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QUARTERLY REPORTS JULY 2010
PROTON THERAPY OR X-RAY-RADIATION?
THE TUMOR RADIOTHERAPY OF THE FUTURE
A CRITICAL EXAMINATION OF CANCER THERAPY
Interview by Uwe Wolff, journalist and book author
Dr. Rinecker, you are the father of this proton therapy center, still the only such large-scale facility in Europe. Many people are now of the opinion that the technical input and the enormous investments for this new treatment method are excessive. Do we really need proton therapy?
Rinecker: Well, every fifth of us does need it. With man’s increasing life expectancy, cancer is on the increase and – according to the latest statistics – 39 % of all women and even 42 % of all men acquire cancer. About half of them are treated with radiation therapy alone or in combination with surgery and chemotherapy. Hence, it’s every fifth person who benefits from the therapeutical progress with protons.
Dr. Hauffe, you are physicist by profession and come from CERN (Conseil Européen pour la Recherche Nucléaire or European Council for Nuclear Research), the huge research institution for elementary particles. You have dedicated your entire work life to the highly demanding physics of this new type of therapy facilities. Why should, in the opinion of a physicist, proton radiation replace the X-ray therapy?
Hauffe: X-ray-radiation is, simply spoken, always a shoot-through method. The X-rays can be easily bundled and precisely targeted at the tumor in the dimensions left/right and top/bottom. But not lengthwise in the third dimension. The X-rays penetrating the body will cause most of the damage just under the skin, with their intensity decreasing until they leave the body: Some 50 % of the X-rays leave the body again on the opposite side. The X-rays cannot be targeted at all at the tumor’s position in the depth. This has the effect that X-rays inevitably damage the healthy tissue surrounding the tumor with a three to five times higher integral radiation dose (depending on the body and tumor geometry) when a certain therapeutic dose in the tumor is to be ensured.
New, more precise X-ray irradiation devices, such as the IMRT method or the cyber knife, are frequently the subject of discussions among experts. Will they not improve the X-ray situation?
Hauffe: Only partly. The currently best X-ray apparatus, the so-called Rapid Arc from an American company, exposes the tumor to X-rays from all sides. The dose overlapping effect achieved in the tumor can thus be much better adjusted to the real shape of the tumor than before, when the irradiation fields still had an e.g. square shape. However, even these advanced X-ray devices cannot overcome their inherent fundamental shortcoming, namely to be unable to target in the third dimension, since X-rays are subject to their natural physical laws. The modern apparatuses only farther distribute the damaging radiation. Therefore more healthy tissue is affected which is still damaged by a three to five fold radiation volume compared to the tumor.
Will the better spread out radiation doses of these new X-ray devices not be so low that they cannot cause any more damage in the vicinity of the tumor?
Rinecker: Not at all, because there is no such thing as a harmless ionizing radiation level, which is also the view of the legislator. The collateral damage – absolutely the right word in this context, by the way – caused by the X-rays in the vicinity of the tumor is extremely varied. It ranges from a degradation in intelligence and memory, when brain tumors are exposed to radiation, over damage to healthy parts of the lung, to blood vessel and nerve damage as well as to dried-out salivary glands which affects the life quality considerably, and a good deal more. The irradiation of healthy tissue may even lead to the growth of secondary tumors years later. This is a problem which, according to the opinion of a large majority of international experts, necessitates the radiation with protons where children are concerned. The main problem is this collateral damage that always forces radio-oncologists who still work with conventional X-ray equipment to select the lowest possible dose. They find themselves in a typical “Catch-22” situation and have to weigh the chances of recovery against the undesirable side effects. This is a rather tight situation for many tumors and tumor localizations, which eventually contributes to the fact that half the patients exposed to X-ray therapy are dying nevertheless.
And why is proton radiation any better?
Hauffe: The protons take advantage of an effect that was discovered by the physicist Bragg some 100 years ago: These accelerated, charged hydrogen atomic nuclei will have the same ionizing effect as X-rays, but with a much more favorable local dosage distribution. When penetrating the body, these particles will not be absorbed, “soaked up”, so to say, like X-rays which are electro-magnetic waves. They will rather be slowed down, although, initially, they discharge relatively little energy. The slower they get, i.e. the longer their transit time is in the atomic electron shells of the living tissue, the more they will be decelerated, the more energy they will discharge, the higher will be the local dose and thus the biological effect. This will eventually reach a pronounced peak which is called Bragg peak in honor of the discoverer. Beyond this peak there is no more radiation, since the protons’ energy has all been spent. We can therefore aim directly at a radiation-sensitive organ and stop in front of it. Before the peak, the radiation effect is lower in comparison with the tumor dose, not higher as in the case of X-rays. Moreover, we can target the Bragg peak at the tumor with millimeter precision by adjusting the speed of the protons. We can penetrate the body 38 cm at a speed of 180 000 km/sec, but we can also localize the Bragg peak on the surface, e.g. in a tumor of the eye. We can apply the radiation three-dimensionally and not just two-dimensionally, as is the case with X-rays.
What does that mean, biologically, so to say, for the patient? Will he respond to proton radiation more favorably?
Rinecker: Here at the RPTC, we do a lot of comparative calculations between X-ray and proton radiotherapy for individual patients simply to show how much better our method is. We would not therapy patients with protons, if we could not reduce the radiation dose that hits the healthy tissue in addition the higher effect on the tumor itself. Depending on the tumor’s position, on its size and on the geometry of the ambient area, we can normally work with only a quarter of the damaging radiation, also in comparison with the most modern conventional X-ray devices. The patient feels better, he does not suffer from acute and subsequent side effects, or at least much less, and our therapists are free to use an optimized tumor dose. We can then also reduce, in many cases, the number of necessary radiation sessions, as is the case with prostate cancer. This is certainly to the patient’s benefit as well.
Professor Herbst, you have been ordinarius for radiotherapy at the Regensburg University. You are one of the pioneers of proton therapy in Germany and have tried for a long time to establish such a facility at your university. The project failed, as so many others, due to a lack of state funds. You left, helped setting up the RINECKER PROTON THERAPY CENTER in Munich and are its Medical Director. Does that mean a dream came true for you?
Herbst: More than a dream. I knew proton therapy from theory, from scientific publications and from the American facilities which, at that time, worked on the scattering principle. I am now in the fortunate position to treat my patients with the currently most advanced proton-scanning facility in the world. The precision in controlling the scanning beam achieved here has never been attained so far and has hardly been conceivable for me. We can now treat many cases with fascinating success, which have previously proved to be beyond radiotherapy.
And here for the lay people amongst us: What do scattering and scanning systems mean in proton therapy? What is the difference?
Hauffe: The proton beam of the older scattering system was widened with filters and was virtually showered over the tumor. One has then tried with individually prepared three-dimensional templates to model the beam in conformity with the tumor’s shape. Although this was much better than X-rays, it had two disadvantages: The templates and filters which had to be prepared for each individual beam direction did not only delay the treatment, they also released a scattered neutron radiation which, although better than the damaging radiation from X-rays, still inflicted damage on the patient. But even worse, the template technique still did not make it possible to restrict the shape of the radiation area to the tumor’s front wall. We, however, with our pencil-shaped, three-dimensionally controlled beam irradiate individual scanning points within the tumor precisely to controlled doses with the scanning system and can thus concentrate the dose solely on the tumor.
How exactly do these novelties improve the chances of recovery?
Herbst: There are three mechanisms, with which proton scanning improves the chances of recovery: First of all, proton scanning harms the patient and the ambient area less. Ionizing radiation has always an immunosuppressive effect. And the lower a patient’s immunosuppression, the better his chances of immunologically overcoming his tumor or residual tumor cells. Secondly, as mentioned earlier, we have, certainly not entirely but to a very high degree, freed ourselves from the limitations caused by collateral damage, and can thus optimize the selected tumor dose. And thirdly, there is the problem of the so-called fractionation: If, due to the expected collateral damage inflicted on the healthy tissue during an X-ray therapy, the radiation dose must be split up into many individual doses and administered on many successive days, not only the healthy tissue will recover during the intermissions, but the tumor as well. A reduction of this fractionation will automatically result in a more efficient dose in the tumor, a better chance of recovery for the patient and less harm to him.
Are X-ray patients subjected to more treatment sessions than patients with proton radiotherapy?
Herbst: Yes, quite regularly. Prostate cancers, as an example, treated conventionally with X-rays will usually be irradiated 42 times on the same number of days. We expose such patients to radiation only 21 times, as it is also done in Loma Linda, USA, and so administer a higher effective dose in the tumor. The lower rate of beam scattering affecting the healthy tissue will make it possible in the future to further reduce the number of recurrent sessions which put a strain on the patient. This will also make proton treatment more and more economical.
Do not critics of the scanning method claim that this pointwise irradiation may leave gaps, so that zones might be generated, where the tumor is not “hit”?
Herbst: These claims are factually unjustified. They remind me of the criticisms voiced during the transition period from the old gramophone shellacs to the CD, when the music was similarly digitized. No, the spacing between the individual target points – there may be up to more than 10 000 in the case of larger tumors – has been calculated precisely in a way that the radiation points will overlap. Since we can measure the dose administered in each individual point and in between, we are absolutely sure to achieve a uniform dosage with a tolerance range of usually less than +/- 3 %. My colleagues have even created a portrait image of Dr. Rinecker “painted” with protons. It shows how evenly the dosage has been administered both to the dark and the bright areas. If there is a difference at all, he looks a few years younger in the picture than in reality.
Nevertheless, couldn’t mobile tumors “escape” this type of combined, sequential scanning radiation?
Hauffe: The old scattering method, too, combined the Bragg-peak doses one after the other. Our medical physicists know exactly how to adapt the individual layers and the scanning directions to the relevant movements in the body: Only the heart and the large vessels close to the heart do move with relevant frequencies. Radiation gaps can be safely excluded by selecting the layer orientation.
The RPTC publishes that it can improve the treatment of all tumors that could have been treated with X-rays in the past. Are there any cancer cases that can not be treated with X-rays but only with your therapy?
Herbst: Yes, there are. 15 % of our cases so far have been patients who had been unsuccessfully treated with X-rays, i.e. where the tumor had started growing again, while the healthy tissue in its immediate vicinity got radiation damage to such a degree that it proved to be impossible to repeat the X-ray therapy. Although we cannot help all patients in these cases, we can help many of them. Our planning also shows that we can often achieve a tumoricidal dosage, i.e. a lethal dose for the tumor, in cases where this proves impossible with X-ray with its less favorable beam concentration. We can also replace surgery: The international medical associations have already confirmed the equivalence of X-rays and surgery in the case of most prostate tumors. The results are even better with proton radiotherapy. It is therefore unnecessary, from my point of view, still to risk the side effects of prostatectomy, such as impotency and incontinency.
Some representatives of the health insurers claim that proton radiation is only suitable for certain types of tumors. What is your opinion and which tumors may not be suitable for proton radiation?
Rinecker: Our official clinical operating permit allows us to treat with proton radiation all tumors treated up to now with X‑rays. The better beam concentration in the tumor gives us an edge over X-rays each time when healthy tissue is in the beam path as well. This is always the case, with one very rare exception. There are absolutely no criteria under radiation-biological aspects nowadays verifying an assumption that certain types of tumors might be treated less effectively with proton radiation in comparison to X-rays. The arguments of those health insurers are exclusively supported by economic intentions. The fact that a comparative evidence X-ray/proton radiation cannot legally be provided by tests on humans, neither today nor in future, does not justify the arbitrary assumption that there are tumors which can be treated less effectively with proton radiation rather than with X-rays.
Your competitors claim that proton therapy is a new method which is still in the experimental stage and should only be applied for scientific studies for the time being. The long-term use of proton therapy in the US teaches us the opposite. Have we gained sufficient experience in the meantime, empirical knowledge, as scientists would call it?
Hauffe: As a physicist, let me clarify one thing: While if the local dosage distribution of the proton therapy is far more advantageous than with X-rays, the effect on site within the cell, is the same. The application of energy through photons, as the energy packages of electro-magnetic waves like light or X-rays are called, or through protons penetrating the body will in both cases at a certain energy level result in a separation of electrons from an atom or molecule. These electrons carry a negative electric charge, so that a positively charged atom or molecule is left, the so called ion. Since humans largely consist of water, believe it or not, this process will mainly create chemical radicals of the water. As the name already suggests, these chemical radicals undergo a chemical reaction with their surroundings. The biologically most important reaction is the destruction of the DNA, the genetic material. The cell can no longer divide and dies. This means that the biological effect of X-ray and proton therapy is identical within the cell. This also means we can use all the clinical experience gained from X-ray and apply it to the better dosage distribution of the proton therapy. Hence, no surprises from protons.
I can hear the physicist talking, but what does the medical expert say?
Herbst: Unlike the effect of each single chemo-therapeutic agent, of which each intervenes in a highly specific way in the metabolic processes of cells, allowing tumor cells, like bacteria, to develop resistancy, the generation of these chemical radicals through ionizing radiation is an always identical and chemically simple process which no cell can escape. Consequently, radiation will damage healthy tissue and tumor tissue alike, which explains why precise targeting and the dose concentration are so important. Like healthy tissue there are tumors which can take more or less radiation, depending on, say, how fast they grow and how often the cells divide. Those tumors that tolerate more radiation require a higher X-ray dose – which may sometimes not be tolerated by the surrounding healthy tissue, while a higher proton dose under the same circumstances may still be tolerated by the healthy tissue due to the better concentration in the tumor. The sterilisation dosage requirements for X-ray and protons for the various relevant tumors will obliviously, empirically proven, run parallel to each other. It is therefore possible to transfer the experience gained from X-rays over a full century with a high degree of certainty to the clinical application of proton radiation.
And yet, critics of proton therapy are known to say that the proton therapy does not necessarily achieve better results than state-of-the-art X-ray units…
Rinecker: This was, indeed, a point of criticism in former times. However, the proton results were, expectedly, equal to X-rays in a historical comparison only then, when the tumor dose in proton therapy was not increased or distributed more efficiently. This was the case during earlier treatments in the first large-size facility at Loma Linda, USA, because of restrictions of the then valid permit. Unfortunately, these outdated publications are still being quoted. However, the recovery results of protons have never been worse than those from X-ray despite the concurrent much more gentle treatment of the ambient tissue. Wherever the dose in the tumor has been increased or administered more effectively over time however, proton results have definitively been better, as has been the case with prostatic tumors, but also with chordomas at the base of the skull and in the body elsewhere as well as with other types of tumors.
After many years of clinical use in the US, some scientists in our country still demand that university studies at first be carried out concerning proton therapy. Why is that? Does it make sense?
Hauffe: No it doesn’t. Worldwide, 70 000 cases have been treated with protons, and their number is increasing from day to day. Since international research has been focused on increasing the doses, the proton results get better and better. Worldwide there are more than 13 proton facilities of the size of our center here in Munich treating cancer patients today, although these facilities are no longer at the technological level we represent. The Americans alone are running or building 13 proton facilities this year. They switch to protons. The only facility run by a German university is supposed to be put into operation in the second half of this year, i.e. one and a half years after our own center became clinically operational. No other German university will have a proton center in the next five years. It is not quite clear, why the American research results are to be repeated in this country after a delay of 20 years. Predominantly, the focus should be on enabling also European patients to benefit from the advantages that have already been known at the international level for a long time.
So, you do not intend to do research work here in Munich?
Rinecker: No, we do not want to experiment with patients. There is no viable strategy for such experiments in Germany at the moment, including universities. We must not forget that a patient would receive a three to five-fold dose in the healthy tissue if he is randomized to the X-ray group in a comparison between X-rays and proton therapy. I do not believe that any of the mandatory ethics committees would approve this exposure to a higher radiation dose merely for comparative purposes. This does not mean that such attempts have not been made in the US before, but, understandably, the patients decided vehemently against such higher exposure. The German legislator demands quite clearly and unmistakably in no less than three articles of the Radiation Protection Directive that the dose targeted at the healthy tissue must be reduced to a minimum. Tolerance doses do not exist in this context. If there is a more gentle treatment as with protons, this is to be preferred – so the wording in the law.
Hence, the direct comparison between these two types of radiation is legally not admissible?
Rinecker: The question with regard to comparative research between proton therapy and conventional X-ray would be, whether the three to five-fold higher exposure of the patient’s healthy tissue in the case of X-rays would be tolerable, or admissible, nothing else. Such kind of research objective is neither ethical nor scientifically justifiable – apart from the fact that it is illegal.
Does it mean that the RPTC in Munich will not carry out studies?
Herbst: Not at all. It rather means no experiments, but studies. Legislation is quite clear in this context. We have obtained an official permit to practice proton therapy in Munich. The permit alone stipulates that we have to store all patient and radiation data for 30 years and that we have to record the position, time and results of all imaging methods and dosages. We also transmit our data to the tumor register of the Munich-based tumor center. The statutes alone thus force us to implement a thorough quality control, which we pursue conscientiously. In addition to that, we have applied for the certification of our institute pursuant to DIN ISO EN9001. Given the large number of our patients, there is an immense volume of data, the results of which are evaluated by way of retrospective studies.
Couldn’t the data generated at RPTC be used also for external studies?
Rinecker: I promised already quite a while ago to feed these data, anonymized but without being re-processed, into a public server that can be addressed by external experts. I hope we won’t be the only ones in this field doing this.
Dr. Rinecker, there has been no cooperation between RPTC and the university until now. Would you like to cooperate with the universities or does it not make sense to you?
Rinecker: Oh, why not? But it are the detailed regulations of the Radiation Protection Directive that interfere heavily with any organization of ionizing radiation therapy, thus rendering many forms of cooperation impossible. Nevertheless, we have made offers to both Munich-based universities to cooperate. It are, first of all, the universities that need to develop a realistic strategy for a proton therapy internally. Neither the taxpayer nor my partners and I are willing to finance large and expensive high-tech facilities, which cannot be built smaller and less cost-intensive for technological reasons, only to allow universities to pursue loss-making research projects.
I have read recently that another type of particles, the so called heavy ions, are more suitable than protons, because the human body already might be accustomed to the protons due to natural radioactivity, but not to the exposure of larger atomic nuclei, such as those of carbon. The latter form of treatment would therefore be more effective. What is your opinion on that?
Hauffe: I am not quite sure, whether the reporter has understood the chief physician from Heidelberg in the first place, when he quoted him in his newspaper. Because the physician concerned does not only hold a PhD in medicine but also one in physics. Proton radiation does not occur at all in natural radioactivity; we are neither confronted with natural radioactive materials on earth nor with radioactive waste which discharges accelerated protons. Such things do not exist. Cosmic radiation does consist of protons, of course, but you will only be exposed to them when flying. Here on earth these protons have long been caught by the atmosphere which has changed them into showers of other particles, as every physicist knows. The report’s statement is simply wrong.
Germany is supposed to have three heavy ion facilities in the near or distant future, the HIT Centre at Heidelberg is already partly operational, two other facilities in Marburg and Kiel are in the planning stage. Will this be the method of the future?
Hauffe: There are older heavy ion facilities in Japan working with carbon atoms which are, of course, better than X-ray, since they use particle radiation. On the other hand, their superiority over protons has not been clinically proven and, according to the latest research results, cannot be expected for this much more expensive method, either. It had been assumed that heavy ions are biologically more toxic at the end of their particle path, i.e. in the tumor, than their physical dose there, so they would be even more effective therapeutically. Nowadays one knows that this effect is a little bit “too good to be true”: It exists only in low, clinically not relevant doses. In fact, the heavy ions only blur the aiming accuracy on the target field edges and can also have a toxic effect on the healthy tissue. All this is difficult to explain, but some tangible proof of it has been published in the meantime. According to his own statements, the head of the facility in Heidelberg hopes to have data in five to ten years that will eventually prove the effectiveness of heavy ions compared to protons. It will certainly be useful to operate this facility at Heidelberg for experiments on a low number of patients. No such heavy ion facilities are planned to be built in the United States. We cannot understand the purpose of the other two projects in Germany.
Dr. Rinecker, you have financed a large part of this facility. Is it not, so the main criticism of some health insurers, too expensive?
Rinecker: You know that my answer to this question is a clear no. The expensive element of cancer therapy is the chemotherapy. Chemotherapy can heal leukemia, but usually not the solid forms of cancer by way of an isolated treatment. Chemotherapy promises to extend the life of the patient by months or will, in combination with other forms of therapy, such as surgery and radiation, increase the chances of recovery in the single-digit percentage range. The annual costs incurred by chemotherapy will often range between € 30 000 and € 100 000.As compared with chemotherapy, proton therapy with our flat fee of € 18 740 including diagnostics for patients with a compulsory health insurance is cost-effective.
As compared with the conventional radiation therapy it is expensive, although nobody knows how much more expensive: The increasing international experience gained with proton therapy will make it possible to reduce the number of therapy sessions and thus to make the facilities more efficient which, in turn, will eventually reduce the overall proton treatment costs further.