Photons, protons or electrons: which will bring FLASH radiotherapy to the clinic?

A balloon debate at the FRPT 2022 conference pondered which particle offers most promise for clinical implementation of FLASH radiotherapy

Debating particles
Debating particles Jean Bourhis, Billy Loo and John Perentesis discuss the benefits of electrons, photons and protons for the clinical implementation of FLASH radiotherapy. (Courtesy: FRPT)

With the first clinical trial of FLASH radiotherapy reported earlier this year, using protons to deliver high-dose rate radiation to bone metastases, does proton-based FLASH offer the greatest potential for clinical translation? Or will we see the electron-based FLASH – as used for most preclinical studies to date – and the emergence of very high-energy electrons (VHEEs) lead the way? Or perhaps the development of advanced linear accelerator technologies could bring photon-based FLASH into the clinic?

In a balloon debate at the recent FLASH Radiotherapy and Particle Therapy Conference (FRPT 2022), experts in each field stated their cases for each option. And the audience got to decide “What has the best long-term potential for FLASH for clinical application?”

Pushing photons

The first speaker was Billy Loo from Stanford University, who argued the case for photon-based FLASH. Loo is part of a multidisciplinary research group that’s developing a range of novel linear accelerator technologies including very high-current photon linear accelerators, as well as compact very high-energy electron linacs and proton linacs.

“We are working on all of these technologies, yet which one are we pushing forward into the clinic as our main emphasis area? It’s really the photon technology,” he said.

So why does Loo believe that photons offer the most promising path forward? He explained that in last few decades, radiotherapy has made huge advances in dose conformity, using intensity-modulated radiotherapy and stereotactic techniques. “Dose conformity is key,” he stated. “We don’t want to give up decades of huge gains in therapeutic index and conformity to adopt FLASH; we really need both.”

One way to achieve highly conformal FLASH therapy could lie in a power-efficient linear accelerator technology that Loo and collaborators are currently developing, which can produce much higher beam current (30 times that of current clinical linacs) to enable high-dose rate X-ray therapy. To deliver beams rapidly in multiple directions and achieve the desired conformity, the prototype PHASER system incorporates 16 of these linacs, resulting in around 500 times the beam current of existing systems.

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Loo cited various requirements for performing conformal FLASH, many of which are met by all three particle types. But critically, he added, you need multiple beam angles. “I’ve shown the strategy for that with photons; whether that can be done practically for electrons and protons is much less clear.”

Finally, Loo pointed out that the clinical impact of a treatment technology also relies on its accessibility, size and cost, where photon-based systems could have a clear advantage. He noted that while proton therapy is a mature technology, looking at the number of patients treated per year, this is 3–4 million for photons compared with about 22, 000 for protons, and for VHEE, none.

Promoting protons

Next up, John Perentesis from Cincinnati Children’s Hospital described why protons have the edge when it comes to delivering FLASH.

“In terms of the physics, and how that eventually impacts the biology, protons really do have favourable spatial characteristics,” he explained. “They have deeper tissue penetration and much tighter penumbra than electrons and less propensity for hotspots. And with the advent of Bragg peak FLASH, there’s the opportunity for no exit dose, in contrast to X-rays, and a lower integral dose while maintaining conformality.”

Another key argument is that proton FLASH is already here. Perentesis cited the FAST-01 and FAST-02 trials of proton-based treatment of bone metastases using the FLASH-enabled ProBeam system. FAST-01 has completed and demonstrated the successful and reliable use of the pencil-beam scanning gantry in transmission. “We can treat deep-seated tumours with FLASH today with currently available proton accelerator technology,” he said, noting that Bragg peak FLASH should be achieved in the near future – it’s just an engineering challenge to implement.

Perentesis finished his presentation with the argument of practicality. Conferring with the audience revealed that most believe there will be some sort of FLASH treatment in the next five years, but nobody thinks FLASH will completely replace traditional radiation oncology.

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“Protons are the Swiss army knife of radiation oncology,” he said, quoting physicist Anthony Mascia. “They can switch back and forth between ultrahigh dose rate and standard dose rate, can do deep-seated and superficial tumours, they are highly conformal, and at the end of the day they are here and ready.”

Endorsing electrons

Finally, Jean Bourhis from Lausanne University Hospital (CHUV) proposed that VHEE and electrons are the way forward for the long term. He described two straightforward indications for electron-based FLASH: cutaneous tumours and intra-operative radiotherapy (IORT), noting that for both of these, the technology is ready, there is strong biological evidence and clinical trials are ongoing.

Current electron FLASH trials include a dose escalation study, IMPulse, treating resistant melanoma, and a randomized study comparing FLASH and conventional dose rates in skin cancer. Bourhis pointed out that both of these use a curative radiation dose. In addition, IORT trials and two further randomized trials for skin cancers are planned. “No doubt, if we are successful here, electron FLASH will be part of the long-term standard treatment,” he said.

Another scenario – and one with the greatest unmet clinical need – is to use electron FLASH to treat large and deep-seated tumours. To achieve this requires a treatment field of at least 15×15 cm at 15 cm depth, while maintaining FLASH parameters of 10–20 Gy delivered in less than 100 ms.

This is where VHEE comes in. Even without FLASH, VHEE offers potential advantages including: reduced sensitivity to heterogeneities; ease of beam acceleration and scanning; and potentially superior dosimetric properties to X-ray VMAT. Adding FLASH could make VHEE a very interesting tool, said Bourhis. “With VHEE, we can already implement parameters which are known to produce a FLASH effect.”

Bourhis also highlighted the rapid advances in accelerator technology that could enable more compact and lower-cost devices, citing the VHEE-based FLASH system being developed by CERN, CHUV and THERYQ, which will offer treatment at 100–140 MeV from several directions in less than 100 ms.

“We already have possible long-term adoption of electron FLASH, depending on the outcome of the ongoing clinical trials,” he concluded. “And for VHEE FLASH, we have the potential now to have high-performance, compact, low-cost, competitive technology. It’s likely the greatest potential for the long term.”

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Let the people decide

Following the presentations, the audience were tasked with selecting their favoured particle, with the top two continuing into the second part of the debate. Protons went into an early lead, with photons and electrons continually switching between second and third place. When the voting closed, however, electrons had edged ahead and the final results were 37% for protons, 33% for electrons, and 30% for photons. As such, the photon balloon was popped, and Perentesis and Bourhis embarked upon their final arguments.

“The fact that proton technology is here, it’s tractable and it’s generating similar biological results to electrons – those are strong points,” said Perentesis, noting that there’s also an opportunity for parallel companion trials, for example with protons and electrons, to learn from the similarities and differences between the two.

“We know the advantage of protons are clear, but we know that the uptake of protons after 40 years is only 1–2% of the patients in our country that we treat with radiotherapy. It’s very unlikely protons will change the game for FLASH, not for the long term,” countered Bourhis. “We have this VHEE opportunity that we shouldn’t miss. “We’ve not studied this before in the clinic, but now is the right time to do this because of all the advantages that already exist with VHEE compared with protons.”

Bourhis apparently made a highly persuasive argument, with the final vote swaying the audience towards electrons, which came out as the winner with 53% of the vote. The proton balloon was popped, leaving the electron balloon intact. As for whether the balloons foretell the future, for now it’s likely worth keeping a close eye on the development and implementation of all three FLASH technologies.

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