Emiel R. van der Graaf

Compared to photon therapy, proton therapy allows a better conformation of the dose to the tumour volume with reduced radiation dose to co-irradiated tissues. Invivoverification techniques including Positron Emission Tomography (PET) have been proposed as quality assurance tools to mitigate proton range uncertainties. Detection of differences between planned and actual dose delivery on a short timescale provides a fast trigger for corrective actions. Conventional PET-based imaging of15O (T1/2= 2 min) and11C (T1/2= 20 min) distributions precludes such immediate feedback. We here present a demonstration of near real-time range verification by means of PET imaging of12N (T1/2= 11 ms). PMMA and graphite targets were irradiated with a 150 MeV proton pencil beam consisting of a series of pulses of 10 ms beam-on and 90 ms beam-off. Two modules of a modified Siemens Biograph mCT PET scanner (21 × 21 cm2each), installed 25 cm apart, were used to image the beam-induced PET activity during the beam-off periods. The modifications enable the detectors to be switched off during the beam-on periods.12N images were reconstructed using planar tomography. Using a 1D projection of the 2D reconstructed12N image, the activity range was obtained from a fit of the activity profile with a sigmoid function. Range shifts due to modified target configurations were assessed for multiples of the clinically relevant 108protons per pulse (approximately equal to the highest intensity spots in the pencil beam scanning delivery of a dose of 1 Gy over a cubic 1 liter volume). The standard deviation of the activity range, determined from 30 datasets obtained from three irradiations on PMMA and graphite targets, was found to be 2.5 and 2.6 mm (1σ) with 108protons per pulse and 0.9 and 0.8 mm (1σ) with 109protons per pulse. Analytical extrapolation of the results from this study shows that using a scanner with a solid angle coverage of 57%, with optimized detector switching and spot delivery times much smaller than the12N half-life, an activity range measurement precision of 2.0 mm (1σ) and 1.3 mm (1σ) within 50 milliseconds into an irradiation with 4 × 107and 108protons per pencil beam spot can be potentially realized. Aggregated imaging of neighbouring spots or, if possible, increasing the number of protons for a few probe beam spots will enable the realization of higher precision range measurement.

Therapy with helium ions is currently receiving significantly increasing interest because helium ions have a sharper penumbra than protons and undergo less fragmentation than carbon ions and thus require less complicated dose calculations. For any ion of interest in hadron therapy, the accuracy of dose delivery is limited by range uncertainties. This has led to efforts by several groups to develop in vivo verification techniques, including positron emission tomography (PET), for monitoring of the dose delivery. Beam-on PET monitoring during proton therapy through the detection of short-lived positron emitters such as ¹² N ( T _1/2 = 11 ms), an emerging PET technique, provides an attractive option given the achievable range accuracy, minimal susceptibility to biological washout and provision of near prompt feedback. Extension of this approach to helium ions requires information on the production yield of relevant short-lived positron emitters. This study presents the first measurements of the production of short-lived positron emitters in water, graphite, calcium and phosphorus targets irradiated with 59 MeV/u ³ He and 50 MeV/u ⁴ He beams. For these targets, the most produced short-lived nuclides are ¹³ O/ ¹² N ( T _1/2 = 8.6/11 ms) on water, ¹³ O/ ¹² N on graphite, ⁴³ Ti/ ⁴¹ Sc/ ⁴² Sc ( T _1/2 = 509–680 ms) on calcium, ²⁸ P ( T _1/2 = 268 ms) on phosphorus. A translation of the results from elemental targets to PMMA and representative tissues such as adipose tissue, muscle, compact and cortical bone, shows the dominance of ¹³ O/ ¹² N in at least the first 20 s of an irradiation with ⁴ He and somewhat longer with ³ He. As the production of ¹³ O/ ¹² N in a ³ He irradiation is 3–4 times higher than in a ⁴ He irradiation, from a statistical point of view, range verification using ¹³ O/ ¹² N PET imaging will be about 2 times more precise for a ³ He irradiation compared to a ⁴ He irradiation.

The quality of cancer treatment with protons critically depends on an accurate prediction of the proton stopping powers for the tissues traversed by the protons. Today, treatment planning in proton radiotherapy is based on stopping power calculations from densities of X-ray Computed Tomography (CT) images. This causes systematic uncertainties in the calculated proton range in a patient of typically 3–4%, but can become even 10% in bone regions [1,2,3,4,5,6,7,8]. This may lead to no dose in parts of the tumor and too high dose in healthy tissues [1]. A direct measurement of proton stopping powers with high-energy protons will allow reducing these uncertainties and will improve the quality of the treatment. Several studies have shown that a sufficiently accurate radiograph can be obtained by tracking individual protons traversing a phantom (patient) [4,6,10]. Our studies benefit from the gas-filled time projection chambers based on GridPix technology [2], developed at Nikhef, capable of tracking a single proton. A BaF₂ crystal measuring the residual energy of protons was used. Proton radiographs of phantom consisting of different tissue-like materials were measured with a 30×30 mm² 150 MeV proton beam. Measurements were simulated with the Geant4 toolkit.First experimental and simulated energy radiographs are in very good agreement [3]. In this paper we focus on simulation studies of the proton scattering angle as it affects the position resolution of the proton energy loss radiograph. By selecting protons with a small scattering angle, the image quality can be improved significantly.

The only method for in vivo dose delivery verification in proton beam radiotherapy in clinical use today is positron emission tomography (PET) of the positron emitters produced in the patient during irradiation. PET imaging while the beam is on (so called beam-on PET) is an attractive option, providing the largest number of counts, the least biological washout and the fastest feedback. In this implementation, all nuclides, independent of their half-life, will contribute. As a first step towards assessing the relevance of short-lived nuclides (half-life shorter than that of ¹⁰ C, T _1/2 = 19 s) for in vivo dose delivery verification using beam-on PET, we measured their production in the stopping of 55 MeV protons in water, carbon, phosphorus and calcium The most copiously produced short-lived nuclides and their production rates relative to the relevant long-lived nuclides are: ¹² N ( T _1/2 = 11 ms) on carbon (9% of ¹¹ C), ²⁹ P ( T _1/2 = 4.1 s) on phosphorus (20% of ³⁰ P) and ^38m K ( T _1/2 = 0.92 s) on calcium (113% of ^38g K). No short-lived nuclides are produced on oxygen. The number of decays integrated from the start of an irradiation as a function of time during the irradiation of PMMA and 4 tissue materials has been determined. For (carbon-rich) adipose tissue, ¹² N dominates up to 70 s. On bone tissue, ¹² N dominates over ¹⁵ O during the first 8–15 s (depending on carbon-to-oxygen ratio). The short-lived nuclides created on phosphorus and calcium provide 2.5 times more beam-on PET counts than the long-lived ones produced on these elements during a 70 s irradiation. From the estimated number of ¹² N PET counts, we conclude that, for any tissue, ¹² N PET imaging potentially provides equal to superior proton range information compared to prompt gamma imaging with an optimized knife-edge slit camera. The practical implementation of ¹² N PET imaging is discussed.

The treatment quality of cancer patients with a proton beam critically depends on accurate predictions of proton stopping powers. Uncertainties in proton range that occur from translation of an X-ray CT patient image, of typical 3-4% or more, lead to necessary enlargements of contours around the tumor, and thus delivery of unnecessary dose to healthy tissues. A 2-dimentional proton radiography imaging technique, in which proton stopping powers of various materials (tissues) are measured directly, can improve quality of proton treatment. The proton scattering angle, causing the image degradation, has to be studied with a special care.