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HEAVY ION RADIOTHERAPY
Y. Jongen
To cite this version:
Y. Jongen. HEAVY ION RADIOTHERAPY. Journal de Physique Colloques, 1989, 50 (C1), pp.C1-
629-C1-641. �10.1051/jphyscol:1989170�. �jpa-00229370�
JOURNAL DE PHYSIQUE
Colloque C1, supplement au n o l , Tome 50, janvier 1989
HEAVY ION RADIOTHERAPY
Y. JONGEN
Centre de Recherches du Cyclotron, Chemin du Cyclotron 2 , B-1348 Louvain-la-Neuve, Belgique
ABSTRACT I RESUME
Aprbs un bref rappel des origines historiques de la radiothbrapie, I'article examine les specifications essentielles des radiations utilisbes B cet effet. Cune des caractbristiques est la distribution de la dose dans le corps du patient. Cautre est "I'effet oxygene", lib au transfert d'bnergie linbaire. Les ions lourds de haute bnergie semblent offrir une combinaison idbale de caractbristiques pour ces deux espectsCependant, la faible pbnbtration des ions lourds dans la matiere requiert des accblbrateurs de haute bnergie, donc de taille et de coDt blevb. Aprbs avoir examine les caractbristiques requises pour de tels accblbrateurs, I'article passe bribvement en revue les principaux projets.
After a short historical note on the origins of radiotherapy, this paper reviews the main specifications of radiations used for therapy. One main characteristic is the dose distribution in the patient's body, the other is the so-called "oxygen enhancement ratio" (O.E.R.) which is related to the linear energy transfer (L.E.T.). High energy heavy ions beams seem to present an ideal combination of those parameters. However the relatively short range of heavy ions requires the use of high energies and, therefore, of large and costly accelerators.
After examining the basic requirements of heavy ion therapy accelerators, the main existing projects for such accelerators are briefly reviewed.
I . Historical background
Soon after the discovery of the X-ray, at the turn of this century, it was discovered that X-rays could kill living cells and, therefore, be used for the therapy of cancer. Somewhat later it was recognised that radium emitted energetic gamma rays that had better penetration than the early therapeutic X-rays. In 1936, just after the completion of the 37-inch cyclotron by Ernest.0. Lawrence, and the first fast neutron beams developments, Ernest's brother, John Lawrence, together with Zirkle, Aebersold, Lampe and others started studies on the comparative effects of neutrons and X-rays on various biological systems. In 1939, the new 60- inch cyclotron was accelerating 16 MeV deuterons and was used to start a careful program of radiobiological studies in the field of neutrontherapy and, in december 1939, clinical trials started on patients.
From 1939 to 1943, 226 patients were treated but, due to the lack of fundamental radiobiological knowledge at the time, those initial treatments resulted in a large proportion of problems and the program was discontinued.
In the late forties, electron accelerators, mostly betatrons were built to reach better penetrations with X-rays.
However, during the same period, the availability of 6 0 ~ o sources coming from nuclear reactors made obsolete the use of expensive radium units and the 6 0 ~ o became the standard source for photon therapy in the world.
It was however recognized that higher energy sources were desirable and in the fifties, numerous high energy betatrons and linacs were built.
At the same time, the development of higher energy proton and heavy ion accelerators for nuclear physics research opened the way for positive ion therapies and, later, for pion therapy.
Article published online by EDP Sciences and available at http://dx.doi.org/10.1051/jphyscol:1989170
C1-630 JOURNAL
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PHYSIQUE11. General requirements of radiations for radiotherapy.
2.1
.
Basic considerations.In radiotherapy, ionizing radiations are used to destroy undesirable tissues (generally, but not always, cancer tumors) within the body of the patient. Ideally, the radiation effect should be restricted to the zone to be destroyed, and should leave the surrounding normal tissues unaffected.
This goal is however impossible to reach : all radiations travel essentially in straight line through the body and destroy cells in the entrance region, from the surface of the body to the tumor. Most kinds of radiations, like photons, electrons or neutrons have also an effect downstream from the tumor to the exit of the body. Those unwanted effects to normal tissues can be minimized by delivering the radiation to the patient, in different directions, crossing at the location of the tumor.
It is worth noting that our inability to locate the radiobiological effect within the tumor is not only due to the physical characteristics of the beams used but also, often, to an imperfect knowledge of the tumor position and limits.
In addition, the unwanted tissues are often more radioresistants than the normal tissues, which makes the situation even worse. As a result, there is a conflict between the radiation dose needed to achieve a satisfactory tumor control and the dose needed to avoid complications.
2.2 Dose distribution
The dose distribution for X-rays is illustrated by figure 1.
Thickness
of
water layer,crn
Fig. 1.. Depth dose as function of thickness of water layer for 200-kV x-rays, 6 0 ~ 0 g-rays, and betatron x- rays with energies of 5, 10, 20, 30 and 35 MeV.(reprinted from {I)).
If electrons are used instead of photons,,we have a reduced dose at large depths. Therefore, for typically available electron energies from linacs, the usefulness of electrons is limited to tumors located close to the surface of the body.
RADIATION STERILIZATION A
Fig. 2- Ranges of high-energy electrons in water () and range of hard 3-MeV x-rays (----).(reprinted from {2)).
Neutrons have dose distribution shapes basically similar to photons, but with generally larger penumbras due to the difficulty to collimate efficiently neutrons..Neutrons produced by D.T. generators have dose distributions comparable to 6 0 ~ o g-rays,while fast neutrons produced by a 66 MeV proton beam on a thin beryllium target can be compared to X-rays produced by an 8 MeV linac.
For protons or light ions, the dose distribution shows the well known "Bragg-peak", characteristic of the stopping of heavy charged particles.
JOURNAL
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PHYSIQUE0 5 10 15 20 2 5
Tissue depth, un
Fig. 3- Depth dose in water for 190-MeV deuterons and 187-MeV protons (after Larsson).(reprinted from { I ] ) .
This w a k is actually too sharp to be used on real tumors, and one needs to sweep the energy to broaden the peak.
DEPTH IN WATER (cm)
Fig. 4- Modified depth-dose distribution of a proton beam (redrawn from Koehler and Preston, 1972) (reprinted from {3}).
For heavier ions like Helium, Carbon, Neon or Argon, the peak-to-plateau ratio decreases considerably with range. The residual dose, beyond the range of the primary beam increases with the increasing charge of the heavy ion.
PENETRATION DISTANCE (cm)
Fig. 5- Depth-dose distributions for helium (150,225). carbon(250,400), neon (400,594), and argon ions (500,900) in MeVIu (redrawn from Leyman and Howard, 1977){3}
One can therefore concludes that the dose distribution of heavy ions is somewhat less desirable than the dose distribution of lighter ions like protons.
2.3 The oxygen effect
-
low and high L.E.T. radiationsn the fifties, different groups and mainly Gray and his associates in Great Britain demonstrated that the biological effects of a radiation were caused by the combination of both direct and indirect interactions : the direct effect is the destruction or modification of chemical bonds in critical molecules, while the indirect effect is mostly due to the creation of oxidizing free radicals in the tissue water. Thus the presence of free oxygen in the cell enhances greatly the indirect effect.
Dose (krad)
Fig. 6- Sunrival of human liver cells after 200-kVP x-rays following equilibration
( - 0 - ) , nitrogen (-A-), and 0.275% oxygen (-A-) in nitrogen (reprinted from {3)).
with oxygen (-0-1, air
C1-634 JOURNAL DE PHYSIQUE
This effect is called the Oxygen Enhancement Ratio (O.E.R.) and is a very serious limiting factor in cancer radiotherapy. Indeed, as tumor tissues are often poorly vascularized and tumor cells therefore less oxygenated, those tumor cells tend to become more radioresistant than the surrounding normal tissues.
It was soon recognized that the O.E.R. was related to energy distribution of the radiation on a microscopic scale.
A significant parameter of this energy distribution at microscopic scale is the Linear Energy Transfer (L.E.T.).
Numerous experiences have shown that both the O.E.R. and the Relative Biological Efficiency (R.B.E.) of a radiation were connected to the L.E.T.
Fig. 7- Variations of RBE and OER as a function of LET, of alpha particles and deuterons, derived from survival curves of cultured cells of human kidney origin. RBE curves 1 and 2 correspond to fractions of 0.5 and 0.01 surviving cells. Curve 3 represents the variation of OER with LET,. (Reprinted from {3})
Photons and high energy electrons have low L.E.T.3 from to 10 KeVI micrometers. For positive ions, the L.E.T. increases with mass for particles of comparable range.
The biological effect of fast neutrons is essentially due to low energy recoil ions, and their average L.E.T. is therefore very high, around 75 KeVImicrometer.
ENERGY (MeV/u)
2.4 Comparaison of different kinds of radiations
If we compare the merits of different kinds of radiations used in radiotherapy,combining the dose distribution advantage and the high L.E.T. advantage, we find the classical figure suggested initially by A.M. Koehler.
NEUTRONS
HIGH LET ADVANTAGE ?
Fig. 9- Schematic comparison of different types of radiations of interest in radiotherapy. The relative price range for particle facilities is indicated by dollar signs. (Reprinted from (3)).
+Fig. 8
-
The LET of heavy ions in water as a function of specific kinetic energy (in MeV/")( reprinted from 131).cl-636 JOURNAL DE PHYSIQUE
114. Accelerators for heavy i o n therapy 3.1 Basic specifications of heavy ion therapy accelerators.
As shown in Tab. 1 , heavy ion beams like Carbon, Neon or Argon seem to offer the best possible combination of dose distribution and high L.E.T. However, due to the relatively short range of heavy ions compared to other radiations, high energies and therefore large and costly accelerators are needed for a practical radiotherapy unit. This consideration has restricted the use of heavy ions radiotherapy to one single accelerator facility in the past : the Bevalac accelerator combination in Berkcley.
Table 1 (reprinted
from {4)).ENERGY CONSIDERATIONS : RANGE IN CM OF WATER
ION ENERGY (MeV/nucleon)
7 0 175 250 400 500
Protons 4 20 3 7 81 115
Helium 4 20 3 7 81 115
Carbon 7 1 2 27 38
Oxygen 5 9 20 29
Neon 4 8 16 2 3
Fig. 10
-
Ranges of energy and mass that are required for selected accelerator applications and that are available from synchrotrons and cyclotrons now operating or in construction. (reprinted from {4}).Due to those large energies, an interesting feature appears with those heavy ions beams used for radiotherapy.
Some of the incident nuclei undergo a fragmentation in the nuclear interactions. Some of the fragmentation products are radioactive and, it turns out, are deposited primarely near the end of the range of the primary beam. Using positron emitting fragmentation products and an appropriate positron emission tomography device (P.E.T. camera), it is possible to visualize the region where the beam energy is deposited.
Fig. 11
-
Distribution of autoradioactivity and target activity of the oxygen ion beam in a Lucite phantom. The Bragg ionization curve also is shown ( reprinted from {4})6
E
4- 3 212
I 0
(d m r n - ~ l ro lbM l u n 1 h . n ~ )
0 1 2 3 4 5 6 7 8 0 1 0 1 1 1 2
Nwamn number
-
-
I I I IOXYGEN BEAM 5-
AUTOACTIVATION 3 -
2-
BRAGG CURVE
-
_ _ _ _ _ _ _ - - - MI L
Fig. 12
-
Portion of the chart of the nuclides of interest to light ion therapy.(reprinted from{4}).0 I 2 3 4 5 6 7
CENTIMETERS OF LUCITE
Another major requirement for an accelerator used for heavy ion radiotherapy is the beam intensity. Those intensities varies from ion to ion and are listed in the following table, if one requires to deliver a 600 Rad dose to a standard one liter volume in a one mhute exposure.
JOURNAL DE PHYSIQUE
Table 2 (reprinted from
(4)).I
DOSE CONSIDERATIONS FOR LIGHT-ION THERAPY --- --Dose : 6 Gray (600 Rad)
Target Volume : 1 Litre (200 cm2 x 5 cm)
Time : 1 minute
Hydrogen
-
1 1 x 1 0 1 0 ionslsecI
Helium-
4 2.5 x 1 0 .9I
1
Carbon-
12 4.5 x 1 0 81
Oxygen - 16 Neon
-
20/
Silicon-
28 1.2x
10 8I
I
Argon-
40 8 x 1 0 7I
Although actual intensities needs probably to be larger than the above mentioned intensities by a factor 2...3 due to beam losses in the beam distribution system, they remain still very modest and even synchrotrons with very low duty cycle are able to reach those goals.
3.2 Existing and planned facilities
In addition to the only one existing facility already mentioned : the BEVALAC at Berkeley (USA), a major accelerator complex has been funded in Japan for heavy ion radiotherapy at the NIRS ( National Institute for Radiological Sciences). This accelerator is based on P.I.G. ion sources, R.F.Q. linac, an Alvarez linac and two superposed synchrotron rings.
Fig. 13.. Preliminary illustration of the NIRS heavy particle medical accelerator and the beam lines for cancer treatment (NIRS) (reprinted from {S)).
Another similar scheme has been studied but not yet funded in Berkeley : LIBRA project.
Fig. 14 - Schematic representation of accelerator systems proposed for LIBRA.(reprinted from 14)).
PREP ROOM
TECHNICAL S I ~ O P S 6r STORAGE
CONTROL ROOM
LEVEL ONE
XOL 8611.41104
Fig. 15- Preliminary plan view of the LIBRA facility
-
phase 1, first floor.(reprinted from {4))JOURNAL DE PHYSIQUE
Table 3 (reprinted from (41).
1
SUMMARY OF PRELIMINARY CONCEPTUAL COST ESTIMATE DIRECT COSTS IN MILLIONS OF 1986 DOLLARSTechnical components 3 0 M
I
Accelerator systems 1 6Injector Synchroton Controls
I
Beam & treatment delivery High energy beam transport Treatment delivery systemsI
Project ManagementI
ContingencyI
Conventional Components 2 0 - 2 5 MBuilding Shielding Utilities
Project Management Contingency
1
TOTAL 5 0 - 5 5 MFinally, in Europe, a number of radiotherapy groups joined to create the project EULIMA ( for European Light Ion Medical Accelerator), a facility able to accelerate ions from protons to neons to energies of 400 MeVInucleon. The accelerator would be a separated sector, isochronous cyclotron with superconducting coils, having a maximum bending limit K=1600. It would accelerate fully stripped ions produced by an Electron Cyclotron Resonance Ion Source.
Fig. 16- The EULIMA cyclotron project.
REFERENCES
(1) Waldemar Scharf " Particle Accelerators and their Uses"
-
part 2-
"Applications of Accelerators in Medicine and Radiobiology" "Radiotherapeutic Applications".{2) Waldemar Scharf " Particle Accelerators and their Uses"
-
part 2-
"Applications of Accelerators in Medicine and Radiobiology" "Radiation Sterilization".13) M. R. Raju " Heavy Particle Radiotherapy."
{4) R.A. Gough " The Light Ion Biomedical Research Accelerator- LIBRA " " The Fifth PTCOG Meeting and lnternational Workshop on Biomedical Accelerators "
-
U.S.A. 1987.{5) H. Tsunemoto and S.Morita " Fast neutrons and protons in cancer treatment with the medical cyclotron at NlRS " " Eleventh International Conference on Cyclotrons and their Applications "
