements in both homogeneous and heterogeneous media. The experimental results demonstrate that for every beam arrangement in heterogeneous media 15 MV photons delivered 5% to 10% lower dose to the tumor periphery than 6 MV photons. The simulations also show that in axial coplanar treatment plans, the loss of electronic equilibrium was greatest in the coronal plane. In conclusion there is a tumor sparing effect at the tumor-lung interface that is a function of beam energy. As an alternative to increasing beam energy, the addition of multiple beam angles with lower energy photons improved target coverage. If higher energy beams are required for patients with large separation, then adding multiple beam angles does offer some improved target coverage. The non-coplanar technique with the lower energy photons covered the tumor with a greatest isodose at the tumor periphery without tangential sparing in the coronal plane.