Purpose: The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results, we designed a randomized phase III trial to investigate the FLASH effect in cat patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-radiotherapy was studied on mini pigs by using large field irradiation. Experimental Design: Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to two arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10 × 4.8 Gy (90% isodose); arm 2 used 1 × 30 Gy (90% isodose) FLASH. Mini pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH. Results: In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis, which occurred 9 to 15 months after radiotherapy in 3 of 7 cats treated with FLASH-radiotherapy (43%), as compared with 0 of 9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded, but severe late skin necrosis occurred in a volume-dependent manner (7–9 months), which later resolved. Conclusions: The reported outcomes point to the caveats of translating single-high-dose FLASH-radiotherapy and emphasizes the need for caution and further investigations. See related commentary by Maity and Koumenis, p. 3636

The FLUKA Monte Carlo Radiation Transport and Interaction code package is widely used to simulate the interaction of particles with matter in a variety of fields, including high energy physics, space radiation, medical applications, radiation protection and shielding assessments, accelerator studies, astrophysical studies and well logging. This paper gives a brief overview of the FLUKA program and describes recent developments, in particular, improvements in the modelling of particle interactions and transport are described in detail. In addition, an overview of selected applications is given.

While Monte Carlo (MC) codes are considered as the gold standard for dosimetric calculations, the availability of user friendly MC codes suited for particle therapy is limited. Based on the FLUKA MC code and its graphical user interface (GUI) Flair, we developed an easy-to-use tool which enables simple and reliable simulations for particle therapy. In this paper we provide an overview of functionalities of the tool and with the presented clinical, proton and carbon ion therapy examples we demonstrate its reliability and the usability in the clinical environment and show its flexibility for research purposes. The first, easy-to-use FLUKA MC platform for particle therapy with GUI functionalities allows a user with a minimal effort and reduced knowledge about MC details to apply MC at their facility and is expected to enhance the popularity of the MC for both research and clinical quality assurance and commissioning purposes.

Large area ionization chambers (LAICs) can be used to measure output factors of narrow beams. Dose area product measurements are proposed as an alternative to central-axis point dose measurements. Using such detectors requires detailed information on the uniformity of the response along the sensitive area. Eight LAICs were investigated in this study: four of type PTW-34070 (LAIC _Thick ) and four of type PTW-34080 (LAIC _Thin ). Measurements were performed in an x-ray unit using peak voltages of 100–200 kVp and a collimated beam of 3.1 mm (FWHM). The LAICs were moved with a step size of 5 mm to measure the chamber response at lateral positions. To account for beam positions where only a fraction of the beam impinged within the sensitive area of the LAICs, a corrected response was calculated which was the basis to calculate the relative response. The impact of a heterogeneous LAIC response, based on the obtained response maps was henceforth investigated for proton pencil beams and small field photon beams. A pronounced heterogeneity of the responses was observed in the investigated LAICs. The response of LAIC _Thick generally decreased with increasing radius, resulting in a response correction of up to 5%. This correction was more pronounced and more diverse (up to 10%) for LAIC _Thin . Considering a proton pencil beam the systematic offset for reference dosimetry was 2.4–4.1% for LAIC _Thick and −9.5 to 9.4% for LAIC _Thin . For relative dosimetry (e.g. integral depth-dose curves) systematic response variation by 0.8–1.9% were found. For a decreasing photon field size the systematic offset for absolute dose measurements showed a 2.5–4.5% overestimation of the response for 6 × 6 mm ² field sizes for LAIC _Thick . For LAIC _Thin the response varied even over a range of 20%. This study highlights the need for chamber-dependent response maps when using LAICs for absolute and relative dosimetry with proton pencil beams or small photon beams.

Purpose: Normal tissue (NT) sparing by ultra‐high dose rate (UHDR) irradiations compared to conventional dose rate (CONV) irradiations while being isotoxic to the tumor has been termed “FLASH effect” and has been observed when large doses per fraction (d ≳ 5 Gy) have been delivered. Since hypofractionated treatment schedules are known to increase toxicities of late‐reacting tissues compared to normofractionated schedules for many clinical scenarios at CONV dose rates, we developed a formalism based on the biologically effective dose (BED) to assess the minimum magnitude of the FLASH effect needed to compensate the loss of late‐reacting NT sparing when reducing the number of fractions compared to a normofractionated CONV treatment schedule while remaining isoeffective to the tumor.Methods: By requiring the same BED for the tumor, we derived the “break‐even NT sparing weighting factor” W_BE for the linear‐quadratic (LQ) and LQ‐linear (LQ‐L) models for an NT region irradiated at a relative dose r (relative to the prescribed dose per fraction d to the tumor). W_BE was evaluated numerically for multiple values of d and r, and for different tumor and NT α/β‐ratios. W_BE was compared against currently available experimental data on the magnitude of the NT sparing provided by the FLASH effect for single fraction doses.Results: For many clinically relevant scenarios, W_BE decreases steeply initially for d > 2 Gy for late‐reacting tissues with (α/β)_NT ≈ 3 Gy, implying that a significant NT sparing by the FLASH effect (between 15% and 30%) is required to counteract the increased radiobiological damage experienced by late‐reacting NT for hypofractionated treatments with d < 10 Gy compared to normofractionated treatments that are equieffective to the tumor. When using the LQ model with generic α/β‐ratios for tumor and late‐reacting NT of (α/β)_T = 10 Gy and (α/β)_NT = 3 Gy, respectively, most currently available experimental evidence about the magnitude of NT sparing by the FLASH effect suggests no net NT sparing benefit for hypofractionated FLASH radiotherapy (RT) in the high‐dose region when compared with W_BE. Instead, clinical indications with more similar α/β‐ratios of the tumor and dose‐limiting NT toxicities [i.e., (α/β)_T ≈ (α/β)_NT], such as prostate treatments, are generally less penalized by hypofractionated treatments and need consequently smaller magnitudes of NT sparing by the FLASH effect to achieve a net benefit. For strongly hypofractionated treatments (>10–15 Gy/fraction), the LQ‐L model predicts, unlike the LQ model, a larger W_BE suggesting a possible benefit of strongly hypofractionated FLASH RT, even for generic α/β‐ratios of (α/β)_T = 10 Gy and (α/β)_NT = 3 Gy. However, knowledge on the isoeffect scaling for high doses per fraction (≳10 Gy/fraction) and its modeling is currently limited and impedes accurate and reliable predictions for such strongly hypofractionated treatments.Conclusions: We developed a formalism that quantifies the minimal NT sparing by the FLASH effect needed to compensate for hypofractionation, based on the LQ and LQ‐L models. For a given hypofractionated UHDR treatment scenario and magnitude of the FLASH effect, the formalism predicts if a net NT sparing benefit is expected compared to a respective normofractionated CONV treatment.