Credit: CERN-PHOTO-202010-130-10

Very high-energy electrons for cancer therapy

15 December 2020

The VHEE 2020 International Workshop saw more than 400 scientists gather virtually to evaluate the production of very high-energy electrons for radiotherapy.

Dosimetry experiment for VHEE studies

Radiotherapy (RT) is a fundamental component of effective cancer treatment and control. More than 10,000 electron linear accelerators are currently used worldwide to treat patients with RT, most operating in the low beam-energy range of 5–15 MeV. Usually the electrons are directed at high-density targets to generate bremsstrahlung, and it is the resulting photon beams that are used for therapy. While low-energy electrons have been used to treat cancer for more than five decades, their very low penetration depth tends to limit their application to superficial tumours. The use of high-energy electrons (up to 50 MeV) was studied in the 1980s, but not clinically implemented.

More recently, the idea of using very high-energy (50–250 MeV) electron beams for RT has gained interest. For higher energy electrons, the penetration becomes deeper and the transverse penumbra sharper, potentially enabling the treatment of deep-seated tumours. While the longitudinal dose deposition is also distributed over a larger area, this can be controlled by focusing the electron beam.

The production of very high-energy electrons (VHEE) for RT was the subject of the VHEE 2020 International Workshop, organised by CERN and held remotely from 5–7 October. More than 400 scientists, ranging from clinicians to biologists, and from accelerator physicists to dosimetry experts, gathered virtually to evaluate the perspectives of this novel technique.

FLASH effect

VHEE beams offer several benefits. First, small-diameter high-energy beams can be scanned and focused easily, enabling finer resolution for intensity-modulated treatments than is possible for photon beams. Second, electron accelerators are more compact and significantly cheaper than current installations required for proton therapy. Third, VHEE beams can operate at very high dose rates, possibly compatible with the generation of the “FLASH effect”.

FLASH-RT is a paradigm-shifting method for delivering ultra-high doses within an extremely short irradiation time (tenths of a second). The technique has recently been shown to preserve normal tissue in various species and organs while still maintaining anti-tumour efficacy equivalent to conventional RT at the same dose level, in part due to decreased production of toxic reactive oxygen species. The FLASH effect has been shown to take place with electron, photon and more recently proton beams. However, electron beams promise to deliver an intrinsically higher dose compared to protons and photons, especially over large areas as would be needed for large tumours. Most of the preclinical data demonstrating the increased therapeutic index of FLASH are based on  a single fraction and hypo-fractionated regimen of RT and 4–6 MeV beams, which do not allow treatments of deep-seated tumours and trigger large lateral penumbra. This problem can be solved by increasing the electron energy to values higher than 50 MeV, where the penetration depth is larger.

Today, after three decades of research into linear colliders, it is possible to build compact high-gradient (~100 MV/m) linacs, making a compact and cost effective VHEE RT accelerator a reality. Furthermore, the use of novel accelerator techniques such as laser-plasma acceleration is also starting to be applied in the VHEE field. These are currently the subject of a wide international study, as was presented at the VHEE workshop.

At the same time pioneering preliminary work on FLASH was being carried out by researchers at Lausanne University Hospital (CHUV) in Switzerland and the Curie Institute in France, high-gradient linac technology advances for VHEE were being made at CERN for the proposed Compact Linear Collider (CLIC). An extensive R&D program on normal-conducting radio-frequency accelerating structures has been carried out to obtain the demanding performances of the CLIC linac: an accelerating gradient of 100 MV/m, low breakdown rate, micron-tolerance alignment and a high RF-to-beam efficiency (around 30%). All this is now being applied in the conceptual designs of new RT facilities, such as one jointly being developed by CHUV and CERN. 

Dose profile

High-energy challenges

Many challenges, both technological and biological, have to be addressed and overcome for the ultimate goal of using VHEE and VHEE-FLASH as an innovative modality for effective cancer treatment with minimal damage to healthy tissues. All of these were extensively covered and discussed in the different sessions of VHEE 2020.

From the accelerator-technology point of view an important point is to assess the possibility of focusing and transversely scanning the beam, thereby overcoming the disadvantages associated in the past with low-energy-electron- and photon-beam irradiation. In particular, in the case of VHEE–FLASH it has to be ensured that the biological effect is maintained. Stability, reliability and repeatability are other mandatory ingredients for accelerators to be operated in a medical environment.

The major challenge for VHEE–FLASH is the delivery of a very high dose-rate, possibly over a large area, providing a uniform dose distribution throughout the target. Also the parameter window in which the FLASH effect takes place has still to be thoroughly defined, as does its effectiveness as a function of the physical parameters of the electron beam. This, together with a clear understanding of the underlying biological processes, will likely prove essential in order to fully optimise the FLASH RT technique. Of particular importance, as was repeatedly pointed out during the workshop, is the development of reliable online dosimetry for very high dose rates, a regime not adapted to the current standard dosimetry techniques for RT. Ionisation chambers, routinely used in medical linacs, suffer from nonlinear effects at very high dose rates. To obtain reliable measurements, R&D is needed to develop novel ion chambers or explore alternative possibilities such as solid-state detectors or the use of calibrated beam diagnostics.

All this demands a large test activity across different laboratories to experimentally characterise VHEE beams and their ability to produce the FLASH effect, and to provide a testbed for the associated technologies. It is also important to compare the properties of the electron beams depending on the way they are produced (radio-frequency or laser-plasma accelerator technologies). 

A number of experimental test facilities are already available to perform these ambitious objectives: the CERN Linear Electron Accelerator for Research (CLEAR), so far rather unique in being able to provide both high-energy (50–250 MeV) and high-charge beams; VELA–CLARA at Daresbury Laboratory; PITZ at DESY and finally ELBE–HZDR using the superconducting radio-frequency technology at Dresden. Further radiobiology studies with laser-plasma accelerated electron beams are currently being performed at the DRACO PetaWatt laser facility at the ELBE Center at HZDR-Dresden and at the Laboratoire d’Optique Appliqué in the Institute Polytechnique de Paris. Future facilities, as exemplified by the previously mentioned CERN–CHUV facility or the PHASER proposal at SLAC, are also on the horizon.

Establishing innovative treatment modalities for cancer is a major 21st century health challenge. By 2040, cancer is predicted to be the leading cause of death, with approximatively 27.5 million newly diagnosed patients and 16.3 million related deaths per year. The October VHEE workshop demonstrated the continuing potential of accelerator physics to drive new RT treatments, and also included a lively session dedicated to industrial partners. The large increase in attendance since the first workshop in 2017 in Daresbury, UK, shows the vitality and increasing interest in this field.

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