Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs.

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.

Commissioning and quality assurance of a novel solution for respiratory-gated PBS proton therapy based on optical tracking of surface markers.

We present the commissioning and quality assurance of our clinical protocol for respiratory gating in pencil beam scanning proton therapy for cancer patients with moving targets. In a novel approach, optical tracking has been integrated in the therapy workflow and used to monitor respiratory motion from multiple surrogates, applied on the patients' chest. The gating system was tested under a variety of experimental conditions, specific to proton therapy, to evaluate reaction time and reproducibility of dose delivery control. The system proved to be precise in the application of beam gating and allowed the mitigation of dose distortions even for large (1.4cm) motion amplitudes, provided that adequate treatment windows were selected. The total delivered dose was not affected by the use of gating, with measured integral error within 0.15cGy. Analysing high-resolution images of proton transmission, we observed negligible discrepancies in the geometric location of the dose as a function of the treatment window, with gamma pass rate greater than 95% (2%/2mm) compared to stationary conditions. Similarly, pass rate for the latter metric at the 3%/3mm level was observed above 97% for clinical treatment fields, limiting residual movement to 3mm at end-exhale. These results were confirmed in realistic clinical conditions using an anthropomorphic breathing phantom, reporting a similarly high 3%/3mm pass rate, above 98% and 94%, for regular and irregular breathing, respectively. Finally, early results from periodic QA tests of the optical tracker have shown a reliable system, with small variance observed in static and dynamic measurements.

Reply to Comment on 'Lateral response heterogeneity of Bragg peak ionization chambers for narrow-beam photon and proton dosimetry'.

Shen (2019) commented on our paper 'Lateral response heterogeneity of Bragg peak ionization chambers for narrow-beam photon and proton dosimetry' regarding the impact of the low dose tail of the collimated x-ray beam we used to acquire individual response maps of large area ionization chambers. The behavior of this low dose tail was measured and compared to the simulations performed by Shen (2019). It was shown that the model of the tail by Shen (2019) is too simplistic and overestimates its effect.

FLUKA particle therapy tool for Monte Carlo independent calculation of scanned proton and carbon ion beam therapy.

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.

Lateral response heterogeneity of Bragg peak ionization chambers for narrow-beam photon and proton dosimetry.

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 (LAICThick) and four of type PTW-34080 (LAICThin). 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 LAICThick 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 LAICThin. Considering a proton pencil beam the systematic offset for reference dosimetry was 2.4-4.1% for LAICThick and -9.5 to 9.4% for LAICThin. 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 mm2 field sizes for LAICThick. For LAICThin 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.

Modelling of cell killing due to sparsely ionizing radiation in normoxic and hypoxic conditions and an extension to high LET radiation.

PURPOSE: An approach for describing cell killing with sparsely ionizing radiation in normoxic and hypoxic conditions based on the initial number of randomly distributed DNA double-strand breaks (DSB) is proposed. An extension of the model to high linear energy transfer (LET) radiation is also presented. MATERIALS AND METHODS: The model is based on the probabilities that a given DNA giant loop has one DSB or at least two DSB. A linear combination of these two classes of damage gives the mean number of lethal lesions. When coupled with a proper modelling of the spatial distribution of DSB from ion tracks, the formalism can be used to predict cell response to high LET radiation in aerobic conditions. RESULTS: Survival data for sparsely ionizing radiation of cell lines in normoxic/hypoxic conditions were satisfactorily fitted with the proposed parametrization. It is shown that for dose ranges up to about 10 Gy, the model describes tested experimental survival data as good as the linear-quadratic model does. The high LET extension yields a reasonable agreement with data in aerobic conditions. CONCLUSIONS: A new survival model has been introduced that is able to describe the most relevant features of cellular dose-response postulating two damage classes.

Simulations of microdosimetric quantities with the Monte Carlo code FLUKA for carbon ions at therapeutic energies.

PURPOSE: Microdosimetric quantities can be used to estimate the biological effectiveness of radiation fields. This study evaluates the capability of the general-purpose Monte Carlo code FLUKA to simulate microscopic patterns of energy depositions for mixed radiation fields which are created by carbon ions at therapeutic energies in phantoms. MATERIALS AND METHODS: Measured lineal energy spectra and linear energy transfer (LET) spectra produced by carbon ions of about 300 MeV/n at different depths in phantoms representing human tissue were chosen from published literature and were compared with results from simulations of the measurement set-ups with FLUKA. RESULTS: Simulations of the dose-weighted lineal energy spectra yd(y) and dose-weighted LET spectra describe the main features of the respective measured spectra. All simulated frequency mean and dose mean lineal energy values are, respectively, within 21% and 11% of the measured ones. A slight underestimation of fragment fluences is notable. It is shown that the simultaneous detection of several charged fragments in the TEPC ('V effect') has considerable impact on the measured lineal energy spectra of fragments. CONCLUSIONS: Agreement between measurements and FLUKA results is encouraging and shows that FLUKA can predict microdosimetric spectra of mixed radiation fields created by therapeutic carbon ions in phantoms reasonably well.