QUARTERLY REPORT OCTOBER 2010
CANCER RADIOTHERAPY – OLD OR NEW?
The wait for the anti-cancer pill, the discussion about x-ray radiotherapy or proton irradiation: A plea for proton therapy.
Dr. med. Hans Rinecker PhD
The Arsenal Against Cancer
Media reporting on advances in medicine have recently stated that one out of every four children born today will live past the age of 100. However, the negative side of current medicine is rarely reported: it is expected that half of all people born today will die of cancer.
Whenever medicine has managed to make a group of diseases treatable – such as cardiovascular diseases today, leading to the striking statistical increase in life expectancy – the door is simultaneously opened for subsequent fatal diseases that are harder to treat. And the success rates of cancer therapy are only 50% in the current status of medical development, at least if one corrects for statistical extenuations such as allowing for only potentially fatal precursors of cancer. At present, the three pillars of cancer therapy - surgical procedures, chemotherapy with its branches of hormone and immunotherapy, and radiation therapy - remain in a stagnant phase rather than in a phase of rapid advancement.
In the past, surgery achieved great progress through the improvement of diagnostic procedures for tumor localisation by means of endoscopy, computed tomography, magnetic resonance imaging, and other methods. Through advancements in anaesthesia and intensive care, it was able to expand its impact up to the later decades of life. However, developments in recent decades have also shown that the ever more radical expansion of the operations no longer brings about improved success. On the contrary, retrograde trends have occurred during this time: In the case of breast cancer, the breast is no longer amputated; the stomach is no longer completely removed and replaced for all carcinomas. Surgery indeed continues to develop, however it is also certain that it cannot stem the increase in cancer mortality resulting from the age-related increase in the incidence of cancer.
We are thus waiting for an anti-cancer pill. Everywhere we read about the pharmaceutical industry’s efforts to develop new and improved chemotherapeutic agents or to find the holy grail of cancer therapy, the cancer pill. Or to invent new hormone therapies or even genetic engineering methods. A thousand new drugs are claimed to undergo development and testing. It is a fact that chemotherapies earn billions for the pharmaceutical industry. Individual cancer drugs that prove successful and gain certification even influence the share prices of major corporations. Particularly in Germany, the prices demanded are astronomically higher than the production costs. And in the final months of life, the cancer patient and the attending physician almost always pin their hopes on the help of the chemotherapy which is administered in nearly all cases. Far more than surgery and radiation therapy, chemotherapy is the most costly, indeed the economically risky pillar of cancer treatment. Yet the reality of its successes is that some cancers disseminated throughout the body – cancers of the blood, leukaemias – can actually be treated very successfully with chemotherapeutic agents alone, particularly in children. In the case of so-called solid tumors, a final cure is unfortunately not generally possible with chemotherapeutic drugs. Chemotherapy by itself affords an average of less than 6 months of additional life expectancy, yet it can cost up to 100,000 Euros and also cause vomiting and other serious side effects. Chemotherapeutic agents are often combined with surgery and irradiation with the aim of killing left over tumor cells or micrometastases. This combination treatment complements the effects of surgery or irradiation by improving chances, but by only a single-digit percentage range in general. Why have the immense investments in research and treatments not achieved more? A similar phenomenon can be seen in the case of bacterial infections. Throughout 70 years of antibiotic therapy, the administration of these antibiotics has allowed many bacterial strains to utilise genetic mutations to become resistant and thus invulnerable to drugs.
Today we know that the determining element of cancer disease are mutations in individual cells, which enable growth that is independent of “social” control (intrinsic to every organised multicellular life form just as in human society) and that is only self-controlled. Below are two numerical examples. When cancer is discovered in the body, it generally has between 100 million and one billion cells. Each of these cells plays a mutation lottery. Comparisons of the genome of cancer cells with that of their mother cells in the local tissue that have recently become possible technically, have yielded devastating results: 15,000 (pancreatic cancer), 23,000 (malignant melanoma) or 50,000 (lung cancer) mutations. This occurs within perhaps only 10 years of development following the initial undetected cancer cell. The parasitic life form of cancer cells, which take over the metabolism of the host, enables these cells to achieve these almost inconceivably high rates of mutation without dying off. These rates of mutation are what soon make every chemotherapeutic agent and every hormone therapy ineffective after their initial successes. Among the many cancer cells, there are always a few which have already mutated, are resistant, and proliferate again after the initial effect of the chemotherapy. Unfortunately, the same problem is also to expected for genetic engineering therapies, which today in any case are a distant prospect.
The third pillar of cancer therapy: How many patients are irradiated? The Robert Koch Institute predicts that there will be 450,000 new cases of cancer in Germany in 2010, a steady increase over previous years. In the USA, with the already significant utilisation of proton therapy facilities, 60% of these cancer cases are irradiated either alone or in combination. In Germany, with only the RPTC as an operational, large proton facility to date, at present only about half of all cancer cases are irradiated: more than 200,000 annually. There is also an internal irradiation method: the excellent therapy of inducing thyroid cancer cells by means of hormonal manipulation alone to take up radioactive iodine isotopes, whose short-range radiation sterilises only these cells. There exists also the method of implanting radioactive needles into the prostate, which is not as prevalent, however, due to technical problems and side effects. But, those treatment forms are limited methodically to less than a tenth of all irradiation cases. The remainder is “teleradiology,“ that is, external distance irradiation – today with x-rays and tomorrow with protons.
This external irradiation with x-rays fails in nearly half of all patients although any cell, healthy or cancerous, can essentially be killed with ionizing radiation, be it x-rays or protons. There is no development of resistance. Technically, it would not be a problem to apply an absolutely sterilising dose to any tumor. In the case of x-ray beams, which can only be targeted in two dimensions - in contrast to protons - the healthy tissue however, receives a multiple dose by this “shoot-through-method.” Side effects and collateral damage are thus unavoidably triggered. These are what limit the effective therapy dosage in the tumor. The majority of x-ray therapy failures result from this inevitable, physical dosage limitation, and not, for example, from missed metastases.
Proton Therapy – Too early or at last?
Over 70,000 patients throughout the world have already been treated with proton therapy. There is no proof, not a single publication, that even in the case of only a single patient, this therapy would have had a worse effect than the conventional x‑ray radiation therapy it replaced. If, because of initial reluctance in the pioneering phase, and especially due to initial certification limitations of the first facility in Loma Linda, USA, dosages identical to x-rays were selected, the therapy results were identical – as expected – but with better patient protection. Whenever the dosages can be increased with protons, the statistics show equally increasing improvements in the chances of recovery. At first, the facility in Loma Linda demonstrated superior results in the proton treatment of prostate carcinomas. In the RPTC, 15% of current patients received proton therapies following previous unsuccessful x-ray radiation treatments, after which the tumor grew further, however too much collateral damage was caused by the treatment with x-rays already. In a further 20% of our patients, the tumor was judged unsuitable for an irradiation with x-rays by the referring physicians. Proton treatment is reliable and well-proven. It clearly affords a new chance:
This all comes as no surprise. The far superior local dose distribution of protons with an, in comparison to x-rays, at least threefold reduction of radiation to the healthy tissue and thus protection of the healthy body can be physically measured and is indisputable. However, the effect within the tumor cell – and also in the healthy cell – of x-rays and protons is identical. Both radiation types trigger ionisations in equal measure which damage the genetic material, the DNA. These radiophysiological and biochemical findings are likewise incontestable. Accordingly, a difference in the intracellular effect depending on the type of tumor between these two radiation types has never been clinically proven! Even if it is still alleged in order to save an application area for the old x-ray facilities. No surprises and no disadvantages for the patient with protons. There is, however, the advantage of protons achieving a much higher beam concentration in the tumor and thus crucially optimizing the tumor dose and the resultant chance for recovery while reducing the dose-limiting collateral damage in the healthy tissue.
The USA is converting to proton facilities. Europe is still lagging behind. In Europe, projects in Orsay, Uppsala, Krakow and Prague are just under construction, more are being planned in many other European sites. In Germany, other than the clinically operating RPTC, there will still be only one proton facility in Essen in the near future. Facilities and developments in Heidelberg, Marburg and Kiel are experimental and intend to use the heavy ion method which is internationally considered as a nonconfomal or experimental method. Germany is lagging behind even within Europe. The reason for this is not at least the aggressiveness with which the operators of existing x-ray facilities rant with an ultraconservative mentality against protons - a criticism that is not patient-oriented medical but economic instead.
Nevertheless, this discussion was conducted for a long time with arguments that were medical or that at least appeared to be medical. These ranged from understandable to comical. They can be consistently disproven: For a detailed account, see the interview with the RPTC management team on the internet [www.rptc.de – Quarterly Report July 2010]. Recently, the defence of conservative radio-oncologists has finally moved away from the originally fundamental questioning of proton therapy. The contrary positions to this improvement are currently based on predominantly two trains of thought:
The new therapy deems to be economically too expensive. However, no-one knows how expensive. Even during the clinical operation of the RPTC the figures that quantify the additional costs are just being developed. Namely, successful radiation therapy avoids the use of the chemotherapies which are nearly always administered in the final stage and, at a cost of between 30,000 to more than 100,000 Euros per case, cost many times the amount of any irradiation. Moreover, a greater amount of experience with proton therapy is highly likely to lower the repetition frequency of the individual sessions, decreasing the number of sessions. In the future, proton facilities will thus be more productive and certainly much more economical to operate.
The second “modern“ argument against proton therapy is nearly philosophical and difficult to understand: Our direct on-site university competitors have just publicized the following critique against protons, stating [that in all cases of radiation therapy] “all relevant side effects result from the high dose exposure of tissues located in close anatomical proximity to the tumor“ (www.klinikum.uni-muenchen.de - Neue Entwicklungen in der Strahlentherapie; if not yet deleted [New Developments in Radiation Therapy]). Thus contrary to the state of knowledge about local x-ray dose distribution, which often scatters more than 2/3 of the level of the tumor dose height far into healthy tissue, it is suggested that the x-ray side effects only occur solely near the tumor, exactly where proton therapy intends to increase the dosage to promote a greater guarantee of success! The unusual term “high dose exposure“ can technically only refer to the PTV (Planning Target Volume). This means the tumor itself and any tissue in the body that closely surrounds the tumor in which no tumor is detected, but in which there might be tumor cells mixed with healthy tissues, in the case of lacking diagnostic precision or organ movements. According to the rules of radiooncology, this surrounding tissue in the PTV is usually irradiated with at least 85–95% of the intended lethal tumor dosage. All healthy tissue there is thus sterilised by any form of irradiation and is given up anyway. In the case of x-rays, it will be killed with a very if not yet deletedhigh degree of probability. If one wishes to kill tumor cells in this entire area with a high degree of certainty - and this is technically possible with protons due to their local target precision - the tumor and surrounding tissue in the PTV are then sterilised not only with a very high degree of probability, but even to a point of near certainty. Side effects are of course not increased due to this statistical increase in certainty. They remain reduced due to the concentration of radiation within the tumor and the PTV despite the increase in proton dosage. But the patient has a greater chance of recovery.
Proton therapy is well-proven, reliable, and significantly more promising than x-ray therapy with a degree of probability approaching certainty. The Rinecker Proton Therapy Center is officially certified for proton therapy as a modern replacement for x-ray irradiation. In contrast to x-ray methods, it meets all new legal radiation protection requirements for patient safety (StrlSchV (German Radiation Protection Ordinance) of 2001, §§ 6, 80, 81). Replacing x-ray therapy with proton irradiation is not a medical but rather an economic question and a matter of time.
Further literature on the discussion about protons versus x-rays: Michael Goitein, Harvard Medical School, Boston, USA: “Trials and tribulations in charged particle radiotherapy.” Radiotherapy and Oncology 95 (2010) 23-21 or http://www.ncbi.nlm.nih.gov/pubmed/19581014.