Parmenides Ärzte GmbH Dr. Sahinbas & Kollegen±lan... · Hyperthermie und Institut für...

Parmenides Ärzte GmbH Dr. Sahinbas & Kollegen

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Ruhr-Universität Bochum Institut für Hyperthermie- u. Ernährungsforschung Dr. med. Hüseyin Sahinbas Amtsgericht Bochum HRB 12812 Geschäftsführer: Dr. med. Hüseyin Sahinbas

Expert opinion on the efficacy control of capacitive, locoregional electro-hyperthermia systems in Germany at the “Praxis-Klinik für Hyperthermie und Institut für Hyperthermieforschung” (Practice-Clinic

for Hyperthermia and Institute for Hyperthermia Research) at the Ruhr-University Bochum

Bochum, 08 February 2012

Dear ladies and gentlemen, my name is Dr. Hüseyin Sahinbas (MD, PhD) and I have been dealing for more than 12 years with the daily application of hyperthermia and the individual systems provided by a wide variety of companies. As the current vice-president of the German Society for Hyperthermia and various hyperthermia societies, I would like to present a short summary of my vita as well as publications and research on temperature control and efficacy measurements. Personal data: Doctoral thesis: Significance of Hyperthermia in Medicine Further education and activities: Interventional pain therapist, medical specialist for radiology, medical practice specializing in oncology since 2002. Direction of the International Training Centre for Hyperthermia Memberships: Deutsche Röntgengesellschaft (RöFo) since 1998 (German Society of Radiology) Deutsche Gesellschaft für Onkologie (DGO) (German Society for Oncology) European Society for Hyperthermic Oncology (ESHO) International Clinical Hyperthermia Society (ICHS) American Society of Clinical Hyperthermic Oncology (ASCHO) De uts che Ge s e lls cha ft für Hype rthe rmie e . V. (DGHT) vice-president (German Society for Hyperthermia) Ge s e lls cha ft für Biologis che Kre bs a bwe hr e . V. He ide lbe rg (GfBK) (Society for Biological Cancer Defence) Interdisziplinäre Arbeitsgruppe Hyperthermie (IAH) (Interdisciplinary Working Group Hyperthermia) The Kadota Fund International Forum Japan De uts che Ge s e lls cha ft für Häma to-Onkologie (DGHO) (German Society for Haemato-oncology) Ge s e llschaft für Bioimmuntherapie und Mikronutrition (GBIT) e. V. (Society for Bio-immunotherapy and Micronutrition) Deutsch-Türkische-Medizinergesellschaft ( DTM-NRW; vice- president) (German-Turkish Medical Practitioners Society) Publications: Books: S a hinba s H Loka le Hype rthe rmie forme n. In: Ingrid Ge rha rd, Marion Kiechle. Onkologie Intergrativ München, Urban & Fischer Verlag 2005

mailto:[email protected]

http://www.hyperthermie-bochum.de/





S a hinba s H Loka le Hype rthe rmie forme n. In: Ingrid Ge rha rd, Marion Kiechle. Gynäkologie Intergrativ München, Urban & Fischer Verlag 2006 S a hinba s H. Hype rthe rmie im klinis che n Allta g. In: Holzhauer/Gröber, Checkliste Komplemeäntäre Onkologie, Medizinverlage 2010 Magazines: Sahinbas H, Szasz A; Mit Wärme gegen Krebs; Biomed park 2003 Sahinbas H, Grönemeyer D, Baier J, Böcher E; Patientin mit multizentrischem Glioblastom multiforma mit Thermochemotherapie: Deutsche Zeitschrift für Onkologie Sahinbas H, R. Zirbel, R.C.Fernando; Afrikanischer Weihrauch Erfahrungsheilkunde u.v.m. Lectures: >250 Lectures on hyperthermia, galvanotherapy and complementary medicine on national and international congresses and events (last international: ASCO 06.2008; Balkan Union of Oncology 10.2008; GfbK Heidelberg 05.09). Abstract books: H. Sahinbas, D.Groenemeyer. Good response to treatment with adjuvant thermochemotherapy in a patient with multicentric glioblastome multiforme (Deutsche Zeitschrift für Onkologie) Sahinbas H, Groenemeyer DHW. Hyperthermia treatment of advanced relapsed glioma and astrocytoma. (multiple Congrespapers 2000-2005) Sahinbas H, Groenemeyer DHW. Boecher E, et al Hyperthermia treatment of advanced relapsed glioma and astrocytoma (Forum Medizin 2004) S a hinba s H, Gröneme ye r. Gre nze n und Möglichke ite n de r Hyperthermie (Hyperthermiekongress Köln Oktober 2004) Sahinbas H., Grönemeyer D.H.W. DEEP RF-HYPERTHERMIA TREATMENT OF ADVANCED GLIOMAS (ESHO 2003 + 2005) H. Sahinbas, Hager , D. H. Groenemeyer Prospective phase II trial for recurrent high-grade gliomas with low radiofrequency (LRF) hyperthermia (ASCO 2008) u.v.m. Purpose of the expert opinion

1. Discussion of the attained temperatures in the currently commercially available capacitive systems for regional hyperthermia and their limitations

2. Juxtaposition of the attainable temperature gradients in the systems of the companies Celsius42+ and Oncotherm.







Temperature measurements The temperature measurement below cited by Mr. Rusakov was conducted on a surface tumor that is located immediately below the skin surface. The penetration depth of the measurement probes on the ultrasound picture on the right can be measured well and the temperature probes do not lie deeper than 4-5 cm (see picture below).

The measurement is certainly correct. Yet, it should be noted that it is a surface tumor of a maximum diameter of 6 cm that lies directly under the skin. Taking into consideration that the temperature probe is placed in the centre of the tumor, the maximum distance to the measurement probe is 3-4 cm. At my institute we have also conducted repeated comparative temperature measurements (see below) and can confirm these temperatures for tumors that are located close to the surface. In fact it confirms the statement of the Kadota Fund International Forum 2004 – Clinical Group Consensus that the EHY 2000 is only suitable for surface tumors.







This was noted in a meeting in Kadato in which, besides me, Prof. Szasz was also present in the function of scientific responsible person of the company Oncotherm, who definitely approved the construction of his EHY 2000 system as a surface hyperthermia system.







I have annexed the work resulting from this meeting. Since I have been working with the EHY 2000 system for a long time but the resulting effects with regard to the temperature development, as noted by the interdisciplinary working group, are not sufficient in the depth, I have had new systems installed in the practice that comply with these criteria. In Japan, such a system was already on the market under the name Thermotron RF-8. There were a great number of publications on it. In the consensus, the precondition is noted that the therapy systems must feature a high power output and therapy electrodes. I have annexed a summary of works on the Thermotron RF-8 system (same capacitive method at 8 Mhz). After a German system named Celsius TCS was brought to market in 2006, we also conducted temperature measurements with this system: • Agar Agar trials (muscle-equivalent temperature phantom) Agar Agar is an alga which, dissolved in physiologic salt solution, can be used as a temperature phantom equivalent to muscle tissue. The advantage is that one can easily conduct measurements in defined depths. Agar Agar can be cut into slices for defined measurements or infrared imaging; other tissue part (bones, inner organs) can be integrated. There is no influence of indefinable irregular cooling by perfusion. (The Agar phantom is also recommended in the ESHO guidelines.







Many trials, of which only two will be presented here as examples, have shown that the general heating potential of the system even with a reduced power output (e.g. at 200 Watt) in comparison with the Celsius (at 600 Watt) is more than sufficient. In the next trial pictured, a median temperature gradient of > 8 Grad Celsius was reached after 20 minutes at 200 Watt.

The characteristics of the distribution of the field must be differentiated. More details on that will follow at the end of this presentation. However, in general, the temperature effect in a homogenous phantom body is relatively uniform in the centre of the phantom.







• Radiobiological radiotherapy – dummy Besides the Agar model, another phantom was used for test purposes. In radiotherapy, radiobiological dummies are used for simulation and test purposes. Cut into slices, they are aimed at emulating the characteristics of human tissue structure. For the tests, the thorax in the area of the lungs/pancreas was chosen and the sensors were distributed centrally.

Results of a radiosensitivizing Celsius+ hyperthermia with a total of about 335 KJoule power input over a period of 60 minutes: The temperatuer gradients without perfusion at realistic and also clinically realizable power input were 3,5 °C at sensor 1, 3,7 °C at sensor 2, 3,2 °C at sensor 3 and 2,3 °C at sensor 4.







Comparison of different systems: On a defined dummy without perfusion (and thus identically comparable), demonstrable differences between capacitive systems of different designs can be shown well. The following test was conducted with:

Oncotherm EHY 2000 system

Celsius C42 TCS system:

In spite of a formally equal power input, the results show a significant difference in temperature rise. This can be explained by the differences in the technical construction. • Animal experiments Static trials on the phantom have undisputable advantages insofar as the power impact can be examined directly without any adulterant factors. The main difference to the in-vivo situation is the perfusion of







living tissue by the blood circuit. It has a cooling effect and, depending on the localization and perfusion of the organ, can have a very significant influence as a cooling circuit. Another complicating factor is that especially in tumor tissue the perfusion, even intra-individually, is highly diverse. The historically first test with perfusion was on a cow’s udder, a tissue structure which resembles the one of the mamma. Perfusion was simulated by a physiological salt solution that was pre-heated. Via optical fiber based thermo-probes, the achieved temperature could be measured at different points, as shown in the figure.

The trial consisted of two warm-up phases. The first warm-up phase with a constant HF input of 400 W over 50 minutes. Afterwards, there was a cooling period of 50 minutes and the second warm-up phase was 30 minutes with the same power input.

Result: It was interesting to see that in both phases the highest tempereature measured was only reached 5-8 minutes after the power input was switched off. Liver - measurements with two dogs Two invasive measurements could be conducted accompanying a therapy. Both cases are liver measurements.







The animals, both about 30kg, were under general anesthesia. The 250 mm electrodes were used and the measurements were again done with the optical fiber sensors. *Dog I

Result: A moderate temperature rise with a maximum of 40,5 °C. *Dog II

Trials in the veterinary clinic Fürstenwalde (Dr. Matzke und Dr. Lenzke) Result: A moderate temperature rise with a maximum of 42,0 °C (li lateral 41,7 °C; median 42,0 °C) was achieved. • Minimally-invasive and invasive temperature measurements on human subjects The different measuring methods available will not be discussed here. The following measurements were conducted with optical fiber temperature probes. They have the disadvantage of only represent punctual measurements but they have the advantage of being methodically valid and exact. *Case I (rectal temperature measurement) The measurements were done with 7 sensors that were arranged in a kind of Pelotte dildo for controlled positioning. One measuring probe was placed on the skin under the upper electrode.

Pelotte-Dildo by Courtesy of the Academic Medical Center Amsterdam







The subject was male, 50 years old, 90 kg, application in the lower pelvis; 2 x 250 mm electrode, distance between the electrodes 29 cm (23 + 4 cm + 2 cm). As shown in the table below, the power range was from an initial 60 watt up to 170 watt. Result

The first thing to be noted is the diverse picture. At the top, 40,0°Celsius were measured. *Case II (rectal temperature - measurement) This case was a radiosensitizing Celsius+ hyperthermia over 60 minutes in a patient with prostate CA. The power input rose from an initial 60 watt to 170 watt, a total of 364 KJoule.

Trial at the Institut für Hyperthermie & Supportive Care, Germany‐Bochum Result: The rectally measured temperature gradient reached 41,9 °C after 30 minutes and subsequently stayed at 45 °C to 46 °C for about 20 minutes. Such a result is usually not measured. In accordance with expectations, the sensor on the skin only showed a moderate rise of 1,4 °C. • Characteristics of the power impact and SAR trials: GUIDELINES and preconditions of the HYPERTHERMIA SOCIETIES (IAH, ESHO) and the German Cancer Society for efficacy control in locoregional deep hyperthermia:







The reference SAR (Specific Absorption Rate): Rise of 0.2 degree per minute, thus 1 degree in 5 minutes (without perfusion) as guideline of the “International Journal of Hyperthermia.“ Wust et al. The newer systems (in this trial: Celsius42+ TCS system) feature the possibility to vary the upper and lower electrode size. This opens up the possibility of a general focusing of the temperature impact in the dielectric medium. On the surfaces contiguous with the electrodes, the body temperature can be reduced by the immanent cooling of the water bolus that surrounds the electrodes. There is a cooling circuit of de-ionized water. This is effective since the thermo-sensors can be kept in the normal range and there is no sensation of heat or pain. Thus the power input can act more on the depth of the tissue. If different electrode sizes are used on both sides of the body in the field, a relatively stronger temperature gradient can be reached on the depth half of the smaller electrode. The next test on the Agar phantom confirms this in an impressive way. We consciously chose again a model without perfusion to confirm the general impact of this effect. Yet, the localization and irregularity of the perfusion is a complexity we always encounter in vivo. The test set-up is shown below with the position of the temperature probes in the muscle-equivalent phantom. The exposure time was 50 minutes, the first 30 minutes at 150 watt power input and the last 20 minutes at 300 watt.

Sensor 8 in the target area shows the greatest temperature rise and thus confirms the focusing thesis mentioned above. A marked







temperature gradient needs a slightly higher power input of >150 Watt. Besides the electrode area, the temperature effect is quickly decreasing and marginal – in this model, as mentioned above, without perfusion. SAR representation One possibility to evaluate the performance of a warming technology is a SAR (Specific Absorption Rate) figure. The aim of the test is to check which power input effects which temperature gradient in a defined short period of time (e.g. 5 minutes). The objective is to achieve a reference temperature gradient of 0.2 0C per minute or, put differently, a temperature rise of 1 °C every 5 minutes (IAH (Interdisciplinary Hyperthermia Working Group) guidline). Results: We analyzed the trial presented above accordingly, primarily for the first 25 minutes with a moderate power input of 150 watt.

In this case the reference of 0.2 degrees C per minute (blue line) is congruent with the line of the temperature gradient of sensor 8 (red), this means that the reference value is achieved. The other points in the field do not attain the set target, yet this can be clinically desirable, since only the tumor tissue and not the surrounding tissue is meant to have the highest impact. (IAH guideline=international hyperthermia group).







Subsequently, the results for the next interval with 300 watt, and again the corresponding gradients:

In this case, the blue line is again the reference with 0.2 degrees per minute. Now two measuring points have surpassed the reference curve: sensor 8 and sensor 1. The other points in the field are again below the reference, as it is clinically desired, this time with less distance yet still passable.







Summary and results:

• In order to check and validate the mere nominal values via temperature measurements different comparative measurements (on a radiology dummy and patients) were conducted.

• The measurements conducted here over a period of 60

minutes in accordance with the GUIDELINES of the HYPERTHERMIA SOCIETY (IAH etc.), the German Cancer Society (DKG) as well as the Federal Committee, for efficacy control in loco-regional deep hyperthermia the reference SAR was measured: (increase of 0.2 degrees per minute, i.e. 1 degree in 5 minutes (without perfusion) as guideline by the “International Journal of Hyperthermia.” Wust et al.).

• The mechanism of ALL capacitive systems is generally based

on the same physical principle: The patient is the dielectric medium between two plates of induced electric tension. The extracellular liquid in the interstinum as well as the intracellular ions react to this rapidly changing electromagnetic field.

• In various laboratory and animal experiments, the efficacy of these systems could be shown to all appearances. The DIFFERENCES in these systems are rather due to their design, especially in the arrangement and flexibility of the upper and lower electrode size (number of active (thus consciously arrangeable) electrodes AND the possibility of applicable ENERGY!

• In most publications, it is argued that in combination therapy (EHT, radio- and chemotherapy), the temperature is an important parameter and the precondition for an increase of efficacy. Thus the performance of the system (energy output in watt) plays a key role in the evaluation of the individual systems.

Dr. med. H. Sahinbas Bochum, 08 February 2012 Conflict of Interests: In accordance with the scientific custom, I want to state here that in the years from 1998 to 2007 I have at times been a scientific adviser for the company Oncotherm. Furthermore, I have been acting in this role for the company Celsius42 from 2005 on. I am also in regular contact with the two leading providers of whole-body hyperthermia systems, Heckel and Ardenne. I own a minority share of less than 4% in the company Celsius42+. Yet, these relations have at no time influenced my therapy recommendations or the direction of my research.



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