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. |
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. |
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. |
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. |
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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