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| Heavy Ions As A Surgical Scalpel |
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Heavy Ions As A Surgical Scalpel
Knowledge about the biological effects of ionizing radiation is of
fundamental importance for many areas of medicine, technology, and
radiation protection, as well as for tumor radiation therapy. Research
using heavy ions has proved to be particularly suitable for investigations in
these areas. Moreover, heavy ions are extremely effective in destroying
tumor cells situated at the end of their "flight path." To take advantage of
this phenomenon, an experimental radiation therapy unit has been
constructed in Darmstadt. The first patients will be arriving for treatment
in the summer of 1996.
There has always been a strong biophysics presence at GSI. And right from the start, this
biophysics working group has been carrying out research into the precise biological effects of
heavy ions with the aim of using this knowledge to develop better radiation therapy. Thanks to
the foresight of the GSI founders, the principle that "the effects of heavy ions upon both
animate and inanimate nature are to be investigated" was enshrined in GSI's constitution in
1969. This meant that the first biophysics experiments at GSI could be conducted at the same
time as experiments in nuclear and atomic physics.
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Schematic illustration showing the different dose distributions of X-rays and ionic
radiation (normalized to the total deposited dose). Whilst X-rays spread their energy very
evenly (above), the dose from ionic radiation is concentrated in a very narrow area around
the particle trajectory (below). The size of a cell nucleus is shown for comparison. The
enlargement in the upper picture shows the typical structure of double-stranded DNA, the
double helix, which has a diameter of about 2 nm.
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A distinctive feature of ionic radiation, in comparison with other types of radiation such as X-
rays or electron beams, is the spatial distribution of its energy deposition. In a thin layer of
cells, for example, X-rays distribute their energy evenly over the entire irradiated layer. By
contrast, ions deposit their energy in a very narrow region concentrated around their trajectory.
Radial spreading of the particle track is typically of the order of a few micrometers. Biological
effects of radiation in cells are predominantly the result of damage to the genetic material
found in the cell nucleus in the form of double-stranded DNA. Consequently, in order to
understand the biological effects of radiation, information is required about dose distribution in
the cell nucleus.
Compared to X-rays, the localized energy deposition of heavy ions is very much higher. As a
result, the biological effectiveness is also significantly increased. In addition, local energy
deposition - and again, therefore, the effectiveness of the therapy - can be controlled by the
choice of ion type and beam energy. For this reason, heavy ions lend themselves particularly to
the investigation of the fundamental mechanisms of radiation damage.
The special effect of particle radiation explained
Following systematic experimentation on more than 100,000 biological samples from different
cultures - from viruses and simple bacteria to mammalian cells - a precise analysis of the
microscopic dose distribution in the particle trajectory led to substantial insight being gained
into the special properties of particle radiation. Based on this breakthrough, scientists have
been able to develop a "biological impact" model over the last few years. This model enables
biological effectiveness to be determined according to the "radiation quality" - i.e., the type of
ion, particle energy, and specific energy deposition for the particle trajectory.
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The probability of inactivation of mammalian cells for different ions with respect to the
LET (linear energy transfer), which is a measure of the energy deposition of an ion passing
through matter. The symbols show the experimentally determined values. The straight line was
predicted using the model.
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What at first glance seems more like a misplaced photo is in fact a typical example of
biological research conducted within the heart of a physics research center. In the GSI
biophysics group, scientists from such diverse disciplines as biochemistry, biology, and
physics collaborate closely in the research of radiobiological effects of heavy ions.
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The figure shows
how the model can be used to calculate the rate of inactivation of mammalian cells, i.e.,
radiation-induced loss of their ability to divide. It is precisely this effect which is so important
in the treatment of tumor tissue.
In addition to experiments into the biological effects of radiation, model calculations also relied
heavily on physical research into the energy deposition of charged particles. This is an
important point, emphasizing as it does the importance of interdisciplinary cooperation within
the biophysics group, where researchers from such diverse areas as biochemistry, biology and
physics work together to elucidate the biological effects of radiation.
The progress
achieved with this model was an essential prerequisite for the radiation therapy project
currently being set up at GSI. Here, the first patients are due to be treated from the middle of
1996 onwards.
Tumors which are still in a localized phase are considered to be curable. Unfortunately, for
about 20% of patients, the methods of localized treatment currently available to conventional
radiation therapy prove unsuccessful. However, the local control of tumors can be improved by
matching the irradiated volume more precisely to the tissue volume to be treated. In normal
radiation therapy using photons of X-ray or gamma radiation, the dose deposited decreases
exponentially with the depth of penetration into the tissue. The integral absorbed dose received
by a deep-seated tumor is always less than that received by the surrounding healthy tissue.
Heavy ions, on the other hand, interact differently with tissue than do photon beams. Their
favorable physical and biological properties can help to optimize therapeutic effects on the
tissue volume to be treated whilst significantly reducing damage to the surrounding, healthy
tissue.
Amongst their favorable physical properties are low radial scattering, a well-defined range, and
increased energy deposition at the end of the particle trajectory. Even fast-moving ions are
only minimally deflected during passage through thicker layers of tissue. For example, the
radial scattering of carbon ions is less than 1 mm for a penetration depth of 10 cm. The
inverted depth dose curve of heavy particle beams is a further advantage for radiation therapy.
Energy deposition increases with increasing penetration depth of the particles and reaches a
maximum value a few tenths of a millimeter before the particles come to a complete halt. This
maximum value is known as the Bragg maximum, after the British physicist Sir William Bragg,
and is coupled with significantly increased biological effectiveness of the ion beam in the region
of the "Bragg peak." In other words, the tissue survival rate in the area where the peak occurs
is drastically reduced.
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Comparison of the physical dose distribution (above) and the survival rate of cells (below)
as a function of the penetration depth of ionic radiation (carbon, energy 275 MeV per nucleon)
and gamma radiation of energy 20 MeV. Increased energy deposition at the end of the particle
path, and thus drastic reduction in the cell survival rate, makes heavy ions an excellent
tool for the treatment of deep-seated tumors.
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The range of the particles can be exactly fixed since it is dependent on their energy. In this
way, it is possible to increase the tumor dose whilst maintaining high spatial precision. At the
same time, the surrounding healthy tissue, which may be radiation sensitive, is protected.
Heavy ions are therefore destined to play a central role in radiation treatment of deep-seated
tumors.
Therapeutic use of protons has already been demonstrated with the clinical treatment of about
15,000 patients worldwide. Ion beams are expected to provide an extra benefit because of their
increased biological effectiveness in tumor tissue. However, the use of particle beams in tumor
therapy is as yet a rarity. One reason for this is the technical difficulties that stand in the way of
generating a beam for therapeutic use which is both readily available and can be guided with
the required precision. After all, a heavy ion beam capable of destroying cells with the
effectiveness of a surgical scalpel must be targeted with extreme precision.
Precise irradiation using the raster principle
The intensity-controlled raster scanning technique, which permits an extremely precise
irradiation of tumor tissue, was developed at GSI specifically for this purpose. Using the raster
scanning process, the target volume is divided into layers each of which corresponds to a
specific particle range.
Starting with the layer furthest away, the beam is guided by
fast dipole magnets to scan, slice by tiny slice, each layer in a raster. The energy of the beam is
matched pulse for pulse to the tissue depth. Inevitably, there is some pre-radiation of the nearer
layers, but this can be calculated and then offset when they come to be irradiated.
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Schematic diagram illustrating the intensity-controlled raster scanning process. A target
volume (tumor) is divided into individual layers each corresponding to a specific range.
Only three layers are shown in the picture; for actual irradiation 20 to 40 layers are
required, each one corresponding to an irradiation energy set individually according to the
penetration depth. Fast magnetic deflection guides the beam, just like in a television tube,
and each layer is scanned in a raster. The scanning speed of the beam can therefore be
controlled in such a way that the precalculated biological effect, i.e., the maximal
destruction of tumor cells, is achieved at each point within the target volume.
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A spherical volume of water measuring 6 cm in diameter at a depth of 9 to 15 cm was
irradiated with a carbon beam of 270 MeV per nucleon. The targeting precision of the
ion beam, fired from the left, was made visible with the help of nuclear track detectors
positioned a few mm apart. The image shows that the dose can be very precisely concentrated
onto the target volume.
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Each layer therefore receives a different amount of radiation in order to obtain an equal effect
throughout the whole target volume. Varying the velocity of the therapeutic beam relative to
radiation intensity enables the applied particle coverage to be precisely controlled. Using this
raster system, it is possible to deliver a homogeneous treatment to a three dimensional,
irregularly-shaped volume.
The state-of-the-art heavy ion synchrotron at GSI is the only accelerator in Europe that can
produce heavy charged particles of sufficient range and intensity for clinical use. This puts GSI
in a position of special responsibility. It is a responsibility that GSI is prepared to take on as it
meets the challenges involved. At present, an experimental radiation therapy unit is being built
at GSI in cooperation with the radiation clinic of the University of Heidelberg and the German
Cancer Research Center (German abbreviation DKFZ), which is also situated in Heidelberg. A
clinical study which will run from mid-1996, with about 70 patients being treated per year,
aims to demonstrate the improved local tumor control that results from superior localization of
dosage and the increased biological efficacy of ion beams in tumor tissue.
Demand for heavy ion radiation units far outstrips the capacity available at the GSI
experimental particle therapy set-up. In order to treat a sufficient number of patients, hospitals
must have their own accelerators which are specifically designed for this use. Feasibility studies
have shown that these could be run at costs comparable to those of conventional tumor
therapy. Against this backdrop, an accelerator study has been drawn up at GSI with the aim of
developing an inexpensive synchrotron, optimized for therapeutic purposes. With a diameter of
only 17 m, this synchrotron would be small enough to be incorporated into a hospital clinic.
About 2000 patients a year could then be treated at a moderate cost.
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