The movie ‘Flashdance’ was a romantic, dance-based drama famous for its title track, ‘What A Feeling’ but with companies and research groups creating their own ‘song and dance’ right now about the rapid advances in Flash RT, what is your feeling on its likely impact on clinical radiotherapy and when?
We decided to take a closer look and see just what the radiotherapy equipment companies and research institutes are up to today.
Staff shortages may well be a thing of the past?
It seems to me today that much of the news in our sector, but not enough is centred around staff shortages, student attrition rates, issues with training for implementing new technologies and ‘catching up’ with the huge backlog of cancer patients. It has been suggested that this be achieved through ‘super-boosted and ring-fenced funding’ for new precision radiotherapy equipment and the professionals to deliver it, post pandemic. However, despite our protestations the Government is not seemingly ‘dancing to our tune’, well not as quickly as we would like.
In Radiotherapy as we are all aware is that we get paid to deliver treatment over largely long and historical fractionation regimens and so this slows advances in new hypo-fractionated techniques like SABR and their timely implementation. The additional precision added to the ability to allow patients to return to normal life more quickly is therefore negated. This argument unfortunately is still lost on our health ministers and the NHS as Prof Pat Price from Action Radiotherapy has shared recently despite her amazing ability and persistence to put forward our case for urgent action and review time and time again.
Pic: The Flashdance poster for the movie.
Aside from plenty of encouraging feedback on the success to date of implementing MRI Linacs as discussed in a previous blog the ether is now filled with talk about Flash RT and how this might become yet another ‘holy-grail’ in our ever and rapidly changing radiotherapy world. Word is that Flash RT will be the ultimate disruptive technology and offer a paradigm shift in treatment, its delivery, QA and impact on staffing. The downside is that as above, it represents the ultimate in hypo-fractionation and so are we really ready for it now?
And who will deliver Flash RT if its clinical implementation is fast-tracked in the next few years when as we know, while development of new technology can be very fast, the critical peripheral needs such as staff including therapeutic radiographers and training is by default, very slow moving? One issue with the clinical implementation of MR guided adaptive radiotherapy presently is the lack of formal or accredited training courses and a need to presently train on the job, anathema to many in our rapidly evolving field. If a treatment only takes a fraction of a second then our present role as a therapeutic radiographer may well be radically different to what it is today. Will it have to be fully automated or robotically controlled with little if any human interaction for safety or other reasons, how will you create a treatment plan and what will that look like? How will we QA the treatment and dose in real time, what if the patient moves and how do we translate trial based treatments from a laboratory or research setting to a real patient, once again from a safety perspective especially when we still don’t really know what actually causes the ‘Flash effect’ or what the ‘mechanistic’ explanations of the Flash normal-tissue protection effects really are?
Introduction to the UK FLASH RT research base
About two years ago and discussed in a previous blog, Cancer Research UK (CRUK) announced a £56 million research network to transform the UK into a global hub for radiotherapy research by pioneering the use of the latest technologies including artificial intelligence and Flash RT.
The new network called ‘RadNet’ was CRUK’s biggest investment in radiotherapy research set up to assist in the development of advanced radiotherapy techniques and to challenge the boundaries of this treatment.
Exploring Flash RT or now more commonly known as ultra-high dose-rate or UHDR for want of a good acronym that we love in our sector, where high doses of radiation are delivered in short, rapid pulses of less than a second is as we know a very fast growing and competitive field in corporate and research-based settings, with a ‘race to the top’ already started to treat the first human clinical cases. Flash RT is considered by many as having the potential to ‘revolutionize radiotherapy’ and so the plaudits are very much up for grabs!
Ultra-fast or high dose rates now increasing up to 40 Gy/s and more in some research environments allow normal tissue tolerance levels to be exceeded, at least in animal models, with a greater probability of tumour control and little or no normal tissue damage.
Funding was initially allocated to teams at the MRC Oxford Institute for Radiation Oncology who have a dedicated research based Linear Accelerator that I actually worked on when I was a radiographer at Mount Vernon Hospital in London in the 80’s (it is now decommissioned and rebuilt/repurposed) and Manchester in their proton therapy centre. Research so far suggests that Flash RT does have the potential to cause less damage to the healthy tissue surrounding the tumour than traditional radiotherapy, where tissues are exposed to lower doses of radiation over a longer period, often resulting in long-term side effects.
Companies such as Varian, Elekta, Intra-Op Medical, Advanced Oncotherapy, Leo Cancer Care, Mevion Medical, RaySearch, PMB Alcen, Sordina and TibaRay are all now announcing breakthroughs in Flash RT with some work leading to human trials and are forming a very long queue to receive the those aforementioned initial plaudits.
These companies are using proton therapy systems, electrons and conventional X-ray based MV Linacs and so there is a relative cornucopia of ways forward should you wish to explore them and I propose to take a brief look at updates from each one that is in the public domain a little later.
So, how does Flash radiotherapy work, a very brief ‘Flash RT for Dummies’ guide that I think I understand!
When radiation is delivered in a fraction of a second this reduces the incidence and the severity of side effects compared to conventional irradiation used in clinical practice. However, the treatment effect on tumours is not reduced. This is called the ‘Flash’ effect.
The very short treatment times used in Flash RT, often less than 0.1 s, have added the very well- advertised value of minimising treatment delivery uncertainties caused by patient or tumour motion, however, as I mentioned at the start, this may be counter intuitive as if the patient is slightly mis-positioned then the complete treatment is too! Yet no one today really fully understands the precise biology underpinning the Flash eﬀect.
Investigating ways to overcome hypoxia, one of the primary mechanisms that some believe to be behind the Flash effect and why some cancers recur after conventional treatment has been a fundamental research field.
Flash RT seems to be more effective in killing hypoxic tumour cells than standard radiotherapy with the added critical advantage of sparing healthy tissue. The depletion of oxygen during radiotherapy creates a temporary hypoxic environment for both healthy and tumour cells. Hypoxic cells are up to 3 times more resistant to radiation than oxygenated cells and as many cancers are already hypoxic and healthy tissue is well oxygenated, Flash RT could provide a protective effect for healthy tissue without impacting on the response of the tumour but the importance of this scenario in Flash RT research is now thought to be less important than initially envisaged.
However, as one door shuts another one opens in this field and others are studying of the role of cancer stem cells in addition to using radiotherapy in combination with other treatments, including immunotherapy while utilising the power of artificial intelligence or AI. DNA damage responses and also the prevention of cytokine activation are other key areas of interest to researchers.
There are loads of scientific papers out there, so just Google Flash RT, sit back and prepare to be astounded by just how many there are!
What are the companies and research institutions doing and saying right now and how are the initial trials, some human, progressing? These summaries are taken directly from each organisation’s website and so I take no credit for what is mentioned.
However, we need to be careful for what we wish for as in the words of Magdalena Bazalova-Carter, (who if you are interested in Flash RT is well worth following on twitter using @BazalovaCarter) said at the ASTRO 21 Presidential Symposium and in her key address called ‘Transforming radiotherapy with ultrahigh dose rates’ that in her opinion and in order to achieve the full potential of the Flash effect, research teams worldwide should work closely together and not compete with each other. Will these be seen as wise words? Let’s take a closer look.
The IntraOp Medical solution is based on electrons.
IntraOp’s mobile electron beam linear accelerator has been equipped with an ultra-high dose rate mode, as an integral part of ongoing research and developments in Flash radiotherapy. The new technology leverages the company’s core technology and demonstrated 20-year track record in manufacturing compact medical-grade linear accelerators. The prospect of adding Flash capability to their portfolio of image-guided electron IORT and electrons for dermatology applications is a compelling pathway for these modalities to advance into the future.
Pic: The Mobetron electron accelerator from Intra-Op
You can read more on the Intra-Op solution for Flash RT here above and their move towards patient treatments in combination with Lausanne University and a paper on the successful treatment of their first ever case below.
Pic: The FLASH Effect Significantly Improves the Therapeutic Ratio for Curing Cancer, image from from IntraOp Medical.
Varian Medical Systems
Varian have recently funded what is called the ‘FlashForward’ Consortium.
This links institutions around the world and has been set up to create preclinical study designs, advance the technology and share research procedures with a view to the clinical implementation of Flash radiotherapy.
One other area of research that Varian are also acknowledging is the combination of Ultra-high Dose Rate Flash Radiotherapy with Immunotherapy.
Given the recent research interest in combining hypo-fractionated radiotherapy with immunotherapy to try to improve clinical outcomes, there is an intriguing clinical question as to whether Flash irradiation may be a rational partner to combine with immune modulating drugs? To better predict the synergistic effect of both modalities, here we review the biological mechanisms of how Flash differentially impacts the immune landscape, including circulating immune cells, tumour microenvironment and the inflammatory response.
Varian, supported by the Inspire-Project, have also partnered with two members of the FlashForward Consortium to test a new ionization chamber for Flash research based on protons to accurately measuring the dose.
An area that will require further dedicated work as the QA of such high, single doses, given in such a short space of time will not be straightforward.
This project received early financial support from Inspire, which was launched in the EU in the Spring of 2018 to promote collaboration and research among clinical proton therapy centers, academic institutions, and industry partners. Led by the University of Manchester in the UK, Inspire (Infrastructure in Proton International Research) secured EU funding to provide a research infrastructure for proton therapy research.
Best abstract at ESTRO 21-At the ESTRO 2021 meeting the winner was Brita Singers Sørensen from Aarhus University Hospital in Denmark, for her study on pencil-beam scanning proton FLASH.
To investigate the effect of proton FLASH delivered with a scanning pencil beam, Sørensen, physicist Per Poulsen, and their colleagues designed an experiment to irradiate a mouse hind leg with protons at either conventional or FLASH dose rates.
‘The conclusion so far is that with pencil-beam scanning proton FLASH, we do see a normal tissue sparing effect on acute skin damage; we see 40 to 50% sparing’
But normal tissue damage is only half of the story when it comes to FLASH – the other half is investigating the impact on the tumour. With this aim, the team is currently conducting a parallel study looking at tumour control with proton FLASH.
Mevion and Raysearch partnership
RaySearch and Mevion have announced plans to develop the next-generation treatment planning techniques for Flash proton radiotherapy treatment.
The collaboration will explore Flash IMPT delivery using a technique that supports the delivery of large-volume clinical Flash fields through the combination of smaller fields.
RaySearch Laboratories AB and Mevion Medical Systems, two companies that are leading the field of proton therapy, have announced a collaboration to develop advanced treatment planning techniques for Flash delivery with the MEVION S250i Proton Therapy System. The collaboration will explore Flash intensity modulated proton therapy (IMPT) delivery using a technique that supports the delivery of large-volume clinical Flash fields through the combination of smaller fields, each delivered at Flash dose rates which complements Mevion’s advanced HYPERSCAN delivery system.
Mevion Medical Systems
Mevion Proton Systems Demonstrate Flash Effect at Bragg Peak-Initial animal study shows Bragg Peak Flash effect improves the survival curve and dose conformality.
Mevion Medical Systems presented publicly the first pre-clinical results of its research demonstrating the Flash effect using a commercial MEVION S250i proton accelerator at the American Society for Radiation Oncology (ASTRO) Annual Meeting on October 27th 2020. The study results showed a clear signal in the survival curves, where the Flash effect has been delivered at the Bragg Peak. This study is also the first demonstration of the Flash effect at the Bragg Peak.
Mevion proton accelerators are inherently able to deliver ultra-high dose rates and speeds necessary for a successful Flash effect due to its Direct Beam Delivery (DBD) system architecture. In addition to a scanning magnet capable of 3-millisecond spot switching and an energy modulation system switching as fast as 50-milliseconds, Mevion’s DBD features a highly efficient beamline where transmission efficiency does not drop below 70%. This design, exclusive to Mevion, enables a Bragg Peak Flash effect at ultra-high dose rates. These core strengths allow Mevion systems to deliver both conformality and Flash dose sparing, which are critical for clinical Flash proton therapy treatments.
LIGHT is perfectly suited for Flash
The Advanced Oncotherapy LIGHT system is fundamentally different in this regard and is designed to provide the needed clinical Flash tool. Critically, LIGHT maintains full output at any energy (see figure below cf. cyclotrons).
For comparison to legacy cyclotrons, we select a 2x2x2 cm3 volume with energy layer scanning. Our modelling represents a full volumetric proton scanning delivery, including the target depth. The comparison with other proton therapy systems is below. The cyclotron and synchrocyclotron values are as publicly reported by the provider. Comparatively, for the expected clinical application of proton Flash, LIGHT is designed to provide superior performance in comparison to all other systems.
Leo Cancer Care, the ultimate treatment room for FLASH?
Everyone is talking about Flash Radiation Therapy but what will the ultimate treatment room of the future need in order to provide better medicine for cancer patients?
Marco Lavagno from Detector and Niek Schreuder from Leo Cancer Care will discuss this in the webinar titled – ‘The Ultimate Treatment Room for Flash’. Key elements of the discussion will be focused on the utilisation of fixed particle beams and upright patient positioning alongside the need for quality assurance products that are proven to be compatible with Flash dosages ensuring the safety of patients and clinicians.
Find out more here: https://www.leocancercare.com/
Novel PHASER technology
SLAC and Stanford researchers have secured funding for two projects that share one goal: to reduce the side effects of radiation therapy by vastly shrinking the length of a typical session.
A prototype accelerator component for the PHASER project, which will use a novel accelerator design hundreds of times more powerful than accelerators in current devices for X-ray therapy.
This technology is being commercialised by a US company called TibaRay.
Clinical Elekta Precise linear accelerator delivers FLASH radiotherapy
Medical physicists and biomedical engineers in Sweden have now developed a way to modify a conventional linear accelerator for FLASH irradiation –
and to rapidly restore it for clinical use without interfering with cancer patient treatment schedules. Such use of clinical linacs could increase the pace of global research into FLASH-RT
The FLASH Radiotherapy System
Flash radiotherapy consists in the delivery of very high dose rates in a fraction of a second and has reproducibly shown a healthy tissue sparing effect in several preclinical studies, while still effectively destroying cancerous cells. The very short irradiation time also eliminates any effect of organ or tumor motion: targeting is better controlled.
To help adapt this new technique to clinical practice, we are developing FLASHKNiFE: the FLASH radiotherapy system.
The first dedicated research accelerator for FLASH RT
SIT is the patent-holder and provider of an innovative high-performance technological solution for Flash RT.
Today thanks to Electron Flash, SIT confirms its commitment to contribute and invest at full speed in clinical research and radiation therapy.
The system is able to operate in a controlled setup based on an accurate dosimetry calibrated according to clinical standards.
Electron Flash is more than just a device: it is a solid technological platform to be operated similar to clinical standard settings specifically designed for FLASH radiation therapy research.
Find out more: https://www.soiort.com/flash-rt-technology/
Clinical Trials – here are two but who was the first to treat a human being, I’ll let you decide?
IntraOp Medical Corporation has recently announced that Lausanne University Hospital enrolled the first patients in the Impulse Trial
A phase I dose-escalation study of high dose rate radiotherapy with electrons in patients with skin metastases from melanoma.
The Impulse Trial is the first in the world to evaluate the potential of leveraging the biological phenomenon known as the Flash effect to provide radiotherapy with curative intent to radio-resistant cancers.
Read more on the trial here: https://intraop.com/news-events/first-patients-enrolled-in-flash-therapy-impulse-trial/
Treatment of a first human patient with Flash RT
Read more on the first patient treated here: https://www.thegreenjournal.com/article/S0167-8140(19)32959-7/fulltext
Varian and the Cincinnati Children’s/UC Health Proton Therapy Center Complete Enrolment of FAST-01, First Human Clinical Trial of FLASH Therapy for Cancer
Varian, a Siemens Healthineers company, and the Cincinnati Children’s/UC Health Proton Therapy Center today announced the completion of enrolment in FAST-01 (FeAsibility Study of Flash Radiotherapy for the Treatment of Symptomatic Bone Metastases), the first human clinical trial of Flash therapy.
The FAST-01 trial, which is evaluating clinical workflow feasibility of the Flash therapy and treatment-related side effects, met its enrolment target of 10 participants with bone metastases in the extremities. The clinical trial, informed by years of preclinical work, was designed by experts at Varian and multiple centers in the FlashForward Consortium, including Cincinnati’s Children’s/UC Health Proton Therapy Center and the New York Proton Center.
A standard palliative dose fractionation regimen of 8 Gy in a single fraction is delivered with a 250MeV transmission proton beam at FLASH dose rates.
The treatment phase of the trial has just ended in October 2021.
And lastly, for anyone wanting to attend the upcoming meeting called the FRPT (Flash Radiotherapy and Particle Therapy) Conference it will take place in Vienna, from the 1-3 December 2021.
Pic: Vienna in summer.
The meeting looks at 3 key areas of research and development:
Flash Modalities look at how Flash beams are delivered (equipment, radiation type, etc.) as well as what should be their dose rate, dose per pulse, spot scanning, and how they are measured (QA, dosimetry, and radiation protection).
This track also covers spatially fractionated radiotherapy: use of mini and microbeams of photons, electrons, protons, and heavier ions and looks at new horizons in the fields of Flash (eg. Laser ions and Very High Energy Electrons (VHEE)), spatially fractionated radiotherapy and particle therapy, and highlights research conducted in the EU projects INSPIRE and UHD Pulse.
Flash Mechanisms looks at the parameter space in which Flash operates and looks at the physical, chemical, and biological mechanisms that are being explored to understand the Flash effect.
This topic is multidisciplinary and draws in strands that include physical modelling of the Flash effect on the nano, micro, and macro scale. It also combines experimental and theoretical studies of the Flash radiochemistry and then goes on to look at the biology of Flash at the molecular scale, in vitro and in vivo studies. Finally, it opens up research on Flash in combination with drugs and immunotherapeutic agents.
Flash in the Clinic’s sessions look at how Flash RT is rapidly moving towards the clinic and what clinical considerations need to be addressed to achieve this from clinical QA and dosimetry to treatment planning and how treatments are planned.
This track also looks at clinical trial design, which patients might benefit most from Flash RT, the clinical workflow, and the health economic consequences of Flash RT. It also brings in the latest news on current and planned Flash clinical trials.
You can find out more here: https://frpt-conference.org/
Duncan Hynd – A Radiographer’s Life, a 40-year career in Radiotherapy – November 2021 blog