Radiation can kill you instantly

Hit with the invisible

Radiation in cancer therapy is a tightrope walk: you want to kill all tumor cells, but spare the surrounding healthy tissue. Medical physics is now making the dream of tailor-made irradiation for any tumor shape come true. In a 3-D computer simulation, the beam path and dose are calculated in advance and concentrated in the tumor. During the treatment, the data are also used to control a protective shield made of tungsten lamellas, so that the healthy tissue is shielded and the rays hit the tumor precisely. Wolfgang Schlegel, Medical Physics, DKFZ, and Markus Götz from the medical technology company MRC-Systems GmbH, Heidelberg, report on the joint efforts to provide the necessary hardware and software for the therapy planning system within the framework of the “BioRegio” program in two to three years to develop to world market maturity.

Cancer remains the most feared disease in the civilized world. Hundreds of thousands of people develop cancer in Germany every year, the results of treatment with the methods commonly used today - surgery, radiation therapy and chemotherapy - are still unsatisfactory, and only about every third cancer patient can be cured in the long term. Hopes in cancer treatment are expected from other developments today: through advances in molecular biology and immunology and through the associated understanding of the causes of cancer. The basic researchers assume that these findings will lead to new approaches in the prevention and therapy of tumor diseases and thus to a fundamentally better control of this insidious disease. However, the period of time that will still be needed to be able to draw practical benefits from new findings in basic research cannot be foreseen. In addition to researching the fundamentals of cancer development, the German Cancer Research Center in Heidelberg is also working on further developing the previous pillars of tumor therapy, especially radiation therapy with high-energy X-rays. An essential advantage here is that the approaches developed at the DKFZ in the last few years can be put into practice immediately and can contribute to sustainably improving the healing rates for various types of tumors today.

The basic problem of radiation therapy is walking the tightrope between tumor healing and the side effects of radiation. Every tumor cell dies if it is treated with a sufficiently high dose of radiation. However, tumors that grow inside the body are surrounded by healthy tissue, which, depending on the sensitivity to radiation, can also be damaged. If a tumor grows in the immediate vicinity of organs sensitive to radiation, such as the optic nerve or the brain stem, it is often not possible to achieve a sufficiently high radiation dose in the tumor tissue: the surrounding healthy tissue would be irreversibly damaged. However, if only a single tumor cell remains after the irradiation, there is a high probability that it will grow again into a malignant tumor. A successful radiation treatment free of side effects can only be achieved if the exact radiation dose is achieved in the tumor that leads to the death of all tumor cells and at the same time the amount of radiation in healthy tissue remains below the damage limit. This tightrope walk is often a major headache for the doctors and physicists involved in radiation treatment. In order to guarantee the success of the treatment, the prescribed dose values ​​must be adhered to with the greatest possible accuracy in every point of the tumor tissue as well as in the neighboring healthy tissues. In order to achieve this goal, the following three problems must be solved. First goals: every tumor cell must be hit by the radiation; second, dosing: a minimum dose must be achieved in each tumor cell; and third, bundling: the radiation must be concentrated on the tumor tissue and healthy tissue must be avoided.

These three problem areas of radiation therapy have been successfully dealt with in recent years through the collaboration of doctors, physicists, mathematicians, computer scientists and engineers using modern computer systems and digital control systems, the use of computer simulation programs, optical sensor technology and precision adjustment devices and direction finding systems. Radiation therapy has received numerous new impulses through these developments and can hardly be compared with the practice of radiation treatment, as it was carried out about twenty years ago. How do you hit an invisible tumor with invisible radiation? The target problem in radiation therapy was solved in three steps: First, the tumors are made visible with the new imaging method. The position and shape of radiation fields are calculated and displayed, and the “location map” of the tumor and radiation is transferred to the patient with the help of precision-mechanical direction finding systems.

How do you target the invisible?

The first step: Tumors become visible with computer and magnetic resonance tomography. The new approaches in radiation therapy are due to the breathtaking development from x-rays to computed tomography. Twenty years ago, radiologists were solely dependent on the often difficult-to-interpret "shadow images" of the X-ray, on which a tumor could often be completely overlooked or only guessed at Magnetic resonance tomography (MR) high-contrast sectional images. The size, position and shape of a tumor can usually be determined very precisely using CT or MRI.

The second step: rays become visible by means of "computer aided design". Another advantage of CT and MR imaging is the fortunate fact that the image information is available digitally and can easily be read and further processed by computers. This is the starting point for a new approach in radiation therapy: the surfaces of tumors and anatomical structures can be determined by computer and mapped with three-dimensional computer graphics. The radiation that was previously hidden from the human eye can also be made visible on the computer screen. Computer simulation now makes it possible to adapt the direction and shape of a radiation field precisely to the shape of a tumor and to protect healthy tissue as much as possible. In this way, the radiation treatment can be optimized for each patient in the sense of the greatest possible effect in the tumor with the best possible protection of the healthy tissue.

The third step: stereotactic aiming. After the radiation treatment has been simulated on the computer, the next step is to implement the radiation conditions that have been determined. The patient must be positioned at the accelerator in such a way that the radiation field hits the tumor exactly. To make matters worse, the irradiation is repeated up to 30 times and the patient has to be brought into the same irradiation position for each irradiation. The target problem of radiation therapy has analogies with other medical fields. In stereotactic neurosurgery, for example, when puncturing functional areas or when puncturing brain tumors, hollow needles must be pushed through the brain tissue to the target point with the greatest precision, a task that is performed there with the help of fine mechanical precision instruments. Similar, so-called “stereotactic” direction finding systems are used today for radiation treatments as well. In the head area, an accuracy of less than one millimeter can be achieved, with other locations the accuracy is at least two to three millimeters.

3-D radiation therapy planning

The dosage problem in radiation therapy is solved with the help of 3-D therapy planning. If tissue is irradiated, the radiation interacts with the tissue atoms according to physical laws and releases energy to the tissue. The amount of energy emitted determines the radiation dose and determines whether a cell will die or survive. In order to achieve the desired cell death in the tumor tissue and to exclude radiation damage in healthy cells, the energy transferred in each irradiated point of the patient must be precisely calculated in advance. This task, which a few years ago was still unsolvable due to the enormous computing effort, can now be solved in a few seconds with the help of powerful, modern computer systems. The three-dimensional image of the patient obtained with a computer tomograph is broken down into several million cube-shaped volume elements about one to two mm3 in size (also called “voxels”). The radiation dose in each voxel can then be calculated according to the laws of physical interaction. The result is the "radiation plan", a representation of the patient's anatomy overlaid with the dose information. The radiation therapist can see from the radiation plan whether the planned radiation treatment covers the tumor tissue with a sufficiently high radiation dose and whether the healthy tissue is sufficiently spared. If this is not the case, the treatment planning program must be consulted again. The modification of the irradiation technique and the dose calculation are alternately repeated until a satisfactory irradiation plan is achieved. However, this trial and error process can be tedious in complicated cases: Sometimes ten or more different plans have to be calculated before a good plan is achieved.

The irradiation techniques available at the accelerator are of decisive importance for optimizing the irradiation plans. The property of high-energy X-rays is that they emit most of the radiation energy on their way through tissue within the first few centimeters. If only one direction of radiation were selected for treating a tumor, this would result in a complete overdose of the radiation on the healthy tissue just below the skin and a considerable underdosage of the radiation on the tumor tissue. So you have to concentrate the radiation in the tumor, that is, irradiate it from many different directions and allow the radiation fields in the tumor to cross. This leads to a “burning glass effect”, the radiation bundled in this way unfolds its effect in the tumor, while the surrounding healthy tissue remains undisturbed. To achieve this effect, there are two important rules: The more different directions of radiation are used, the lower the level of radiation exposure in healthy tissue; and if the shapes of the radiation fields are adapted to the shape of the tumor, then the shape of the resulting radiation dose distribution also adapts to the shape of the tumor. Only with strict adherence to these rules can a high radiation dose be achieved in the tumor and at the same time keep as much healthy tissue as possible out of the radiation field.

In the past, the main problem with radiation therapy was adhering to the second rule. As long as the location and spatial shape of the tumors were not precisely known, the radiation fields could not be adjusted. Therefore one worked with rectangular radiation fields and had to accept the unnecessary irradiation of healthy tissue. Now that the 3-D structures of the tumors can be precisely determined, the radiation fields can also be adapted to the shape of the tumor, and the unnecessary and stressful irradiation of healthy tissue can be avoided. This new form of radiation therapy with irregular radiation fields adapted to the tumor shape is called "conformation therapy". It is now considered certain that this method of treatment will significantly improve the results of radiation therapy.

A short-term possibility of conformation therapy, already practiced in many clinics, is to cast radiation diaphragms from lead-containing alloys with a low melting point and to blend them into the respective beam path. The disadvantage is that several such diaphragms have to be made individually for each patient and the irradiation process has to be interrupted several times in order to be able to exchange the beam diaphragms. Furthermore, the irradiation techniques are limited by the restriction to a few irradiation directions and thus often do not lead to optimal dose distributions. Long preparation and treatment times also have to be accepted, and the handling of the heavy-lead radiation diaphragms places a considerable strain on the radiological-technical staff.

Computer-controlled ray diaphragms

A logical alternative to the complex and limiting casting process are computer-controllable radiation diaphragms, such as those developed at the DKFZ in cooperation with the Radiation Clinic of the University of Heidelberg. The construction of a computer-controllable radiation diaphragm, also known as a “multi-leaf collimator”, or MLC for short, is very simple: It consists of movable tungsten disks that are opposite each other in pairs and can be moved with the help of motors. The collimators developed in Heidelberg consist of 40 pairs of tungsten blades that are driven by 80 motors. The travel path of each individual slat is determined by a control computer and set using a microprocessor connected to the motor.

For the radiation treatment of a tumor patient, the contours of the radiation fields to be set are calculated in advance with the “Voxel Plan” planning program. The contour data are sent to the control computer of the diaphragm system, and during the treatment the pre-calculated shape of the radiation field is automatically set for the respective direction of irradiation. In principle, irradiation techniques can be implemented with any number of radiation fields adapted to the tumor shape. The new technology of computer-controlled conformation therapy can be used for most types of tumors.

Unfortunately, however, there are a number of cases in which it is not possible to achieve a satisfactory adaptation of the dose distribution to the tumor in this way. This includes all tumors with concave indentations. These are mainly tumors that grow around a radiation-sensitive organ, for example near the rectum, prostate carcinoma, or near the spinal cord, so-called lymphomas, and brain tumors near the eyes, called meningiomas. A simple limitation of the radiation fields to the tumor shape means that the healthy tissue located in the indentation is irradiated with too high a dose.

One possible way out of this dilemma is to use inhomogeneous radiation fields. In contrast to previous radiation therapy, where homogeneous, i.e. uniformly illuminated radiation fields are used, the intensity of the radiation is varied in all radiation fields so that the superposition of the inhomogeneous radiation fields again leads to a homogeneous, tumor-compliant radiation dose distribution. In this way, conformational therapy can also be implemented for extremely complex tumors. The calculation of the intensity variation in the individual radiation fields is called "inverse planning". Such an "inverse planning program" has the great advantage over the conventional type of planning that the often lengthy trial procedure described above is no longer necessary: ​​the computer itself takes over the optimization.

Inhomogeneous (“intensity-modulated”) radiation fields can be generated by superimposing several irregularly shaped, homogeneous radiation fields. In order to realize this, the computer-controllable diaphragm system is again an option. With the intensity-modulated radiation fields and the inverse planning, the limit of what is feasible in radiation therapy with high-energy X-rays has been reached from a physical-mathematical point of view.

At the DKFZ, the new approaches to conformational radiation therapy were developed in the form of prototypes and successfully tested in clinical studies together with the cooperation partners at the university clinics in Heidelberg and Cologne. So that this optimal form of radiation therapy can now benefit as many patients as possible, it is now important to quickly put the method into practical application and spread it worldwide.

Before widespread clinical use can be thought of, the professional implementation of the prototypes into safe, easy-to-use and marketable software and hardware products, tests and approvals according to national and international guidelines as well as clinical tests of these products must follow. The DKFZ works closely with the accelerator company Siemens Medical Systems / Oncology Care Systems to implement the intensity-modulated radiation technology and its clinical testing. An electron linear accelerator equipped with a large field multileaf collimator from this American Siemens subsidiary was recently installed at the DKFZ. In a joint research and development project, the accelerator is currently being modified and expanded so that the first patient treatments with inverse therapy planning and intensity-modulated fields can take place this year.

The “BioRegio” program offers excellent conditions for the revision, approval and marketing of the computer programs for inverse therapy planning. A medical technology company recently founded in Heidelberg, MRC-Systems GmbH, intends to work together with the DKFZ and the university clinics in the field of radiation therapy with high-energy X-rays as part of the “BioRegio” funding program.The company plans to convert the existing approaches of inverse therapy planning and computer-controlled conformational techniques into a market-ready product and thus create the conditions for worldwide distribution. This market launch should be achieved within the next two to three years.

A welcome side effect of this technology transfer is that several new, highly qualified jobs are being created at MRC, some of which are to be filled by young scientists who have already worked on the development of the process as part of their diploma and doctoral theses. In this way, there is a transfer of knowledge and technology that could hardly be more direct.

Authors:
Prof. Dr. rer. nat. Wolfgang Schlegel
Department of Medical Physics in Radiation Oncology, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg,
Telephone (06221) 42 25 51

Dr. rer. nat. Markus Götz
MRC-Systems GmbH, Im Breitspiel 19, 69126 Heidelberg