A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect.

BACKGROUND AND PURPOSE: FLASH radiotherapy, a technique based on delivering large doses in a single fraction at the micro/millisecond timescale, spares normal tissues from late radiation-induced toxicity, in an oxygen-dependent process, whilst keeping full anti-tumor efficiency. We present a theoretical model taking into account the kinetics of formation and decay of reactive oxygen species, in particular of organic peroxyl radicals ROO. formed by addition of O2 to primary carbon-centred radicals R. and known to play a major role at the origin radio-induced complications. MATERIALS AND METHODS: The model focuses on the time-dependent evolution of radiolytic products in living matter exposed to continuous irradiation at dose-rates in the range 10-3-107Gy·s-1. The 9 differential rate equations resulting from the radiolytic and enzymatic reactions network were solved using the published values of these reactions rate constants in a cellular environment. RESULTS: The model suggests a correlation between the area-under-the-curve of time-evolving [ROO.] and the probability of normal tissue complications. The model does not lend weight to the hypothesis of transient oxygen depletion as a main determinant of FLASH but rather suggests a major role of radical-radical recombination. CONCLUSION: The model gives support to the reduction of ROO. lifetime as the main root of FLASH and compares favorably with published experimental results. We conclude that any process - in this case radical recombination - that shortens the lifetime or limits the radiolytic yield of ROO. is likely to protect normoxic tissues against the deleterious effects of radiation.

Prompt Gamma Imaging for In Vivo Range Verification of Pencil Beam Scanning Proton Therapy.

PURPOSE: To report the first clinical results and value assessment of prompt gamma imaging for in vivo proton range verification in pencil beam scanning mode. METHODS AND MATERIALS: A stand-alone, trolley-mounted, prototype prompt gamma camera utilizing a knife-edge slit collimator design was used to record the prompt gamma signal emitted along the proton tracks during delivery of proton therapy for a brain cancer patient. The recorded prompt gamma depth detection profiles of individual pencil beam spots were compared with the expected profiles simulated from the treatment plan. RESULTS: In 6 treatment fractions recorded over 3 weeks, the mean (± standard deviation) range shifts aggregated over all spots in 9 energy layers were -0.8 ± 1.3 mm for the lateral field, 1.7 ± 0.7 mm for the right-superior-oblique field, and -0.4 ± 0.9 mm for the vertex field. CONCLUSIONS: This study demonstrates the feasibility and illustrates the distinctive benefits of prompt gamma imaging in pencil beam scanning treatment mode. Accuracy in range verification was found in this first clinical case to be better than the range uncertainty margin applied in the treatment plan. These first results lay the foundation for additional work toward tighter integration of the system for in vivo proton range verification and quantification of range uncertainties.

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer.

PURPOSE: An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning. METHODS AND MATERIALS: The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the target's distal surface. RESULTS: The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology. CONCLUSIONS: A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.

First clinical application of a prompt gamma based in vivo proton range verification system.

BACKGROUND AND PURPOSE: To improve precision of particle therapy, in vivo range verification is highly desirable. Methods based on prompt gamma rays emitted during treatment seem promising but have not yet been applied clinically. Here we report on the worldwide first clinical application of prompt gamma imaging (PGI) based range verification. MATERIAL AND METHODS: A prototype of a knife-edge shaped slit camera was used to measure the prompt gamma ray depth distribution during a proton treatment of a head and neck tumor for seven consecutive fractions. Inter-fractional variations of the prompt gamma profile were evaluated. For three fractions, in-room control CTs were acquired and evaluated for dose relevant changes. RESULTS: The measurement of PGI profiles during proton treatment was successful. Based on the PGI information, inter-fractional global range variations were in the range of ±2 mm for all evaluated fractions. This is in agreement with the control CT evaluation showing negligible range variations of about 1.5mm. CONCLUSIONS: For the first time, range verification based on prompt gamma imaging was applied for a clinical proton treatment. With the translation from basic physics experiments into clinical operation, the potential to improve the precision of particle therapy with this technique has increased considerably.