Background and Aims

Reduced skin toxicity is now shown pre-clinically after >40Gy/s FLASH radiotherapy (RT) as compared to ~0.03Gy/s conventional RT. While this area of study has been advanced significantly, the biological basis of the FLASH sparing effect on skin is yet to be discovered, and diagnostic tools to assess the response biological mechanisms and tools that can be used in the translation of FLASH study in humans are needed. Here we report on direct mechanistic in situ measurements of skin damage, with the aim to quantify and compare microstructural and microvascular changes in skin after RT, while varying dose and supporting the findings with ex vivo histological observations.

Methods

In IACUC approved animal study, right thighs of 54 nude mice (n=6 per dose group) were treated with 0-40Gy single doses of 300Gy/s FLASH and conventional RT. Skin was imaged with functional optical coherence tomography - a non-invasive microscopic 3D imaging technique with light penetration at 1-3 millimeter depths in biological tissues.

Results

Quantification was completed for skin pigmentation, epidermal thickness, remodeling of collagen fibers, alteration of blood and lymphatic networks. These demonstrated inter-connected “passenger versus driver” temporal behaviors of skin tissue components in both RT-treatment types. Response to FLASH RT was characterized by reduced damage to collagen bundles and blood/lymphatic networks together with less desquamation of skin surface (less damage to epidermis) and higher pigmentation.

Conclusions

This study presents first of its kind in-vivo functional longitudinal observations and quantification of the comparative FLASH effects in a mouse model of skin early damage, healing and recovery.

Background and Aims

Dosimetry for FLASH radiotherapy, VHEE radiotherapy as well as for laser-driven beams cause significant metrological challenges due to the ultra-high dose rates and pulsed structure of these beams, in particular for real time measurements with active dosimeters. It is not possible to simply apply existing Codes of Practice available for dosimetry in conventional external radiotherapy here. However, reliable standardized dosimetry is necessary for accurate comparisons in radiobiological experiments, to compare the efficacy of these new radiotherapy techniques and to enable safe clinical application. UHDpulse aims to develop the metrological tools needed for reliable real-time absorbed dose measurements of electron and proton beams with ultra-high dose rate, ultra-high dose per pulse or ultra-short pulse duration.

Methods

Within UHDpulse, primary and secondary absorbed dose standards and reference dosimetry methods are developed, the responses of available state-of-the-art detector systems are characterised, novel and custom-built active dosimetric systems and beam monitoring systems are designed, and methods for relative dosimetry and for the characterization of stray radiation are investigated.

Results

Prototypes of different active dosimetry systems show promising results for real-time dosimetry for particle beams with ultra-high pulse dose rates. The results of the UHDpulse project will be the input data for future Codes of Practice.

Conclusions

A brief overview of the progress in the UHDpulse project and the involved institutions will be given.

Acknowledgement: This project 18HLT04 UHDpulse has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme.

Background and Aims

There are at least two very plausible radiobiological mechanisms for the oxygen effect in FLASH: 1) Directly, by depletion of oxygen at critical molecular sites directly changing the amount of radiation damage; 2) Indirectly by modifying physiologically mediated changes in response to radiation damage via alterations in repair and/or cell signaling. The overwhelming amount of radiation-induced damage that ultimately leads to cell death occurs in DNA. Oxygen directly radiosensitizes by reaction with transient intermediates in the DNA. Hypoxia also can modify damage from ionizing radiation inducing changes in signaling and in repair mechanisms that differ between tumors and normal tissues.

Methods

Radiobiological Principles

Results

Based on studies with cells there are lesions in DNA that have lifetimes as long as 10^-5 or 10^-6 seconds. The pertinent distance from which oxygen can diffuse to the sensitive site is 100-1000 nm assuming the diffusion rate of oxygen is 2.1x10^-5 cm²/sec within the environment around the DNA. Therefore a technique is needed that can follow the oxygen level with spatial resolution of the nucleus and a time scale of 10^-5 seconds or faster. No currently available method can do this directly. This might be done if detailed spatial distribution of oxygen inside the cell is known and the rate of oxygen depletion in a nucleus can be determined by a combination of direct measurements of oxygen, genomic alterations, and appropriate calculations.

Conclusions

Using established principles of radiation biology it should be feasible to rigorously determine if and how oxygen is involved in the mechanism of FLASH.