The feasibility of off-line positron emission tomography/computed tomography (PET/CT) for routine three dimensional in-vivo treatment verification of proton radiation therapy is currently under investigation at Massachusetts General Hospital in Boston. In preparation for clinical trials, phantom experiments were carried out to investigate the sensitivity and accuracy of the method depending on irradiation and imaging parameters. Furthermore, they addressed the feasibility of PET/CT as a robust verification tool in the presence of metallic implants. These produce x-ray CT artifacts and fluence perturbations which may compromise the accuracy of treatment planning algorithms. Spread-out Bragg peak proton fields were delivered to different phantoms consisting of polymethylmethacrylate (PMMA), PMMA stacked with lung and bone equivalent materials, and PMMA with titanium rods to mimic implants in patients. PET data were acquired in list mode starting within 20 min after irradiation at a commercial luthetium-oxyorthosilicate (LSO)-based PET/CT scanner. The amount and spatial distribution of the measured activity could be well reproduced by calculations based on the GEANT4 and FLUKA Monte Carlo codes. This phantom study supports the potential of millimeter accuracy for range monitoring and lateral field position verification even after low therapeutic dose exposures of 2 Gy, despite the delay between irradiation and imaging. It also indicates the value of PET for treatment verification in the presence of metallic implants, demonstrating a higher sensitivity to fluence perturbations in comparison to a commercial analytical treatment planning system. Finally, it addresses the suitability of LSO-based PET detectors for hadron therapy monitoring. This unconventional application of PET involves countrates which are orders of magnitude lower than in diagnostic tracer imaging, i.e., the signal of interest is comparable to the noise originating from the intrinsic radioactivity of the detector itself. In addition to PET alone, PET/CT imaging provides accurate information on the position of the imaged object and may assess possible anatomical changes during fractionated radiotherapy in clinical applications. a) Present address: Heidelberg

The dose distribution of a proton beam stopping in water has components due to basic physics and may have others from beam contamination. We propose the concise terms core for the primary beam, halo (cf. Pedroni et al. [1]) for the low dose region from charged secondaries, aura for the low dose region from neutrals, and spray for beam contamination.We have measured the dose distribution in a water tank at 177 MeV under conditions where spray, therefore radial asymmetry, is negligible. We used an ADCL calibrated thimble chamber and a Faraday cup calibrated integral beam monitor so as to obtain immediately the absolute dose per proton. We took depth scans at fixed distances from the beam centroid rather than radial scans at fixed depths. That minimizes the signal range for each scan and better reveals the structure of the core and halo.Transitions from core to halo to aura are already discernible in the raw data. The halo has components attributable to coherent and incoherent nuclear reactions. Due to elastic and inelastic scattering by the nuclear force, the Bragg peak persists to radii larger than can be accounted for by Molière single scattering. The radius of the incoherent component, a dose bump around midrange, agrees with the kinematics of knockout reactions.We have fitted the data in two ways. The first is algebraic or model dependent (MD) as far as possible, and has 25 parameters. The second, using 2D cubic spline regression, is model independent (MI). Optimal parameterization for treatment planning will probably be a hybrid of the two, and will of course require measurements at several incident energies.The MD fit to the core term resembles that of the PSI group [1], which has been widely emulated. However, we replace their T (w), a mass stopping power which mixes electromagnetic (EM) and nuclear effects, with one that is purely EM, arguing that protons that do not undergo hard single scatters continue to lose energy according to the Beth-Bloch formula. If that is correct, it is no longer necessary to measure T (w), and the dominant role played by the 'Bragg peak chamber' (BPW) vanishes.For mathematical and other details we will refer to [2], a long technical report of this project.

A recent clinical pilot study demonstrated the feasibility of offline PET/CT range verification for proton therapy treatments. In vivo PET measurements are challenged by blood perfusion, variations of tissue compositions, patient motion and image co-registration uncertainties. Besides these biological and treatment specific factors, the accuracy of the method is constrained by the underlying physical processes. This phantom study distinguishes physical factors from other factors, assessing the reproducibility, consistency and sensitivity of the PET/CT range verification method. A spread-out Bragg-peak (SOBP) proton field was delivered to a phantom consisting of poly-methyl methacrylate (PMMA), lung and bone equivalent material slabs. PET data were acquired in listmode at a commercial PET/CT scanner available within 10 min walking distance from the proton therapy unit. The measured PET activity distributions were compared to simulations of the PET signal based on Geant4 and FLUKA Monte Carlo (MC) codes. To test the reproducibility of the measured PET signal, data from two independent measurements at the same geometrical position in the phantom were compared. Furthermore, activation depth profiles within identical material arrangements but at different positions within the irradiation field were compared to test the consistency of the measured PET signal. Finally, activation depth profiles through air/lung, air/bone and lung/bone interfaces parallel as well as at 6 degrees to the beam direction were studied to investigate the sensitivity of the PET/CT range verification method. The reproducibility and the consistency of the measured PET signal were found to be of the same order of magnitude. They determine the physical accuracy of the PET measurement to be about 1 mm. However, range discrepancies up to 2.6 mm between two measurements and range variations up to 2.6 mm within one measurement were found at the beam edge and at the edge of the field of view (FOV) of the PET scanner. PET/CT range verification was found to be able to detect small range modifications in the presence of complex tissue inhomogeneities. This study indicates the physical potential of the PET/CT verification method to detect the full-range characteristic of the delivered dose in the patient.

Extremely high-dose-rate irradiation, referred to as FLASH, has been shown to be less damaging to normal tissues than the same dose administrated at conventional dose rates. These results, typically seen at dose rates exceeding 40 Gy/s (or 2,400 Gy/min), have been widely reported in studies utilizing photon or electron radiation as well as in some proton radiation studies. Here, we report the development of a proton irradiation platform in a clinical proton facility and the dosimetry methods developed. The target is placed in the entry plateau region of a proton beam with a specifically designed double-scattering system. The energy after the double-scattering system is 227.5 MeV for protons that pass through only the first scatterer, and 225.5 MeV for those that also pass through the second scatterer. The double-scattering system was optimized to deliver a homogeneous dose distribution to a field size as large as possible while keeping the dose rate .100 Gy/s and not exceeding a cyclotron current of 300 nA. We were able to obtain a collimated pencil beam (1.6 3 1.2 cm 2 ellipse) at a dose rate of ;120 Gy/s. This beam was used for dose-response studies of partial abdominal irradiation of mice. First results indicate a potential tissuesparing effect of FLASH.