Kristoffer Petersson

University of Oxford | OX · Department of Oncology

Background The role of radiolytic oxygen consumption for the in‐vitro “Ultra‐High Dose Rate” (UHDR) sparing and in‐vivo FLASH effect is subject to active debate, but data on key dependencies such as the radiation quality are lacking. Purpose The influence of “dose‐averaged Linear Energy Transfer” (LETd) and dose rate on radiolytic oxygen consumpti...

Introduction FLASH radiotherapy (RT) has emerged as a promising modality, demonstrating both a normal tissue sparing effect and anticancer efficacy. We have previously reported on the safety and efficacy of single fraction FLASH RT in the treatment of oral tumors in canine cancer patients, showing tumor response but also a risk of radiation-induced...

Introduction FLASH proton therapy (FLASH-PT) requires ultra-high dose rate (≥ 40 Gy/s) protons to be delivered in a short timescale whilst conforming to a patient-specific target. This study investigates the feasibility and constraints of Bragg peak FLASH-PT treatment planning, and compares the in silico results produced to plans for intensity modu...

AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when comb...

This study aims to investigate the feasibility of enhancing the charge collection efficiency (CCE) of a transmission chamber by reconfiguring its design and operation. The goal was to extend the range of dose-per-pulse (DPP) values with no or minimal recombination effects up to the ultra-high dose rate (UHDR) regime. The response of two transmissio...

Introduction We have previously adapted a clinical linear accelerator (Elekta Precise, Elekta AB) for ultra-high dose rate (UHDR) electron delivery. To enhance reliability in future clinical FLASH radiotherapy trials, the aim of this study was to introduce and evaluate an upgraded beam control system and beam tuning process for safe and precise UHD...

Background Radiotherapy increases survival in patients with glioblastoma. However, the prescribed dose is limited by unwanted side effects on normal tissue. Previous experimental studies have shown that FLASH radiotherapy (FLASH-RT) can reduce these side effects. Still, it is important to establish an equal anti-tumor efficacy comparing FLASH-RT to...

At Lund University and Skåne University Hospital in Lund, Sweden, we have, as the first clinic, modified a clinical Elekta Precise linear accelerator for convertible delivery of ultra-high dose rate (FLASH) irradiation. Whereas recently published reviews highlighted the need for standardised protocols for ultra-high dose rate beam dosimetry to be a...

Background FLASH radiotherapy (RT) is a novel method for delivering ionizing radiation, which has been shown in preclinical studies to have a normal tissue sparing effect and to maintain anticancer efficacy as compared to conventional RT. Treatment of head and neck tumors with conventional RT is commonly associated with severe toxicity, hence the n...

Purpose The increased normal tissue tolerance for FLASH radiotherapy (FLASH‐RT), as compared to conventional radiotherapy, was first observed in ultra‐high dose rate electron beams. Initial clinical trials in companion animals have revealed a high risk of developing osteoradionecrosis following high‐dose single‐fraction electron FLASH‐RT, which may...

Purpose: When compared to conventional dose rate irradiation (CONV), ultra-high dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect", also depends on the tumour toxicity obtained by UHDR. Based on a combined analysis of published lite...

Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being...

FLASH radiotherapy, delivered with ultra-high dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared to currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinic...

Drug delivery to the brain is restricted by the blood brain barrier (BBB), limiting up to 98% small molecule drugs and almost 100% biologics. This severely limits the treatment options for diseases of the CNS. The use of microbubbles (MBs) in combination with focused ultrasound (FUS) has successfully delivered multiple classes of therapeutics throu...

Radiotherapy using conventional x-ray irradiation is still the most effective treatment for solid tumours of the head and neck and brain, although adverse treatment side effects are common and inherent tumour radioresistance remains a significant barrier to effective treatment. Use of alternative radiation modalities such as precision targeted prot...

Purpose: To ensure a clinical translation of FLASH radiation therapy (FLASH-RT) for a specific tumor type, studies on tumor control and toxicity within the same biological system are needed. In this study, our objective was to evaluate tumor control and toxicity for hypofractionated FLASH-RT and conventional radiation therapy (CONV-RT) in an immuno...

FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy in...

Objective: FLASH irradiation reportedly produces less normal tissue toxicity, while maintaining tumour response. To investigate oxygen’s role in the ‘FLASH effect’, we assessed DNA damage levels following irradiation at different oxygen tensions, doses and dose rates. Methods: Samples of whole blood were irradiated (20 Gy) at various oxygen tensio...

As radiotherapy using ultra-high dose rates has gained new interest, the dosimetric challenges arising at these conditions needs to be addressed. Ionization chambers suffer from a large decrease in ion collection efficiency due to ion recombination, making on-line dosimetry difficult. In this work we present experimental setups and dosimetric proce...

Purpose Hypoxia (low oxygen) is a common feature of solid tumors that has been intensely studied for more than six decades. Here we review the importance of hypoxia to radiotherapy with a particular focus on the contribution of hypoxia to immune responses, metastatic potential and FLASH radiotherapy, active areas of research by leading women in the...

Purpose/Objective(s) Studies of electron FLASH radiotherapy (FLASH-RT) in companion animals are being conducted at several institutions. High energy electron beams are generally suitable for treatment of superficial cancers, but of limited use for deep-seated tumors. In this case report, the feasibility of intracavitary electron FLASH-RT is demonst...

Introduction The aim of this study was to evaluate if surface guided radiotherapy (SGRT) can decrease patient positioning time for localized prostate cancer patients compared to the conventional 3-point localization setup method. The patient setup accuracy was also compared between the two setup methods. Materials and methods A total of 40 localiz...

Purpose Preclinical studies using ultra-high dose rate (FLASH) irradiation have demonstrated reduced normal tissue toxicity compared to conventional dose rate (CONV) irradiation, although this finding is not universal. We investigated the effect of temporal pulse structure and average dose rate of FLASH compared to CONV irradiation, on acute intest...

Background Irradiation with ultra-high dose rate (FLASH) has been shown to spare normal tissue without hampering tumor control in several in vivo studies. Few cell lines have been investigated in vitro, and previous results are inconsistent. Assuming that oxygen depletion accounts for the FLASH sparing effect, no sparing should appear for cells irr...

Research efforts in FLASH radiotherapy have increased at an accelerated pace recently. FLASH radiotherapy involves ultra-high dose rates and has shown to reduce toxicity to normal tissue while maintaining tumor response in pre-clinical studies when compared to conventional dose rate radiotherapy. The goal of this review is to summarize the studies...

FLASH radiotherapy has emerged as a treatment technique with great potential to increase the differential effect between normal tissue toxicity and tumor response compared to conventional radiotherapy. To evaluate the feasibility of FLASH radiotherapy in a relevant clinical setting, we have commenced a feasibility and safety study of FLASH radiothe...

An electron beam of very high energy (50–250 MeV) can potentially produce a more favourable radiotherapy dose distribution compared to a state-of-the-art photon based radiotherapy technique. To produce an electron beam of sufficiently high energy to allow for a long penetration depth (several cm), very large accelerating structures are needed when...

When relativistic electrons are used to irradiate tissues, such as during FLASH pre-clinical irradiations, the electron beam energy is one of the critical parameters that determine the dose distribution. Moreover, during such irradiations, linear accelerators (linacs) usually operate with significant beam loading, where a small change in the accele...

Purpose: Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves re...

Purpose Ultra-high dose rate FLASH radiotherapy was shown to minimize side effects of irradiation in various organs while keeping anti-tumor efficacy. This property, called the FLASH effect, causes enthusiasm in radiation oncology community as it opens opportunities for safe dose escalation and improved radiotherapy outcome. Here, we investigated t...

In the novel and promising radiotherapy technique known as FLASH, ultra-high dose-rate electron beams are used. As a step towards clinical trials, dosimetric advances will be required for accurate dose delivery of FLASH. The purpose of this study was to determine whether a built-in transmission chamber of a clinical linear accelerator can be used a...

Overview The National Cancer Institute’s Radiation Research Program in collaboration with the Radiosurgery Society hosted a workshop on Understanding High-Dose, Ultra-High Dose rate and Spatially Fractionated Radiotherapy on August 20-21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically,...

Introduction Radiotherapy treatment planning is a multi-criteria problem. Any optimization of the process produces a set of mathematically optimal solutions. These optimal plans are considered mathematically equal, but they differ in terms of the trade-offs involved. Since the various objectives are conflicting, the choice of the best plan for trea...

Background: Recent demonstrations of normal tissue sparing by high dose, high dose rate FLASH radiotherapy have driven considerable interest in its application to improve clinical outcomes. However, there remains significant uncertainty about the underlying mechanisms of FLASH sparing, and how deliveries can be optimised to maximize benefit from t...

[This corrects the article DOI: 10.3389/fonc.2019.01563.].

Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates...

Ultra-high dose rate (FLASH) radiotherapy is a new way of treating tumours caused by cancer. Higher doses of radiotherapy are associated with trauma to the healthy tissue surrounding the tumour, whereas FLASH radiotherapy demonstrates a sparing effect of the healthy tissues without compromising the anti-tumour action. Dr Kristoffer Petersson at the...

Objectives: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this has been lacking. The aim of the current study was to compare FLASH to CONV ir...

Background Patients with esophageal cancer commonly suffer from dysphagia, leading to nutritional problems and impaired quality of life. Self-expanding metallic stents (SEMS) is frequently used in the palliative setting providing a rapid but short-term relief. In this phase II study we assessed a novel first-line treatment schedule with short-cours...

Background: The majority of patients with incurable esophageal adenocarcinoma suffer from dysphagia. We assessed a novel treatment strategy with initial short-course radiotherapy followed by chemotherapy with the primary aim to achieve long-term relief of dysphagia. Methods: This phase II trial included treatment-naîve patients with dysphagia due t...

Purpose: Preclinical studies using a new treatment modality called FLASH Radiotherapy (FLASH-RT) need a two-phase procedure to ensure minimal uncertainties in the delivered dose. The first phase requires a new investigation of the reference dosimetry lying outside the conventional metrology framework from national metrology institutes but necessar...

Significance Ultra-high dose-rate (≥100 Gy⋅s ⁻¹ ) irradiation, termed FLASH radiotherapy, affords some remarkable (if not unexpected) normal tissue sparing in the irradiated brain when compared with conventional dose rates (0.07–0.1 Gy⋅s ⁻¹ ) used in clinical practice. Radiation-induced neurocognitive deficits, persistent neuroinflammation, and the...

Objectives: The purpose of this study was to modify a clinical linear accelerator, making it capable of electron beam ultra-high dose rate (FLASH) irradiation. Modifications had to be quick, reversible, and without interfering with clinical treatments. Methods: Performed modifications: (1) reduced distance with three setup positions, (2) adjuste...

https://prezi.com/69rn4_1gg03x/optimising-the-clinical-use-of-tomotherapy/

Background and purpose: Adjuvant radiation therapy (RT) of the whole breast (WB) is still the standard treatment for early breast cancer. A variety of radiation techniques is currently available according to different delivery strategies. This study aims to provide a comparison of six treatment planning strategies commonly adopted for breast-conse...

This study is the first proof of concept that the FLASH effect can be triggered by X-rays. Our results show that a 10 Gy whole-brain irradiation delivered at ultra-high dose-rate with synchrotron generated X-rays does not induce memory deficit; it reduces hippocampal cell-division impairment and induces less reactive astrogliosis.

Background: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Methods: Pig skin was used to investigate a potential difference in toxicity between irradiat...

Purpose The Oriatron eRT6 is an experimental high dose‐per‐pulse linear accelerator (linac) which was designed to deliver an electron beam with variable dose‐rates, ranging from a few Gy/min up to hundreds of Gy/s. It was built to study the radiobiological effects of high dose‐per‐pulse/dose‐rate electron beam irradiation, in the context of preclin...

Background and purpose: Treatment plan evaluation is a clinical decision-making problem that involves visual search and analysis in a contextually rich environment, including delineated structures and isodose lines superposed on CT data. It is a two-step process that includes visual analysis and clinical reasoning. In this work, we used eye tracki...

We present a clinical distance measure for Pareto front evaluation studies in radiotherapy, which we show strongly correlates (r = 0.74 and 0.90) with clinical plan quality evaluation. For five prostate cases, sub-optimal treatment plans located at a clinical distance value of >0.32 (0.28–0.35) from fronts of Pareto optimal plans, were assessed to...

This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100 Gy/s, whereas 10 Gy WBI at a conventional radiotherapy dose rate (0.1 Gy/s) totally impairs spatial memory.

Purpose: The purpose of this work was to establish an empirical model of the ion recombination in the Advanced Markus ionization chamber for measurements in high dose rate/dose-per-pulse electron beams. In addition, we compared the observed ion recombination to calculations using the standard Boag two-voltage-analysis method, the more general theo...

Purpose: The aim of this study was to assess the suitability of Gafchromic EBT3 films for reference dose measurements in the beam of a prototype high dose-per-pulse linear accelerator (linac), capable of delivering electron beams with a mean dose-rate (Ḋm ) ranging from 0.07 to 3000 Gy/s and a dose-rate in pulse (Ḋp ) of up to 8·10(6) Gy/s. To do...

Multi-criteria optimization provides decision makers with a range of clinical choices through Pareto plans that can be explored during real time navigation and then converted into deliverable plans. Our study shows that dosimetric differences can arise between the two steps, which could compromise the clinical choices made during navigation.