The physical properties of proton beams offer the potential to reduce toxicity in tumor-adjacent normal tissues. Toward this end, the number of proton radiotherapy facilities has steeply increased ...over the last 10–15 years to currently around 70 operational centers worldwide. However, taking full advantage of the opportunities offered by proton radiation for clinical radiotherapy requires a better understanding of the radiobiological effects of protons alone or combined with drugs or immunotherapy on normal tissues and tumors. This report summarizes the main results of the international expert workshop “Radiobiology of Proton Therapy” that was held in November 2016 in Dresden.
It addresses the major topics (1) relative biological effectiveness (RBE) in proton beam therapy, (2) interaction of proton radiobiology with radiation physics in current treatment planning, (3) biological effects in proton therapy combined with systemic treatments, and (4) testing biological effects of protons in clinical trials.
Finally, important research avenues for improvement of proton radiotherapy based on radiobiological knowledge are identified. The clinical distribution of radiobiological effectiveness of protons alone or in combination with systemic chemo- or immunotherapies as well as patient stratification based on biomarker expressions are key to reach the full potential of proton beam therapy. Dedicated preclinical experiments, innovative clinical trial designs, and large high-quality data repositories will be most important to achieve this goal.
•Feasibility of proton Flash irradiation demonstrated at a clinical therapy facility.•Zebrafish embryo experiment Flash vs. conventional proton irradiation performed.•No significant protective effect ...by proton Flash irradiation observed.
Motivated by first animal trials showing the normal tissue protecting effect of electron and photon Flash irradiation, i.e. at mean dose rates of 100 Gy/s and higher, relative to conventional beam delivery over minutes the feasibility of proton Flash should be assessed.
A setup and beam parameter settings for the treatment of zebrafish embryo with proton Flash and proton beams of conventional dose rate were established at the University Proton Therapy Dresden. Zebrafish embryos were treated with graded doses and the differential effect on embryonic survival and the induction of morphological malformations was followed for up to four days after irradiation.
Beam parameters for the realization of proton Flash were set and tested with respect to controlled dose delivery to biological samples. Analyzing the dose dependent embryonic survival and the rate of spinal curvature as one type of developmental abnormality, no significant influence of proton dose rate was revealed. For the rate of pericardial edema as acute radiation effect, a significant difference (p < 0.05) between proton Flash and protons delivered at conventional dose rate of 5 Gy/min was observed for one dose point only.
The feasibility of Flash proton irradiation was successfully shown, whereas more experiments are required to confirm the presence or absence of a protecting effect and to figure out the limits and requirements for the Flash effect.
To investigate the outcomes of patients with centrally located non-small-cell lung cancer (NSCLC) treated with proton beam therapy (PBT) using moderate hypofractionation.
Between 2006 and 2019, 34 ...patients with centrally located T1-T4N0M0 NSCLC who received moderate hypofractionated PBT were retrospectively reviewed.
The median follow-up was 50.8 months (range=5.8-100.4 months). The 3-year overall survival, progression-free survival (PFS), and local control rates were 70.4%, 55.5% and 80.5%, respectively. Grade 2 or 3 lung adverse events (AEs) after PBT were observed in five (14.7%) patients; however, grade 3 radiation pneumonitis was observed in one (2.9%) patient. Notably, no grade 4 or higher AEs were observed. Regarding the correlation between the lung dose and proximal bronchial tree maximum dose and grade 2 or higher lung AEs, a weak correlation was observed between the mean lung dose and AEs (p=0.035). Although the clinical target volume (CTV) was a risk factor for poor PFS, no significant correlation was found between the CTV and lung AEs after PBT.
Moderate hypofractionated PBT may be a useful radiotherapy method for centrally located cT1-T4N0M0 NSCLC.
This work investigated the most suitable type of degrader (Cu, Al or Nb) and its thickness, taking into consideration the salient aspects of concrete activation for high-purity 89Zr production by ...89Y(p,n)89Zr nuclear reaction. The MCNP and FISPACT codes were used to determine the optimal degrader thickness and the radioactivity of shielding concrete by neutron activation, respectively. The results showed that the optimal thickness of the beam degraders was 1.16, 3.19, and 1.33 mm for Cu, Al, and Nb, respectively. The neutron production rate per proton and the energy and angular distributions of neutrons varied depending on the type of degrader. Considering the radioactivity of the target-room concrete and the amount of radioactive waste expected to be generated, the use of a 1.33-mm-thick Nb degrader for 89Zr production was determined to be the best choice.
This paper presents the results of experimental determination and computational simulation of the independent cross sections of 178m2Hf production in natTa and natW thin targets irradiated by ...mono-energetic proton beams in the energy range from ∼0.04 up to 2.6 GeV. The cross sections were determined using the γ-spectrometry technique without chemical separation of irradiated samples. The obtained experimental results were compared with the results of simulations based on the modified CEM03.03-ext intranuclear cascade model, which allows to analyze both the cross sections of residual nuclei production and the probabilities of long-lived isomeric states formation. Verification of the isomeric yield calculation model was demonstrated based on experimental data on high-spin isomer production cross sections in 208Pb target irradiated by protons.
Abstract
Background
As it promises more precise and conformal radiation treatments, magnetic resonance imaging‐integrated proton therapy (MRiPT) is seen as a next step in image guidance for proton ...therapy. The Lorentz force, which affects the course of the proton pencil beams, presents a problem for beam delivery in the presence of a magnetic field.
Purpose
To investigate the influence of the 0.32‐T perpendicular magnetic field of an MR scanner on the delivery of proton pencil beams inside an MRiPT prototype system.
Methods
An MRiPT prototype comprising of a horizontal pencil beam scanning beam line and an open 0.32‐T MR scanner was used to evaluate the impact of the vertical magnetic field on proton beam deflection and dose spot pattern deformation. Three different proton energies (100, 150, and 220 MeV) and two spot map sizes (15 × 15 and 30 × 20 cm
2
) at four locations along the beam path without and with magnetic field were measured. Pencil‐beam dose spots were measured using EBT3 films and a 2D scintillation detector. To study the magnetic field effects, a 2D Gaussian fit was applied to each individual dose spot to determine the central position , minimum and maximum lateral standard deviation ( and ), orientation (θ), and the eccentricity (ε).
Results
The dose spots were subjected to three simultaneous effects: (a) lateral horizontal beam deflection, (b) asymmetric trapezoidal deformation of the dose spot pattern, and (c) deformation and rotation of individual dose spots. The strongest effects were observed at a proton energy of 100 MeV with a horizontal beam deflection of 14–186 mm along the beam path. Within the central imaging field of the MR scanner, the maximum relative dose spot size decreased by up to 3.66%, while increased by a maximum of 2.15%. The largest decrease and increase in the eccentricity of the dose spots were 0.08 and 0.02, respectively. The spot orientation θ was rotated by a maximum of 5.39°. At the higher proton energies, the same effects were still seen, although to a lesser degree.
Conclusions
The effect of an MRiPT prototype's magnetic field on the proton beam path, dose spot pattern, and dose spot form has been measured for the first time. The findings show that the impact of the MF must be appropriately recognized in a future MRiPT treatment planning system. The results emphasize the need for additional research (e.g., effect of magnetic field on proton beams with range shifters and impact of MR imaging sequences) before MRiPT applications can be employed to treat patients.
With the recent clinical implementation of real‐time MRI‐guided x‐ray beam therapy (MRXT), attention is turning to the concept of combining real‐time MRI guidance with proton beam therapy; MRI‐guided ...proton beam therapy (MRPT). MRI guidance for proton beam therapy is expected to offer a compelling improvement to the current treatment workflow which is warranted arguably more than for x‐ray beam therapy. This argument is born out of the fact that proton therapy toxicity outcomes are similar to that of the most advanced IMRT treatments, despite being a fundamentally superior particle for cancer treatment.
In this Future of Medical Physics article, we describe the various software and hardware aspects of potential MRPT systems and the corresponding treatment workflow. Significant software developments, particularly focused around adaptive MRI‐based planning will be required. The magnetic interaction between the MRI and the proton beamline components will be a key area of focus. For example, the modeling and potential redesign of a magnetically compatible gantry to allow for beam delivery from multiple angles towards a patient located within the bore of an MRI scanner. Further to this, the accuracy of pencil beam scanning and beam monitoring in the presence of an MRI fringe field will require modeling, testing, and potential further development to ensure that the highly targeted radiotherapy is maintained.
Looking forward we envisage a clear and accelerated path for hardware development, leveraging from lessons learnt from MRXT development. Within few years, simple prototype systems will likely exist, and in a decade, we could envisage coupled systems with integrated gantries. Such milestones will be key in the development of a more efficient, more accurate, and more successful form of proton beam therapy for many common cancer sites.
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