π Science and technology
Lasers: promising applications for research and beyond

How to achieve deeper treatment of tumours with laser-plasma acceleration

Isabelle Dumé, Science journalist
On June 29th, 2022 |
5 min reading time
Alessandro Flacco
Alessandro Flacco
Associate professor at ENSTA Paris (IP Paris)
Key takeaways
  • Laser-plasma accelerators propel high-energy particles over short distances using intense, ultra-short pulses of laser light.
  • Ionising radiation is used in medicine for many purposes: from imaging to diagnosis and treatment of cancers.
  • In radiotherapy the toxicity of ionising radiation on living organisms is used, taking advantage of the different capacity to repair the damage caused to tumour cells and those caused to surrounding healthy cells.
  • Studies have also begun on VHEE (“very high energy electrons”), which theoretically allow a more complete and deeper treatment of tumours.

Laser-plas­ma accel­er­a­tors (LPA) pro­pel high-ener­gy par­ti­cles over short dis­tances thanks to intense, ultra­short puls­es of laser light. These accel­er­a­tors can pro­vide high-qual­i­ty par­ti­cle beams (of elec­trons, pro­tons, and X‑ray pho­tons) for radio-bio­log­i­cal stud­ies that will help sci­en­tists bet­ter under­stand how radi­a­tion dam­ages DNA and, ulti­mate­ly, opti­mise can­cer treat­ments that make use of ion­is­ing radiation.

Recent stud­ies have shown that the bio­log­i­cal effect of radi­a­tion depends not only on the total dose deliv­ered, but also the time and the rate over which it is deliv­ered. At the LOA (Lab­o­ra­to­ry of Applied Optics), we are study­ing the effect of ultra-high dose rates in order to devel­op irra­di­a­tion pro­to­cols capa­ble of increas­ing the dif­fer­en­tial response between healthy and can­cer­ous cells.

The lasers we use pro­duce very short puls­es, in the picosec­ond (10-12 s) or fem­tosec­ond (10-15 s) range and are very intense – so much so that when a laser pulse strikes the tar­get mate­r­i­al, it imme­di­ate­ly ionis­es it, trans­form­ing it into a plas­ma, a state of mat­ter in which elec­trons and ions form a kind of “soup” with a col­lec­tive motion. Thus, detached from their nuclei, the elec­trons react to the laser field through the plasma.

In the case of a very dense plas­ma, in which the laser fails to prop­a­gate, the elec­trons escap­ing from the tar­get cause it to explode, thus accel­er­at­ing the ions in it. The result: ions in the mega-elec­tron­volts (MeV) ener­gy range are pro­duced over lengths as short as millimetres.

In the case of a low-den­si­ty plas­ma, the prop­a­ga­tion of the laser pulse pro­duces a wake wave behind it that prop­a­gates at the speed of light. The elec­trons trapped in this wave are accel­er­at­ed – like a surfer on a wave – and thus gain ener­gy. Elec­tric field gra­di­ents as high as those pro­duced by this strat­e­gy (around (100 GeVm-1) are not pos­si­ble with con­ven­tion­al struc­tures (radio fre­quen­cy cav­i­ties), which can reach about just 0.1 GeVm-1.

Ion­is­ing radi­a­tion is used in med­i­cine for many pur­pos­es: from imag­ing to diag­no­sis and can­cer treat­ment. There are a range of pos­si­ble ther­a­pies based on the harm­ful effect of this radi­a­tion on liv­ing organ­isms. Elec­tron beams dam­age can­cer cells in a very sim­i­lar way to high-ener­gy pho­tons, which are the most com­mon radio­ther­a­py modal­i­ty in clin­i­cal prac­tice. This is because high-ener­gy elec­trons con­vert much of their kinet­ic ener­gy into X‑ray pho­tons by “bremsstrahlung”, which trig­gers a cas­cade of elec­trons, positrons, and pho­tons, and also ionis­es the mate­r­i­al by inelas­tic col­li­sions. It is the lat­ter that even­tu­al­ly dam­ages can­cer cells, either by direct­ly ion­is­ing the DNA or by indi­rect­ly cre­at­ing rad­i­cals that dam­age it.

Differences in radioresistance between healthy and cancer cells

In any type of ther­a­py, there is a dif­fer­en­tial between the desired effect and the unin­tend­ed side effects. In radio­ther­a­py, the tox­i­c­i­ty of ion­is­ing radi­a­tion on liv­ing organ­isms is exploit­ed. Basi­cal­ly, healthy cells have a slight­ly high­er radiore­sis­tance than can­cer cells. This dif­fer­ence allows the devel­op­ment of ion­is­ing radi­a­tion dose deliv­ery pro­to­cols in which the harm­ful effect on healthy cells is less impor­tant than the destruc­tive effect on tumour cells.

For laser-accel­er­at­ed par­ti­cles, there are two aspects. The first is relat­ed to the qual­i­ty of the par­ti­cles used. Cur­rent­ly, the most com­mon­ly used par­ti­cles in radio med­i­cine are pho­tons and pro­tons, but each has very dif­fer­ent char­ac­ter­is­tics of dose deliv­ery in bio­log­i­cal tis­sue. Pho­tons deliv­er their ener­gy accord­ing to a decreas­ing expo­nen­tial curve, so that there is a max­i­mum dose at the tis­sue sur­face and a min­i­mum at depth. Irra­di­a­tion pro­to­cols for deep tumours must there­fore be designed in such a way as not to exceed cer­tain dos­es at entry and to achieve a ther­a­peu­tic dose at depth, which is not easy.

Pho­tons are wide­ly used in radio­ther­a­py because they are easy to pro­duce, where­as pro­tons are just begin­ning to be used because they require much larg­er machines. For exam­ple, a pho­ton radio­ther­a­py machine requires a room of about 20 m2 in sur­face area, where­as pro­ton ther­a­py, which requires a cyclotron, must be installed in a build­ing sev­er­al hun­dred square metres in size.

Elec­trons, on the oth­er hand, have been lit­tle used in the past for sev­er­al rea­sons. First, they have a rather flat dose deliv­ery curve. They were also more dif­fi­cult to accel­er­ate than photons.

The flash effect

This sit­u­a­tion changed with the dis­cov­ery of the flash effect, a phe­nom­e­non observed as ear­ly as the 1970s and redis­cov­ered at Orsay in the 2000s. Researchers there found that the same ther­a­peu­tic dose of ion­is­ing radi­a­tion has a dif­fer­ent effect depend­ing on the time scale over which it is delivered.

Researchers found that the same ther­a­peu­tic dose of ion­is­ing radi­a­tion has a dif­fer­ent effect depend­ing on the time scale over which it is delivered.

The whole field of radio­ther­a­py is based on the pos­tu­late that for the same dose, we have an equal response. It’s the same as for a drug, like a dose of parac­eta­mol, for exam­ple: the dose deter­mines the bio­log­i­cal effect. What we found is that if you deliv­er the same dose over an extreme­ly short peri­od of time, the ther­a­peu­tic effect changes. Healthy tis­sue seems to be much more resis­tant to the same dose if it is applied over a very short peri­od of time, while the sen­si­tiv­i­ty of tumour tis­sue remains unchanged. This means that if this ther­a­peu­tic dose is deliv­ered over 50 ms rather than 10 min­utes, noth­ing changes for the tumour cells but the dam­age to healthy tis­sue is con­sid­er­ably reduced.

The flash effect thus allows for a much more effec­tive and effi­cient treatment.

The first exper­i­ments on the effect (between 2016 and 2020) were car­ried out with low ener­gy elec­trons (LEE), which have an ener­gy of less than 5 MeV, sim­ply because these elec­trons were the most read­i­ly avail­able. They can only pen­e­trate to a depth of a few mil­lime­tres into the tis­sue, and there­fore can­not be used to treat deep tumours.

Very high energy electrons and fast fractionation

We have now turned our atten­tion to very high ener­gy elec­trons (VHEE), that is, elec­trons with ener­gies above 150 MeV, which have been lit­tle stud­ied in the past. The beams of these elec­trons pen­e­trate deep into tis­sue and can treat tumours that pho­ton irra­di­a­tion can­not reach. How­ev­er, a linac-based VHEE treat­ment sys­tem, for exam­ple, would have to be com­pact enough to fit in a hos­pi­tal treat­ment room to be com­pet­i­tive with photons.

VHEEs are like­ly to be more expen­sive to pro­duce than pho­tons, but cheap­er than pro­tons. Depth-dose curves show that in addi­tion to deliv­er­ing the dose at depth, VHEEs should also be more resilient to unex­pect­ed tis­sue inho­mo­geneities than X‑rays.

VHEEs can also allow deep tumours to be pre­cise­ly tar­get­ed by con­cen­trat­ing the dose in a small vol­ume. This dose can be con­trolled, which may be an advan­tage for the treat­ment of radi­a­tion-resis­tant tumours. The abil­i­ty to deliv­er the dose in a small spot can also ben­e­fit ultra-pre­ci­sion ther­a­py, where very small areas of tis­sue need to be irra­di­at­ed. In addi­tion, the very low dose at entry and the low dis­tal and prox­i­mal dos­es of VHEE focused beams can help min­imise dam­age to healthy tis­sue and sen­si­tive organs.

Clin­i­cal appli­ca­tions of this type of ther­a­py are still some way off and much work still remains to be done to devel­op the laser and accel­er­a­tor tech­nol­o­gy to make it suit­able for the real world. We have called this irra­di­a­tion modal­i­ty « fast frac­tion­a­tion » and have start­ed to study its bio­log­i­cal effects. Pre­lim­i­nary results show that the rate of laser puls­es has an effect on the tox­i­c­i­ty of ion­is­ing radi­a­tion: it is not only the dura­tion of the flash but also the total dose of a sin­gle pulse that has an effect on tox­i­c­i­ty. We are not able to explain the mech­a­nisms behind the flash effect as yet, but our stud­ies have only just begun. One thing is cer­tain, it holds great promise for the devel­op­ment of high­ly effec­tive radiotherapy.



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