*Tel.: #49-6159-71-2607; fax: #49-6159-71-2106.E-mail address: g.kraft@gsi.de (G. Kraft).

1GSI Darmstadt, FZR Dresden, Radiological Clinic and DKTZHeidelberg.

Nuclear Instruments and Methods in Physics Research A 454 (2000) 1}10

Tumortherapy with ion beams

G. Kraft*

For the Heavy Ion Therapy collaboration1

GSI Biophysik, Planckstrasse 1, 64291 Darmstadt, Germany

Abstract

Beams of heavy-charged particles like protons or carbon ions represent the optimum tool for the treatment ofdeep-seated inoperable tumors: in contrast to the conventionally used photons the dose increases along with thepenetration depth through the body, culminating in a sharp maximum at the end of the particle range. In order to achievea precisely conform irradiation of the selected target volume, this maximum can be shifted in depth by energy variationand distributed laterally through magnetic de#ection of the particle beam. Because carbon ions have a lateral scatteringof only about 1mm at 10 cm depth they o!er the most conform irradiation. In addition to this excellent physicalselectivity the biological e$ciency concerning cell killing increases towards the end of the carbon ions' range. Therefore,the increase in dose is potentiated by an increase in biological e$ciency. Finally, the stopping of the carbon ions can bemonitored by tracing a small amount of b` active 10C and 11C ions which are produced in nuclear reactions with atomsof the penetrated tissue. This b` distribution can be visualized by applying PET-techniques, thus allowing a good controlof the beam distribution. At GSI Darmstadt a heavy-ion therapy unit has been designed and constructed in collaborationwith the Radiological Clinic and the DKFZ Heidelberg and the FZR Dresden. The layout of this facility as well as thetreatment of now more than 30 patients will be reported on. The proposal for the layout of a dedicated medical facility atHeidelberg will be presented ( 2000 Published by Elsevier Science B.V. All rights reserved.

PACS: 87.53.!j; 87.53.Pb; 87.53.Qc; 87.59.!e; 87.59.Vb

Keywords: Tumor therapy; Protons; Heavy ions; Beam scanning; PET

1. Motivation for particle therapy

Since December 1997 patients with radioresis-tant tumors in head and neck are treated at GSIwith high-energy carbon ions. Carbon therapy hasa large advantage of an extreme precision in thedose application and of a high biological e$ciency

in the malignant tissue. This therapy is the result ofa long-standing radiobiological research and a verysophisticated technical development.

As early as at the beginning of the experiments atGSI the radiobiological experiments had been car-ried out by the Biophysics group in parallel to thephysics experiments. Their goal was a better under-standing of the biological action of ion beams aswell as the development of a more precise beamapplication procedure for large volumes. However,the "nal reason that this development reached anexperimental therapy is the clinical demand fora high-precision therapy. Almost half of the 380 000

0168-9002/00/$ - see front matter ( 2000 Published by Elsevier Science B.V. All rights reserved.PII: S 0 1 6 8 - 9 0 0 2 ( 0 0 ) 0 0 8 0 2 - 0 INVITED LECTURE

Fig. 1. Comparison of the depth-dose distribution of photons(conventionally used) and carbon ions. With photons the dosedecreases exponentially with increasing depth, i.e. the dose in thetarget volume of deep-seated tumors is smaller than the dosedelivered to the healthy tissue around. Carbon ions dispose of aninverse dose pro"le, i.e. the dose increases with increasing pen-etration depth. This pro"le can be shifted by energy variationover the target volume, leading to a much higher dose depos-ition inside the tumor than outside in the healthy tissue.

cancer incidents every year in Germany can becured in the long run. These patients predomi-nantly have a single solid tumor in the beginningthat could be removed through surgery or sterilizedthrough high radiation doses. However, also in thisgroup of patients almost 20% cannot be curedpermanently with conventional therapy because thetumor can neither be removed completely nor beradiated with a su$ciently high dose. In principle, itis possible to sterilize any tissue in the body if a su$-cient radiation dose can be applied. In the radi-ological practice the maximum dose is alwayslimited by the tolerance of the healthy tissue around.

Therefore, it has always been the goal through-out the 100 years of radiation therapy to increasethe precision of the irradiation in order the concen-trate the dose in the target volume and to reducethe dose in the healthy tissue or distribute thisinevitable dose over a larger tissue area. Usingvariable collimators like multi-leaf collimators andintensity-modulated Bremsstrahlung from linearelectron accelerators, radiation therapy in the lastyears has reached a signi"cantly better dose distri-bution and in consequence improved clinicalresults. However, a further increase in precision andbiological action is only possible with the use ofparticle beams as was postulated by Wilson [1] in1946. Yet, ion beam therapy got started ratherslowly at Berkeley where the "rst patients weretreated with protons in 1954, with helium in 1957and with heavy ions }mostly neon } in 1975. Fromthere, ion beam treatment spread all over the worldand until today more than 20 000 patients havebeen treated successfully }mostly with protons [2].Four hundred and thirty patients have been treatedwith neon ions at Berkeley and another 400 withcarbon, almost all of them at NIRS; Chiba, Japan.Harvard University played a pioneering role in thedevelopment of proton therapy, treating nearlyone-third of all patients, while Loma Linda later oninstalled the "rst dedicated medical therapy centerwhere today 1000 patients a year can be treated.

2. The physical basis

At high energies, heavy-charged particles likecarbon ions interact very weakly with the pen-

etrated tissue. Thus, in the beginning the energyloss is small and the dose is low. At the end of theparticle range the interactions becomes strongerand the energy loss increases steeply. This en-hanced interaction has two signi"cant conse-quences for particle therapy: First, a better dosepro"le and second the increased relative biologicale$ciency inside the target volume [3].

Compared to photons, particle beams show aninverse dose pro"le: with increasing penetrationdepth the dose increases up to a sharp maximum.Beyond this so-called Bragg maximum the dosedecreases within a few millimeters to a small valuewhich consists of nuclear fragments of the carbonbeam. Through energy variation the dose max-imum can be shifted over the depth of the targetvolume. Today, in most of the particle therapies} predominantly proton therapies } the necessary

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Fig. 2. Principle of the rasterscan technique: the target volume is dissected into slices of equal particle range and each slice is paintedwith a pencil beam in a rasterlike procedure. The velocity of the scanning procedure is controlled by the beam intensity in such a waythat any homogeneous or inhomogeneous particle distribution within a layer becomes feasible.

energy variation is generated using passive absorb-er systems [4]. The lateral distribution is reachedby scattering foils and the spread beam limited withcollimators. This procedure leads to a better dosedistribution than was possible with the conven-tional photon therapy 10 years ago. However, inthe meantime a similar dose distribution can beproduced through proton beams using intensity-modulated applications. For the "rst time ever itwas possible at GSI to produce a range modulationfor heavy ions by a computer-controlled energyvariation of the heavy-ion accelerator SIS and touse fast magnetic lateral de#ection. This systemallows to perform an extremely tumor conformalirradiation.

In order to translate the optimum physical prop-erties in adequate irradiation procedure the raster-scanning system has been developed at GSI in thelast 10 years [5]. During this three-dimensional(3D) procedure, the target volume as delineated bythe physician is divided into di!erent layers ofequal particle range and each layer is irradiatedwith a pencil beam in a raster-like pattern. The bigadvantage of this system is the possibility to adaptthe irradiated volume to the irregular shape of the

target volume. Yet, the central problem of thisprocedure consists in the pre-irradiation of thelayers in front when the deeper layers are treated(Fig. 1). In consequence, except for the most distallayer all the proximal layers have to be irradiatedwith an inhomogeneous dose pattern in order toproduce a homogeneous dose distribution or a ho-mogeneous biological e!ect in the complete targetvolume. To produce the necessary complex particledistribution, a conventional technique } normallyused in TVs } was adjusted for the use of heavyions. In each TV set the picture is divided into lineswith distinct picture points (pixels). For each pixelthe beam's intensity is controlled in order toachieve the correct brightness of the picture. Inanalogy, in the ion beam scanning, each layer of thetarget volume is dissected in di!erent pixels and thebeam will be moved from one pixel to the next afterthe necessary number of particles has been reached(Fig. 2). With this method individual dose distribu-tion can be achieved for each layer.

However, in contrast to the two-dimensional(2D) TV the third dimension can be added inthe ion scanning system with a depth modulationby energy variation form the accelerator. In a

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Fig. 3. Treatment plan for a GSI patient having a large tumor in the base of the skull. The target volume is very close to the brain stemwhich can be spared due to a steep dose fall-o!.

synchrotron this can be done from pulse to pulse,i.e. within 1 s or less. This way it is possible toirradiate irregularly shaped volumes with a veryhigh precision and without excessively damagingthe healthy tissue around the tumor. Therefore, ionscanning therapy is most adequate for tumors withirregular geometries in head and neck becausethere are often critical structures like brain stemand spinal cord in close neighbourhood to thetarget volume, which should as far as possible bespared from radiation damage. A similar method oftarget-conform proton irradiation has been de-veloped at PSI, Switzerland [6].

3. Treatment planning

In a typical treatment of a patient at GSI(Fig. 3) a large target volume in the base of the skullsituated close to the brain stem and the opticalnerve was irradiated. The same was true for manyof the other GSI patients where the target volumewas close to critical and sensitive structures. Inorder to execute these treatments the particle rangehas to be calculated according to the density of thestructures to be penetrated. If the ion beam has topass an extremely dense structure such as bones,the energy has to be increased. But when passing

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Fig. 4. Irradiation layers in the tumor from Fig. 2. Due to density inhomogeneities, such as bones or air-"lled holes, a large varietyof energies has to be used in order to get to the same depth level, leading to very complicated irradiation patterns of individuallayers. Within every layer, the individual target points are displayed and "lled during irradiation with the precalculated numberof particles.

air-"lled gaps as in nose or ear smaller energieshave to be applied in order to place the Bragg peakin the correct position in the target volume.

In Fig. 4 the di!erent energy layers are shownwith their very complex contours. During theirradiation the layer being irradiated is shownin enlargement. The requested positions of thebeam are displayed as circles and are comparedwith the measured value as produced by the controlsystem which is installed directly in front of thepatient.

4. Beam monitoring and PET-control

On the one hand, the rasterscan system is verye!ective producing precise target contours, on theother malfunctions of the system signify an en-larged risk because a high-intensity beam like thevery narrow pencil beam is applied very close tocritical organs and malfunctions could produceserious damage in these structures.

Therefore, one has to make sure that the beam isnot misplaced at any moment during irradiation.

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At the GSI system this control is performed withdetectors, that were predominantly developed forhigh-energy physics. The precision is assured atdi!erent levels. First, the position and the intensityof the beam is measured during irradiation andcompared to the desired values.

For this purpose multiwire and ionization cham-bers are mounted directly in front of the patient. Inthe ionisation chambers the intensity is measuredapproximately once every 12 ls while the positionof the beam center is recorded once every 120 ls inthe multiwire detector. Both values are then com-bined and compared with the requested values. Foreach pixel at least four measurements are sequen-tially performed and only one of these measure-ments is allowed to deviate from the requestedvalues. If more than one measurement di!ers thebeam will be shut o! in the accelerator within lessthan half a millisecond. Only the use of such a de-tector system, that was originally developed forhigh-energy physics, guarantees the necessary se-curity which cannot be assured by manual control.In addition, the measured position and intensityco-ordinates can be visualized directly on the con-trol panel as shown in Fig. 4. This o!ers a veryprecise on-line status control [14].

A second and also novel control system is thePET-control for the localisation of the beam insidethe patient during irradiation. It was developed bythe FZR Dresden [7]. Stable carbon ions of a pri-mary beam are fragmented inside the patient toa small percentage into 10C and 11C isotopes whichboth decay under positron emission and sub-sequent c-emission. The c-rays are simultaneouslyemitted within 1803 to each other. Because a largefraction of these c-rays leaving the patient can bemeasured with the help of two c cameras fromoutside, the stopping region of the primary beamcan be traced back. However, the reconstruction ofthe PET image can only be performed after irradia-tion. Possible deviations can therefore only be cor-rected in the next irradiation fraction by changingthe treatment plan. Yet, PET imaging of volumesunder irradiation is of major use since with noadditional dose the quality of the irradiation can bemonitored with an accuracy of 2.5mm. This is ofimmense importance for dose gradients close tocritical structures.

5. Increased biological e7ciency

Apart from precision in dose application theincreased biological e$ciency in the target volumeis the second main advantage of carbon therapy [8,9]. In all biological systems the DNA represents thetarget for the attack of ionizing radiation. TheDNA contains all the information that is needed foran organism to live, reproduce and function. TheDNA of single chromosomes represents the largestmolecules in a cell and is therefore most sensitive toradiation. In order to guarantee the integrity ofDNA, cells developed a system of redundantinformation and repair throughout evolution.The redundancy mainly consists in the fact thatthe DNA molecule has two strands containingidentical information. An information lossin one strand can be repaired on the basis ofthe information in the other strand. Only whenboth strands are hit at the same time and havebeen damaged to a major extent, repair becomesimpossible.

The increase of energy loss with decreasingvelocity is characteristic for all ions, from protonsto uranium. On a molecular scale, this increasemeans the increase of the local ionization density,which can directly be correlated with the localdensity of the DNA damage (Fig. 5). Veryextensive experiments, that were carriedout at LBNL, NIRS and GSI throughout manyyears, revealed that regarding lighter ions carbon isthe optimum for therapy [9]: For the highenergies in the entrance region the low ionizationdensity mostly produces repairable damage. Butwith an increased energy loss towards the BraggPeak a signi"cant increase in irreparable damageis observed which yields a higher relative biologicale$ciency (RBE). For heavier ions like neonor argon the fraction of irreparable damage in theentrance channel is already signi"cant thusdamaging the healthy tissue in front of the tumor.For very light ions like protons no damagepotentiation can be observed in the targetvolume. Carbon ion beams therefore representan optimum in biological e$ciency in tumor ther-apy } also in the molecular level, measuringDNA damage and repair along a therapeuticbeam [10].

6 G. Kraft / Nuclear Instruments and Methods in Physics Research A 454 (2000) 1}10

Fig. 5. Comparison of the microscopic structure of carbon tracks at di!erent energies with a simpli"ed depiction of a DNA molecule.Ionisation and consequently the damage to the DNA is low at high particle energies but increases signi"cantly at lower particle energiesyielding clustered damage that is di$cult to repair.

6. RBE and treatment planning

The increased RBE represents one of the greatestadvantages of the carbon ion therapy. However,this advantage is also linked to some complicationssince the increase of RBE mainly depends on thedi!erent repair capacity. Tissues that are radiosen-sitive due to their reduced repair capacity do notexhibit an enlarged biological e$ciency when irra-diated with carbon ions. Yet, tissues being veryradioresistant due to a high repair capacity showa drastically increased RBE when irradiated withcarbon ions. This yields a signi"cantly higherchance of cure for the conventionally di$cult totreat tumors.

To include the variance of RBE in therapy plan-ning, it was necessary to develop a quantitativemodel of the biological action of particle beams[11]. The model is based on the long-term experi-ence of radiobiological research at GSI and de-scribes the radiobiological action of particle beamson the basis of physical data of particle tracks, theX-ray sensitivity of cells and the morphology ofcells. Using this model the RBE is calculated in thedi!erent voxels of the target volume and the dose isadjusted to this RBE in order to reach a homogene-ous biological e!ect in the complete target volume

[12]. The experience with patients who were irra-diated at the GSI facility has con"rmed the correct-ness and soundness of this procedure in every aspect.

7. The facility at GSI

GSI operates the only accelerator throughoutEurope which is capable of delivering the energiesand intensities required for therapy. Thus, the con-struction of a therapy unit was started in summer1993 and the operation began in December 1997(Fig. 6) [13]. There are several institutions takingcare of the various parts of the therapy project. TheRadiological Clinic Heidelberg takes the responsi-bility for all medical aspects such as patient selec-tion, diagnosis and dose calculation. The DKFZ(German Cancer Research Center) Heidelberg is re-sponsible for the patients' immobilization throughmasks, the treatment planning and quality controlby appropriate dosimetry. The FZ Rossendorf(Research Center Rossendorf ) near Dresden instal-led the PET camera and developed the analysiswhich is applied during patient irradiation. But theirradiation itself actually takes place at GSI Darm-stadt. Here, the treatment plans are biologicallyoptimized and converted into coordinates for the

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Fig. 6. Groundplan of the GSI therapy facility and the adjacent building for the physicians, the patients and the control room.

accelerator and the rasterscan system and here thebeam is generated.

The patients (Fig. 7) are out-patients fromHeidelberg or come directly from home. A patientmay receive up to 20 fractions on 20 days running,including week ends, and generally receives noother treatment. But for a small number heavy-iontherapy is applied as a boost to a conventionalradiation therapy, i.e. part of the photon doseis substituted by a carbon ion dose. Until Septem-ber 1999, a heavy-ion treatment was given to 48patients, who were su!ering from slowly growingtumors such as chordomas, chondrosarcomas oradenoid-cystic carcinomas in head or neck region.Three of the patients treated had pelvic tumorsvery close to the spinal cord. Medicalwise as wellas technicalwise, these treatments were very suc-cessful.

Although the coordination of the accelerator andthe rasterscan system during irradiation is ratherdemanding, patient treatment was carried outsmoothly with only some minor interruptions. Thereliability of the system proved to be as good as

that of the technically much simpler hospital-basedlinear electron accelerators and thus the system isperfectly "t for use in clinics, too.

All expectations regarding the medical successof the treatment were met or even exceeded byreality. No patient showed more than very slightside e!ects like hair loss and reddening of the skinwas rare. Other side e!ects occured hardly, a factthat con"rmed the very advantageous properties ofthe carbon ions' inverse dose pro"le: the low-dosedeposited in the entrance channel and the high-dose deposited in the target volume.

Also the PET analysis after the treatments re-vealed a very good agreement between the targetvolume and the actually irradiated volume. Inthe follow-up of patient treatment a very satis-fying tumor control in the target volume couldbe observed, sometimes even an unexpected andfast tumor regression. This backs two general ideasof radiation therapy, that a better dose distri-bution leads to better results and that an enhancedbiological e$ciency multiplies the radiationimpact.

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Fig. 8. Model of a medical accelerator consisting of a synchrotron (up left) and three treatment areas, two of which dispose of a mobilebeam delivery device (gantry). With a gantry the beam can be applied from any angle.

Fig. 7. A patient is prepared for a carbon ion treatment. In orderto get an exact positioning of the target volume the head of thepatient is "xed with an individually manufactured mask. Theend of the beam pipe with ionization and multi-wire chambersfor the beam control is visible at the left side. During irradiation,the PET cameras above and below the ionization chambers areplaced over the patient.

8. Future plans for a medical dedicated heavy-ionaccelerator

Although it is too early to speak of curing thepatients, i.e. a "ve-year survival without recurrenttumors, the clinical success of the GSI facility is soconvincing, that it has prompted plans for a centerthat will be dedicated to medical purposes alone[14] and will serve 1000 patients a year (Fig. 8). It isestimated that the costs for a patient's treatmentwill correspond more or less to those of surgery andwill be much less than those caused by a failedtreatment. These advantages have also beenrecognized elsewhere, resulting in the constructionof similar facilities in France, Italy and Austria.Japan, already disposing of a large medical heavy-ion unit, is building another one. The US favorsproton centers, due to the lack of know-howin extremely tumor-conform dose applicationwhich is indispensable for heavy-ion therapy.Construction and operation of the GSI facilitydemonstrate the immense advantage of a tumor-conform treatment with heavy-ions beams, a

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treatment that only became possible through thetransfer of many a technique originally developedfor high-energy physics.

Acknowledgements

I would like to thank all the members of the GSIbiophysics, the detector laboratory, the acceleratordivision, the FZR detector laboratory, the DKFZdosimetry and radiation therapy as well as theRadiotherapy of the University hospital atHeidelberg. Especially, I would like to thank Dr.J. Debus, the medical project leader, Dr. T. Haber-er, the project manager, Dr. O. JaK kel for supplyingthe treatment plans shown in Fig. 3, Dr. H. Esselfor the development of the therapy on-line monitorshown in Fig. 4, Dr. M. KraK mer for the trackstructure calculation and Dr. U. Weber for provid-ing Fig. 5.

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