Thursday, November 12, 2009

HIT, the Heidelberg Ion-Beam Therapy Center

Last Monday morning, more cars than usually were crowding the road through the Heidelberg "Neuenheimer Feld" Campus. A parking lot had been reserved for guests, and signs all over the Campus showed the way to a "Press Conference". Later I learned that all this gathering was for the opening ceremony of the Heidelberg Ion-Beam Therapy Center (HIT).

With a background in heavy-ion physics from Frankfurt University, it would have been hard for me not to have heard of this project before: Kind of a large spin-off of the GSI facility near Darmstadt, the Heidelberg Ion-Beam Therapy Center is a dedicated heavy-ion accelerator for deployment in radiotherapy to treat tumours. It is the first medical heavy-ion machine in Europe.

The HIT building in Heidelberg. Source: Photo Gallery of the HIT.
The building, half-buried in the ground to minimise radiation exposure for the environment, houses an ion source, a linear accelerator (LINAC) and a synchrotron with a circumference of 65 metres, which can accelerate protons (hydrogen nuclei), alpha particles (helium nuclei), or nuclei of carbon and oxygen to final energies of 50 to 430 MeV/nucleon. For carbon nuclei with 12 nucleons, this means a maximal energy of 5.16 GeV. This energy corresponds to a bit less than half the rest mass of the carbon nucleus, meaning a gamma factor of 1.45, or motion of the nucleus at 73 percent of the speed of light.

HIT accelerator layout. Source: T. Winkelmann et al., Proceedings of ECRIS08 (PDF).
The HIT facility. Source: Photo Gallery of the HIT.
The heavy-ion beam, which is focussed to a diameter of about a millimetre, is steered by the high energy beam transport (HEBT) system to one of two treatment places, or into a big, pivotable installation of bending magnets, the so-called gantry. The gantry allows the beam to be directed from any direction of a vertical plane into one point.

The HIT gantry. Source: Photo Gallery of the HIT.
At the treatment places, the beam, which is focussed to a diameter of about a millimetre, enters the body of patients, and deposits its energy in tumour cells, thereby corrupting the DNA of the tumour cells and stopping their runaway replication.

Treatment place at the focus of the HIT Gantry. Source: Photo Gallery of the HIT.
What is so special about heavy ions for the treatment of cancer that justifies the construction of a large, highly specialised 120 million Euro facility?

It's an effect discovered in 1904 by the Australian physicists William H. Bragg and Richard D. Kleeman, who studied energy energy deposition of alpha particles from radioactive decays when penetrating matter. To their surprise, and different from gamma rays or X rays, alpha particles deposit their energy predominantly around the end point of their track.

The Bragg peak for carbon ions. From Fokas et al.: "Ion beam radiobiology and cancer: Time to update ourselves", Biochimica et Biophysica Acta 1796 (2009) 216–229.)
On a plot showing energy deposition along the path, this pattern shows up as a curve strongly peaked at the end point, in the so-called Bragg peak. (The Bragg peak should not be confused with the Bragg reflections in X ray scattering, which were discovered by William H. Bragg and his son, William Lawrence, in 1913, winning them the 1915 Nobel Prize in physics.)

This strongly localised energy deposition, along with the sharp focus of the beam, makes heavy ions such as carbon an ideal tool to attack tumour cells while doing as less harm as possible to the surrounding tissue. The penetration depth can be controlled by the ion beam energy. Thus, the ion beam hits its target precisely and transfers an exact dosage of energy to the tumour.

HIT will be used to treat tumours which are deeply situated in the body and can hardly be reached by conventional radiation treatment. Tests at GSI so far have been very promising, and there are good chances that a large part of the about 1300 patients per year who will be treated at HIT eventually can be cured.




  • Web page of the Heidelberg Ion-Beam Therapy Center (HIT)
  • Photo Gallery of the HIT
  • HIT Brochure as PDF file
  • For technical details about the accelerator facility, check out T. Winkelmann et al, "Experience at the Ion Therapy Center (HIT) with two years of continuous ECR ion source operation", Proceedings of ECRIS08, Chicago, IL USA (PDF file).
  • About the costs of HIT, check out e.g O. Jäkel et al.: "On the cost-effectiveness of Carbon ion radiation therapy for skull base chordoma.", Radiotherapy and Oncology 83(2) (2007) 133-8.


27 comments:

Bee said...

What happens to the ions after they have dumped their energy into the cell?

Anonymous said...

I'm a bit confused by "The building, half-buried in the ground to minimise radiation exposure for the environment".

If the heavy ions deposit most of their energy in the tumour, doesn't that mean that very little secondary radiation is produced? I'm thinking of radiation like gamma rays and neutrons, which would require very thick shielding.

Indeed, if enough secondary radiation were produced to warrant bunker-style shielding, wouldn't it cause undo harm to the patient!

I'm guessing the design is simply nice to look at - or perhaps to soothe the German people's well-known mistrust of all things nuclear?

If we want to someday do ion therapy in hospitals (perhaps using lasers to accelerate the ions) it's probably best to lose the bunker mentality!

Hamish

Phil Warnell said...

Hi Bee,

“What happens to the ions after they have dumped their energy into the cell?”

Just before impact they hang a sign reading “gone fission” and then promptly thereafter deionize:-) Seriously though if for instance if it were a carbon ion wouldn’t it just become another one of the many unremarkable carbon atoms that make up any living creature, after of course first finding a few electrons to hang out with,

Besr,

Phil

Bee said...

Carbon is not exactly a "heavy" ion, is it?

Phil Warnell said...

Hi Bee,

No they certainly wouldn’t be considered heavy in the conventional sense, only as far as their relative momentum is concerned. Just as long as sum overzealous environmental group has it to be considered detrimental as increasing our personal carbon footprints:-)

Best,

Phil

Phil Warnell said...

Hi Stefan,

A great piece explaining a remarkable device with the potential to cure people who before were left without hope. We truly live in most fascinating times, where machines first constructed to reveal the secrets of nature now are used to extend human life. It will be interesting to discover how many will be apprehensive of taking advantage of such therapy when they realize its directly connected with machines like the LHC. I can just imagine all the misinformation that could be propagated regarding this.
Best,

Phil

Georg said...

Hello bee,
when loosing the last few Elektronvolts
the carbon atom will start to
abstact hydrogen from the
organic molecules or water.
Thus some carbene or a Methyl
radical is some likely intermediate
which then ends up as some addition
procuct or as methane.
But compared to the millions (or gazillions)
of bonds broken by energy tranfer/ionisation
before that happens,
the carbon atom is of really no
importance.
On irridation by electron beams
the pedominant intermediate produced
is OH radical, if sufficient water is present.
This OH radicals then attack the organic substrates.
I think (by general analogy) that
this is true for ion beams as well.
Regards
Georg

Kay zum Felde said...

Hi Stefan,

I think this machine is really a step ahead to fight cancer in a good way. A couple of years ago, I got into a conversation with a physicist from Darmstadt working on this therapy form. The physicist talked the way, that the therapy form was already finished. That time back I didn't thought that it took so long to establish a machine.

Best Kay

Steven Colyer said...

How is this different from conventional radiation again? I note that the beam is a millimeter wide, but does it pass right through the body or focus on a 1-millimenter sphere?

The answer to my question is important. Our 20-yr-old son, now a Junior in Biomedical Engineering at university, has cancer of the lymph nodes, Hodgkin's disease, at age 10. He followed a strict Chemo regimen for 5 months, followed by a 5-days-per week 5-min/day treatment of radiation for one month. They put lead over all the body parts except the ones they wanted to hit. Things worked out well - he was in complete remission after 6 months as has been fine ever since, but whoa what a scare for the Mrs. and I and our families.

Low Math, Meekly Interacting said...

I have a related question that I guess must be related to the actual physical mechanism behind the Peak. The ion behaves a bit less like a cannon ball, then, and more like a shell that explodes only when it has slowed down to a particular velocity (related to the maximum cross section). Why is this peak so tight? The ions are themselves acting like ionizing radiation, shedding some of their energy until they reach the critical velocity by presumably dislodging electrons on their way, but then what actually happens? Are the ions captured by another nucleus? Do they pick up enough electrons to suddenly experience a lot of electrostatic repulsion from the electron clouds of surrounding atoms? Once the ion slows down to the critical velocity, is it some kind of pressure due to Pauli exlusion (there's lots of carbon in tissue, so maybe the carbon nucleus suddenly feels this degeneracy pressure)?

Thanks!

stefan said...

Dear all,

sorry for the delay - I hope I can still give a few partial answers to your questions...


What happens to the ions after they have dumped their energy into the cell?

Thanks, Georg, for the detailed description of the late-stage chemistry going on... I'd like to add that the total mass of carbon used in the beam for radiotherapy is really tiny:

From the the proceedings paper by Winkelmann et al., I learned that the carbon flux at the patient is 500 million ions per second. Treatment sessions are quite short, between 60 and 300 seconds per day, and usually are repeated over a cycle of 15 days (see page 7 of the HIT brochure). But this means that per session not more than 150 billion carbon ions, or 3×10^-12 gram carbon, are deposited in the body!


Dear Bee,

Carbon is not exactly a "heavy" ion, is it?

Well, ... of course, "heavy-ion" makes us think of the lead, gold, or uranium ions used at GSI, CERN, or RHIC... But even given the tiny amount of matter involved, maybe people don't want to get uranium injected at three quarter the speed of light ;-)

More seriously, I guess that using carbon is a good compromise between having a sharp enough Bragg peak and an easy to handle ion beam luminosity.


Hi Hamish,

I'm a bit confused by "The building, half-buried in the ground to minimise radiation exposure for the environment".

Well, the patient is exposed to the ion beam only for a few minutes a day, and wouldn't want to do that if healthy.

But running an ion synchrotron for particles at 0.5 GeV/nucleon always produces some amount of harmful side products in hard X ray and neutrons, I guess, and you don't want to expose the people working there to that. Moreover, the facility is in the middle of the medical campus, just next to the children's hospital, so taking some precautions probably isn't wrong.

I'm afraid as long as there is no other technology available to produce and handle the ion beam (the energy of the beam is modulated in energy during one session to shift the depth of the Bragg peak), these measures for shielding the actual accelerator machine will be necessary.


Hi Kay,

The physicist talked the way, that the therapy form was already finished.

The method has been applied at GSI in Darmstadt, where they of course have an ion beam ready at hand, since 1997. It probably has taken some time to get the funding for the construction of the dedicated Heidelberg facility.

stefan said...

Hi Steven,


sorry to hear about you son, and I am glad that he could be cured completely! This must have been a hard time for you! But please note that I am just a physicist, and that I cannot and do not want to give any medical statements.

As for the physics, what is the main point about ion beams in cancer therapy is what you can see on the last figure in the post, the Bragg peak:

Protons, or, even better, carbon ions, can penetrate a quite deep into the body (for which "water" is a good model, as it mainly consists of water) - 15 centimetre in the figure - without loosing too much energy, and then deposit a large part of their energy within a range of less than a centimetre. As the beam is very well focused, to about a millimetre, this is a tool to deposit energy deep inside the body, with not too much harm to the tissue above or around the actual target. In fact, when applied, the beam is modulated in direction and energy (which means location of the Bragg peak), so that the peak can be made kind of scanning the tumour.

As a result, this method is especially suited to treat tumours which are located deep inside the body and can no be reached by other therapies.

X rays or gamma rays, in contrast (the blue curve in the figure), deposit more energy closer to the surface and are less localised in energy deposition.

You probably know more about Hodgkins disease than I do to have an idea which kind of radiation may be better suited.

Anyway, here is a quote from HIT's medical director (from the HIT brochure check out page 6; there is more about the medical indications for ion beams):

About 5 to ten percent of all cancer patients will benefit from ion radiation. These patients suffer from tumors which are deeply situated in the body and are therefore hardly attainable for conventional radiation treatment.

The brochure also says

So far, the effectiveness of heavy ion radiotherapy is solely documented for a small number of tumors. These are malignant soft tissue tumors on the spine (Chordoma) and cartilage at the base of the scull (Chondrosarcoma). Furthermore, rare tumors of the salivary glands (Adenocarcinoma) can be successfully treated with heavy ion radiation.

and, relevant to your son

Ion beam treatment is especially beneficial for children suffering from malignant tumors, because it avoids long-term side effects. It is possible to treat gently and with greatest care and at the same time prevent further cancer growth and occurrence of new tumors.

But I do not know what is the state of art in this respect.

BTW, unrelated to your comment, but maybe also of interest (still from the same brochure):

The German Health insurance companies have already agreed to bear the expenses if the treatment in HIT. The costs for one treatment cycle of approximately 19,500 Euro are three times as high as for conventional radiation, but are in the same dimension as extensive medication or operation of patients.

stefan said...

Hi Low Math,


the essential physical concept behind is the "energy loss per path length" or stopping power. For charged particles with energies above a few hundered keV, this is very well described by the famous Bethe Formula (or Bethe-Bloch formula), which says that energy loss is

dE/dx = −const. × Z²/β² × ...

where β = v/c is the velocity. This means that the energy loss per path length increases inversely to the square of velocity - the slower the particle, the higher the loss - and that the effect is the more pronounced the higher the charge of the particle.

Hence, charged particles loose a large part of their energy at the end of their track, resulting in the peak, and the effect is stronger for completely stripped carbon nuclei than for protons.

Here is a plot for the stopping power of protons in an aluminium target, which shows that the Bethe formula works fine for proton energies above 200 keV.

Interestingly, there is a peak in stopping power below that energy (note, logarithmic scale), but my guess is that in the regime where stopping power drops again at lower energies, the largest share of the initial ion energy has already been deposited.

What is happening is that the ions kick around the nuclei of the atoms they encounter, due to Coulomb repulsion, and that this kicking is the more effective the "slower" the ion. To my knowledge, there is no critical velocity where another effect sets in.

Please note that the electron cloud, or the Pauli principle, do not play a role in this - the energy scale is way to different:

The carbon ion enters the body with a total energy of the order 1 GeV, while atomic effects should set in once the energy is down to a few keV. But then the ion has already got rid of 99.999% of its initial energy. So, the whole Bragg peak of the dE/dx curve still lays safe in the "trans-atomic" energy region, meaning that atomic physics effects do not play a role.


Best, Stefan

stefan said...

Hi Phil,

apropos carbon footprint:

According to this report, HIT consumes as much electricity as a town of 10,000 people, or 3 MW... kind of a footprint..

Cheers, Stefan

Low Math, Meekly Interacting said...

Hi, Stefan,

Believe it or not, I actually understood most of that. Thanks so much for taking the time to explain!

LMMI

Bee said...

Well, yeah, sure. I was just wondering. There's heavier atoms that I think would be pretty harmless because they appear frequently in cells. Calcium maybe?

Phil Warnell said...

Hi Stephan,

Thanks once again for your great post which I find tremendously uplifting. Three million watts, that certainly would power a lot of curly bulbs:-) However when it comes to saving lives this is where the edges blur and such considerations seem out of place. Personally, I’m confident that in the not too distant future cancer, along with other disease will become more identifiable, treatable and ultimately pre-empted from the DNA perspective, where the genetic and viral triggers are identified and dealt with more directly.

In the mean time this high tech scalpel will save many who had no hope in the past. One thing for certain it’s nice to see the first practical use (outside of course nuclear research) of a particle beam machine is to save lives, rather than end them, as in being weaponized. I wonder if Ernest Lawrence ever imagined his invention would be used for such a noble purpose.

Best,

Phil

stefan said...

Dear Bee,


There's heavier atoms that I think would be pretty harmless because they appear frequently in cells. Calcium maybe?

Good point... I don't know why not calcium, nobody would object to that.

Maybe it's as simple reason of practicability. The elements they use, hydrogen, helium, oxygen, carbon, all are easily available as gas to produce the ions in the first place, not so calcium.

Perhaps a calcium ion source requires constant pampering by a grad student? Any experts on this around?

Cheers, Stefan

Phil Warnell said...

Hi Stefan,

Yet we are carbon based life forms, while only silicone and not calcium being the only considered alternative. Personally I like that we have a natural carbon foot print and fingerprints :-)

Best,

Phil

Georg said...

Hello Stefan, Bee,
I could imagine two reasons for the
ions selected:
the element should be available
isotopically pure or nearby pure,
and the nuclei should be as stable as possible, to avoid nuclear reactions. Helium and Oxygen have "magic" nucleon numbers, carbon has not.
Regards
Georg

LMMI said...

Sulfur would be readily available in gaseous form, is found in relative abundance in cells, and is about double the mass of oxygen. Maybe lighter elements are simply good enough?

Georg said...

Maybe lighter elements are simply good enough?

That is a good reason, making the peak shorter than its diameter
does not improve something.
Another thing is 4.18 % of
S(33).
The availability in gaseous form
is not so important, vaporizing a
earth alkali metal like calcium
is quite easy. A ion gun for calcium is simpler in construction and
control than one who has to handle say, methane or hydrogen sulfide.
For such metals You can control vapor pressure
in the range needed to operate a
ion source directly by variation of temperature.
Regards
Georg

Anonymous said...

The choice of particle depends largely on the biological effects. The primary way that is measured is using what is called Relative Biological Effectiveness (RBE). RBE is the ratio of dose from one type of radiation to the dose from a standard source (usually 250 kV x-rays) needed to damage cells to a certain extent. The RBE varies by ions species, but also by location in the Bragg curve. Because the Bragg Peak is placed in the tumor and the low "plateau" region is placed in healthy tissue, the peak/plateau RBE ratio is very important. It turns out that carbon has the highest known peak to plateau ratio. There are a few other factors that might make heavier ions attractive for a given scenario. Of course, further research is always needed.

Phil Warnell said...

Hi Anonymous,

So if I understand what you are saying, the choice of carbon assures a high level of destruction for the cancerous cells, while the radiation produced will be the least harmful to the surrounding healthy tissue. If one considers that carbon forms to be the bases for all known life , yet at times can be to be the hardest substance and more recently been found can be made to be the strongest, it truly holds special significance amongst all of the elements. I therefore find it more than a little ironic that a substance held at times as being one synonymous with future disaster and ruin is also one that has such intrinsic beauty which may indeed be the key to our successful future .

Best,

Phil

Low Math, Meekly Interacting said...

Thanks again, all, for the interesting discussion. I don't know terribly much about highly directed forms of radiotherapy beyond cursory knowledge of the gamma knife, or the use of implants. I guess this is a bit more like a directed energy weapon, but really the goals are quite similar: Use energetic particles (of light or matter) to damage the components of cancerous cells (primarily the DNA, so as to induce apoptosis or necrosis) while minimizing damage to healthy cells. I find the physical principle behind this approach, and the associated chemistry, to be quite fascinating, so it's a fun read.

Steven Colyer said...
This comment has been removed by the author.
RadioBiology said...

Two principle reasons why ions heavier than carbon are not used: 1) cost of infrastructure (bending magnets to steer ion beam)
2) secondary reactions

accelerated Carbon ions are attenuated via Van Der Waals interactions until slowed enough to be momentum-matched with nearby electrons either in DNA or water. The Carbon ions steal electrons from tumor DNA to directly break chemical bonds holding DNA strands together; or if the electrons are stolen from water molecules then free radicals are created very near tumor DNA such that the free radicals break up DNA strands.

Dr J, PhD and medical-physicist