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RINECKER PROTON THERAPY CENTER STATUS REPORT: FIFTH MONTH OF CLINICAL OPERATIONS, AUGUST ´09
PROTON-THERAPY OR HEAVY-ION-EXPERIMENTS? THE FUTURE OF CANCER RADIATION THERAPY: PROTON SCANNING
Why is radiation therapy necessary for the treatment of cancer? Surgery, i.e. the radical removal of all cancer cells, is indisputably the best treatment for cancer. However, it reaches a limit at which the intervention is unacceptably invasive, leaves behind too much damage, e.g. prostatectomy, or is no longer technically feasible due to the cancer being too large.
Although extensively researched, chemo, hormonal and immunotherapies have so far not cured a solid cancer (in contrast to diffuse leukaemia) by themselves. They are successful in prolonging life, but are costly and beset with side effects. They find their limit in a statistic play of nature: cancer cells mutate - even faster than bacteria. Even the destruction of over 99% of cancer cells, as can be achieved with chemotherapy, is regularly survived by a mutated and chemotherapy-resistant minority of cancer cells. Sooner or later this will result in a relapse (see figure 1).
The third pillar of cancer treatment is radiation therapy. Irradiation with current technical equipment, be it X-rays, protons (particle radiation) or similar, can kill any cell (the term “radiation-resistant” tumor is basically incorrect - it is used to designate forms of cancer that tolerate considerably more radiation than the healthy tissue that surrounds them). The lethality of radiation for all living cells, hence for all types of cancer as well as healthy cells, without any possible development of resistance is due to the “primitive” non-specific action mechanism of radiation (see figure 2).
Ultimately, all these types of radiation, rightly uniformly termed “ionising” by the Law, act in the same way: they shatter molecules leading to the formation of chemically radical fragments which destroy the prerequisite of all life, the genetic material. Thus an ideal cure for cancer? No. Radiation acts indiscriminately in cancerous as well as healthy cells. It is all a matter of the right dose of radiation in the right place.
All three treatment methods can also be combined. Nevertheless, depending on how many preliminary and early stages of cancer are included in the statistics, only “about half” of cancer patients can be permanently cured, according to the oncologists.
How far away are we from the ideal cure for cancer: radiation that can kill every single cancer cell while preserving the surrounding tissues?
Cancer treatment would not be a problem if each cancer cell could be irradiated separately. While individual cancer cells can be easily identified under a microscope, under clinical conditions in the human body they can only be reliably diagnosed in accumulations of 100 million to 1 billion, which corresponds to a tumor size of around 1 cm. But even diagnostic advances unforeseeable today would not improve the clinical situation for it is not yet possible to aim radiation more precisely. The improvement of radiation therapy is a race to achieve local dose precision and target accuracy!
What does the current technical optimisation of X-ray radiation achieve?
X-ray radiation, like light and radio waves, is made up of electromagnetic waves, but with a shorter wavelength and more energy. As with light it can be easily bundled. Highly precise targeting in the two lateral dimensions is not a problem with X-rays. The problem lies in the third dimension, the depth of the body. As we know light cannot be “stopped” at one point. In the body it is absorbed and the intensity naturally decreases with depth (on the basis of an exponential curve that tails off over a long distance). The X-ray method is also penetrative, with a levelling off of the dose; it is impossible to stop it right in the tumor.
Nonetheless X-ray techniques could be considerably refined. With increasingly shorter waves carrying more energy, “hard” X-rays (with generator voltages ranging from 0.8 to 30 million volts) have a lesser dosage dissipation in the body; the effective does not disappear so closely under the skin as with the traditional devices. However, the healthy tissue in front of the tumor receives more radiation than the tumor itself, and hazardous radiation is also found behind the tumor.
The entire development of modern X-ray technology (Intensity Modulated Radio Therapy IMRT, Rapid Arc, Cyberknife, Tomotherapy) is focussed solely on attempting to irradiate the target from as many sides as possible whilst precisely modifying the respective dosage and using lateral dimensioning to enable the resulting overlap to match the shape of the tumor as closely as possible. This is much better than in the past when the radiation “fields” were scarcely able to take account of the tumor shape. The flip side of the coin is that with more radiation directions (the Rapid Arc system and Tomotherapy actually continuously irradiate the patient in an orbiting manner) more healthy surrounding tissue is enveloped in a “dose bath” (see figure 3).
Even the most modern X-ray methods cannot evade the vicious circle of irradiating healthy tissue with tumor-equivalent doses, or lower doses in healthy tissue involving a large amount of tissue. In every X-ray method the large volume of bodily tissue surrounding the tumor is exposed to many times the integral tumor dose. This leads to a large range of side effects, including the formation of radiation-related secondary tumors. And above all, it restricts the dosage level that can be applied to the tumor. In X-ray procedures the dose in the tumor is not limited due to technical reasons but with almost all patients by the unacceptability of severe side effects called collateral damage. Thus, the tumor dose limited due to these considerations is not always enough to kill the cancer.
Assistance from the physicists: particle radiation, protons
With radioactive decay, in addition to electromagnetic radiation, electrons and nucleus particles are emitted at such high speed that the scientists formerly could not distinguish them from each other. The word “radiation” continues to denote these particle streams today, even if they are produced with a particle accelerator, such as the one at the RPTC in Munich. When penetrating tissue, they also give off energy to the molecules of the cells, which, as with electromagnetic radiation, react with a splitting off of electrons, known as “ionisation” (see figure 2 above). These biological effects are so similar in X-rays and protons – the nuclei of hydrogen – that both can be mathematically calculated from the physically absorbed dose: Protons are more biologically active by a factor of 1.10 than equal amounts of absorbed X-rays. This fixed effect relationship allows the entire clinical experience of dosing with X-rays to be applied in relation to protons as well, i.e. it is known exactly how much of a proton dose a particular healthy organ will tolerate and what dose is required for sterilisation of the tumor. This conversion rate is also laid down by the German Federal Office for Radiation Protection in the official operating licence issued to the Munich Proton Therapy Center.
All these particles are not simply absorbed on passing through the tissue, but slow down during passage. Can a better dose distribution be achieved by this?
In 1904 a physicist, the Nobel Prize winner Sir William Henry Bragg, observed a strange effect. Incoming charged nuclei have a precise range in matter and effect increasing ionisation the slower they become; i.e. this peaks at the end of their path – this effect is known as the Bragg Peak. Protons, including carbon nuclei and other “heavy ions”, result in little ionisation initially, and therefore do little damage in the body short of the tumor, but their maximum level of damage is achieved right at the end of their trajectory. And as their speed can be manipulated, the depth of penetration can be adjusted into the tumor (see figure 4). The resulting three-dimensionally targetable dose distribution is clinically ideal (see figure 5)! There now only remains the question: which of these particles should be used, and how to aim them?
When using protons this fascinating concentration of the dose in the tumor as a result of the Bragg Peak allows the harmful radiation to be reduced to 1/3 to 1/5 as compared to X-rays, while keeping the tumor dose the same. Alternatively, given the current frequency of unsatisfactory results when using radiotherapy, protons can be used to increase the dosage directed into the tumor whilst still achieving a lower level of side effects (see RPTC internet monthly reports April, May, June). This is a proven fact: it can no longer be rationally asserted that the reduction in the dose in the healthy tissue by a factor of 3 or more in comparison with X-rays is “clinically insignificant” – German legislation explicitly requires this reduction in the Radiation Protection Ordinance of 2001 (Sections 6, 80, 81). A dose increase with the aim of improving the chances of healing is always possible with protons if the spatial resolution of the beam is so good that only negligible amounts of healthy cells in the vicinity of tumors are exposed to the tumor dose. Unfortunately, in some cases tumor cells (e.g. glioblastomas in the brain) and healthy tissue are so intimately interwoven that such a differentiation is not possible. In order to limit the numbers of these problem cases, RPTC in Munich - the current world-leader in precision – achieves technical levels of targeting and beam accuracy unsurpassed anywhere else today. Optimum results are attained in this regard by image-guided radiotherapy with CT-assisted patient positioning (see RPTC internet monthly report April 2009) and a scanning procedure in which the beam (generated in a superconducting proton accelerator) scans the tumor in up to 10,000 mini-target areas separately.
Currently there are 26 proton therapy installations throughout the world, 11 of which are large-scale clinical units with 3-5 treatment rooms, with a further 11 major installations under construction. In total, over 60,000 patients have been treated, predominantly at American facilities. The RPTC is treating patients since March 2009. Clinical experience of proton therapy is based on no fewer than 1700 publications in the worldwide literature.
Further improvements with heavy ions?
The fact that heavy ions, today mainly carbon nuclei, are scattered to a lesser extent due to their greater mass appeared to be very promising. In comparable conditions the figure is 3.4 mm in the brain as opposed to 3.9 mm in the case of protons; though deep in the body it is 4.2 mm as opposed to 7.8 mm for protons. Clinically, this advantage is of little relevance: on penetrating the body, protons do not burst, whereas carbon nuclei and other heavy ions do. This releases a shower of radioactivity which mainly emerges on the side of the tumor away from the source of radiation, i.e. there where in usual radiation directions the organs at risk lie, which can be spared by using protons. In the case of scanning system fields are comprised of mini-target areas, therefore a certain beam width is necessary to ensure an even overlapping dose level from target point to target point without duplications or gaps. However, the anticipated advantage of less scattering in the case of heavy ion disappears entirely as soon as the distribution of the relative biological efficacy of heavy ions, as set out below, is taken into account.
The original raison d'être - that indeed still exists with respect to research into heavy ions - was the achievement of an effect that was almost too good for radiotherapists to contemplate. At the end of their path the heavy ions proved to be biologically much more toxic than the corresponding energy absorbed there. The aforementioned factor of 1.10 for protons compared to X-rays increases to many times this rate in the case of heavy ions. And this only at the end of the path which can always be targeted into the tumor using the scanning method! In all the cases which are not, as described above, restricted by the spatial resolution, through the optimisation of dosage, damage to the healthy tissue was to be reduced again as the Bragg Peak and/or the Bragg Plateau appeared to undergo an additional elevation due to the increase in toxicity at the end of the path in the tumor, so that the physical dose might have been reduced.
However, these effects do not relate to the physical dose distribution that can be calculated and measured, but need to be biologically worked out on cell cultures, on animals pressed into containers and experimentally in the clinic. It should be noted, however, that for statistical reasons observation periods of 5 years and more are required for side effects and tumor healing. Nevertheless, in the desperate battle against cancer mortality such a chance has to be followed up. Completed in 1994, a heavy ion centre has been built in Japan. Another one, though with much lower radiation energy and penetration depth, was also constructed in Japan and completed in 2002. To date a total of less than 6000 patients have been treated with heavy ions. In Heidelberg, attached to the German Cancer Research Centre, a heavy ions/proton combination facility is now under construction and shall begin operations in 2009.
Heavy ions, how promising is this research?
The mysterious effect of “hypertoxicity”, the local effect over and above the physical dose, with heavy ions is today explained by the much denser ionisation pattern in the tissue compared with X-rays and protons. This is thought to bring about more frequent double-strand breaks in the DNA spiral which are not repaired by the cell with a success probability of 1:10,000 as with breaks in just one DNA strand, but only at a rate of 1:5. The unrepaired damage to the DNA is then lethal for the cell. According to the hypothesis, the narrow ionisation pattern correlates with the spatial distribution of the DNA wrapped around protein bodies. It was research into this hypothesis that brought about disillusionment with regard to heavy ions (for further literature see below): biological hyper-efficacy does indeed exist, but only at doses that are lower than clinically required in the tumor. As shown by a research centre in Darmstadt, the heavy ion dose distribution is on the one hand much better than with X-rays, but it is not as good as that using protons (see figure 6).
But that is not all. Biological hyper-efficacy does indeed occur, however not within the tumor. It occurs in a shoe-shaped area surrounding the tumor and in the area of the illustrated radioactivity tail (see figure 7) i.e. precisely there where the physical doses are already low and should remain so biologically!
The preconditions for superiority of heavy ions, which first have to be clinically tested tumor by tumor and determined over the course of many years, can not be seen particularly positive. Added to this is the fact that the high costs of heavy ion facilities have forced constructors to largely abandon the targetability of the beam from all directions, as it is the absolute standard in X-ray radiation systems and is repeated with the gantry technique at the Munich RPTC. There is just one mobile heavy ion gantry under construction in the world today - in Heidelberg. The high degree of targeting precision that is possible with the proton scanning system, is, however, only feasible through the use of gantries.
Proton therapy or heavy ion experiments?
Of course it is necessary to follow the dream of even less harmful tumor irradiation at heavy ion research centres. Cancer is becoming more widespread and will soon become the most frequent cause of death in Germany. We have to do everything to slow it down and should use the most modern and promising methods. But in doing so we must make a clear distinction between what are experiments on patients and what is the best possible assured treatment today (see figure 8).
- Ma C. C. and Maughan R. L.: Controversies in Medical Physics: Medical Physics, Vol. 33, No. 3, pp. 571-573, March 2006
- Hall E.J.: Intensity–Modulated Radiation Therapy, Protons, and the Risk of Second Cancers, Int. J. Radiation Oncology Biol. Phys., Vol. 65, No. 1, pp. 1-7, 2006
- Strahlenschutzverordnung vom 20. Juli 2001, §§ 40, 55 (4)
- Goitein M.: Fractionation of Proton Therapy, PTCOG 43, Munich, Dec. 2005
- Jäkel O. and Debus J.: Selection of beam angles for radiotherapy of skull base tumours using charged particles, Phys. Med. Biol. 45 (2000) 1229-1241
- Krämer M.: Treatment Planning for Carbon Ion Beams, PTCOG 43 Munich, Dec. 2005
- Zulassungsdefinition für das RPTC, ausgestellt vom Bundesamt für Strahlenschutz (BfS) am 27.10.2003 mit diesbezüglichen Fachgutachten Prof. Dr. Eugen B. Hug, Prof. Dr. Dr. Jürgen Debus, Prof. Dr. Th. Herrmann
- Wilkens J.J. and Oelfke U.: Direct Comparison of Biologically Optimized Spread-Out Bragg Peaks for Proton and Carbon Ions, Int. J. Radiation Oncology Biol. Phys., Vol. 70, No. 1, pp. 262-266, 2008
- Krämer M.: Treatment Planning for Carbon Ion Beams, PTCOG 43 Munich, Dec. 2005
- Müller R.: Warum ist der Kohlenstoffstrahl den Protonen im klinischen relevanten Direktvergleich nicht überlegen? Strahlenther. Onkol. 2008 No. 4 pp 227-229
- Nardi J.: Partikeltherapie – Marktchancen und Finanzierungsmodelle. Siemens AG. Medica 2006 Düsseldorf
- Halperin E. C., C. A. Perez, L. W Brady, D. E. Wazer, C. Freeman:
- Principles and Practice of Radiation Oncology
- Lippincott Williams & Wilkins 2007
BONE MARROW-EMBRACING RADIATION WITH PROTONS
In June/July 2009, a 59-year old patient with bone metastases in the thoracic spine underwent proton radiation therapy. The cancer had grown from the vertebrae into the surrounding organs and had not stopped before the adjacent vertebral canal and had already brought about the initial stages of paraplegia. The patient’s gait was unsteady and she could only move in small steps.
One of the difficulties of radiation therapy in this case was that the spinal cord had already been previously exposed to X-rays. Repeated X-ray therapy of the new tumor growth was therefore out of the question.
With the opening of the RPTC, the method of spot scanning gave real hope to the patient, who had already undergone surgery twice as well as chemotherapy – both in vain. Only this modern technique of proton therapy, in which a target area is scanned point by point in a meandering manner, allows sharply defined dose modulations within a radiation volume. By using this method the radiation dose in the spinal cord in the middle of the irradiated area in our patient could be reduced to the desired lower level, without limiting the tumor dose.
The treatment using protons proved successful for our patient. She is delighted to be able to walk again unhindered.
Proton plan: With the spot scanning technique at the RINECKER PROTON THERAPY CENTER it is possible to perform sharply defined dose modulations such as this channel-shaped dose sink at the spinal cord.
RPTC – WAITING LIST AND CALL CENTRE
Even though the RPTC initially held back with public relations measures, soon after opening in March 2009 demand already exceeded the (still limited) treatment capacity. But in order to attract attention within health politics and to counter media criticism based more on economics than scientific facts, we had to intensify our media presence at the beginning of August. This in turn has triggered a now massive excess demand.
Call Centre. The point of contact for patients and enquiries is our Call Centre (Tel.: 0049/89/660680). At the beginning of August it was congested at times, for which we apologise. The number of personnel has now been increased in order to provide a smoother service.
At the beginning, we tried to put all telephone enquiries through to doctors at the RPTC. However, due to excessive demand, this very soon proved to be unmanageable: we kindly ask for your understanding as we reorganize:
Admission procedure. Patients indicating a desire for treatment at the Call Centre receive a standard admission form by e-mail, fax or mail (depending on their own request). As soon as it is returned to the RPTC by one of the above-mentioned methods, the information contained is evaluated by one of the doctors. If the patient is suitable for treatment he/she is given a identification number and included on the waiting list and asked to come to Munich to submit all relevant documents. If a patient expresses a wish for treatment by means other than via the Call Centre, for example via a staff member, this staff member is required to initiate the procedure using the admission form.
Waiting list. The medical directors of the RPTC will exercise their right to give priority to emergencies and to rapidly growing, life-threatening tumors and, in particular, to children on the waiting list. However, it is a strict corporate covenant of ProHealth AG not to grant preferential treatment in return for special payment. The operating times of the RPTC are currently subject to technical limitations. In the future, they will be based on technical and personnel considerations; there is also the desire of the statutory health insurance companies for an economic running of the institution which implies economic operating times. Within this context running the facility on an “overtime” basis would be extremely cost-intensive. It could only be undertaken in cases of absolute emergency and at the expense of general operational requirements.
We are currently doing everything to increase the treatment capacity as quickly as possible – where we depend on the manufacturer - in order to meet urgent treatment requirements.