Conference of the International Clinical Hyperthermia Society 2012View this Special Issue
Oncothermia as Personalized Treatment Option
Oncothermia is a nanoheating technology personalized for individual status depending on the state, stage, grade, and other personal factors. The guiding line of the treatment keeps the homeostatic control as much effective as possible. One of the crucial points is the surface heat regulation, which has to be carefully done by the electrode systems. The applied stepup heating supports the physiological selection. Recognizing the hysteresis type of SAR-temperature, development of the protocol could be well conducted. Using the Weibull distribution function of the transport processes as well as considering the typical physiological relaxation time of the tissues, special protocols can be developed. It has wide-range applicability for every solid tumor, irrespective of its primary or metastatic form. It could be applied complementary to all the known oncotherapy methods. It is applicable in higher lines of the therapy protocols, even in the refractory and relapsed cases as well.
The personalization of the oncological treatments is the new trend in modern medicine . Oncothermia is a personalized treatment using energy delivery to the targeted tumor . This energy is well focused on cellular level  and makes the dose of energy optimal for cell destruction . The personal feedback of the patient together with the natural homeostatic control of the treatment actions makes the treatment realistically personalized . The central task is to find the proper dose in the given application and optimize the safety and curative limits of the applied dose. The lower limit is of course determined by the minimal effect by heating and the upper limit determined mainly by the safety issues, like it is usual for overdoses. The lower limit of oncothermia dose is indefinite because in case of normothermia nothing else has action except the complementary treatment alone, which has no danger and has such curative effect as we expect from the gold standards. For the upper limit, however, there are very definite technical and physiological parameters: the surface power density of the signal is limited by the blistering to 0.5 W/cm2, (60 min basis), the internal hot-spots could hurt the healthy tissue, and in systemic application the physiology anyway is limited at 42°C. The ultimate challenge is the developing heat resistance, which could make the hyperthermia ineffective and the disease refractory to heating. The presently applied dose concept (CEM) in conventional hyperthermia is physically incorrect (temperature is not a dose), and due to its inhomogeneity concept it is hard to measure. The systemic (whole body) heating in extreme case reaches 42°C (even 43°C is applied sometimes in special conditions; CEM 100%), but the expected distortion of the tumor does not happen. The high energy of the local heating (in most of the cases more than 1 kW is applied) at the start makes vasodilatation, which turns to vasocontraction over a definite physiological threshold at about 40°C. In consequence, over this threshold the high temperature blocks the complementary drug delivery and causes severe hypoxia, which is a severe suppression of the effect of complementary radiotherapy. Furthermore, the conductivity and permittivity of the skin is physiologically controlled by blood perfusion, which definitely modifies all the electromagnetic applications through it.
Hyperthermia overheats the actual target. It does not limit the target size at large (like whole-body hyperthermia) or at small (like heating with nanoparticles) volumes. These methods are all characterized by the temperature, but they are characteristically different in their thermal state. In whole-body heating, the thermal equilibrium drives the process; the body temperature characterizes the treatment technically. However, the body temperature characterizes the process less and less by decreasing the volume of the heated target; the body temperature becomes stable and almost independent of the local heating of a smaller volume in the body. Contrary to the thermal equilibrium in whole body heating, the nonequilibrium dominates in local treatments, and consequently thermal gradients will appear in the system. Heating in nanoscopic range creates huge fluctuations of the local temperatures while the hot nanoparticles try to equalize their high temperature with their neighborhood. This process is typical for the commercial microwave heating, where not the extra nanoparticles, but especially the water molecules are heated in their nanoscopic sizes, and those which give the temperature to the entire volume by time.
To construct a nanoheating process, the targeting of the nanostructures is a clue. Their selection from the other materials makes their controlled heating and also targeting the heat on the desired volume possible. Extra nanoparticles could selectively absorb the electromagnetic energy heating up these small particles extremely in their neighboring spheres. Our approach is definitely similar, but by not using extra particles for selective energy absorptions. Our nanoscopic targets are naturally in the body, in the membrane of the malignant cells. The selection is based on the metabolic differences (Warburg’s effect), the dielectric differences (Szent-Gyorgyi’s effect), and beta-dispersion (Schwan’s effect) as well as uses the structural (pathological) differences (fractal effect) of the malignant lesions.
The main medical advantages of the method are its personalized targeting together with the effective selection and distortion of the malignant cells. The new direction of application focuses on the blocking of their dissemination as well as promoting the bystander (abscopal) effect acting on far distant metastases by a local treatment. The method is successfully developed in the direction of the immune support, and a new patent covers an exciting area: cancer vaccination with oncothermia.
The physiological processes are determined by a dynamic equilibrium process character, which is dominantly determined by special transports and logistics in the complex biosystems. The distribution which is typical for general logistics, failure analyses, and even for survivals is the Weibull distribution , which cumulatively looks as Where is the unit time, when the value of the function is ; the -exponent in the distribution defines the shape (see Figure 1.).
The -exponents were observed in various processes in wide-range applications. The generalized logistic function (sigmoid) could be constructed by various ways, but the so-called Avrami exponents (, which is the exponent of the above Weibull function) are functionally appearing based on the extended works of Cope [7, 8], there are some collected Avrami exponents for various solid-state and biological processes which show the universality of this logistic function.
The application of the Weibull distribution function approaches multiple clinical applications and it is well established theoretically and practically [9–12]. It has been used for a long time for survival description in gerontology [13, 14] and in oncology  as well.
The function has its inflexion point (where the tendency of decreasing changes) in at value. The derivative in this point is proportional to . (The derivative there is exactly .) Therefore, the parametric evaluation could be well checked in the point.
Note that the Weibull distribution could be well approached by normal (Gaussian) distribution over . The area under the curve (shaded in Figure 2) represents the complete energy dose which is provided to the patient.
A certain realistic stepup treatment is shown below, W, W, min, min, and (). The obtained dose is 371 kJ, Figure 2.
However, the continuous increase of the temperature does not fit the homeostatic steady-state requests. Physiological response time (when the homeostatic equilibrium is reestablished after a definite disturbance) is 5–7 min. We propose at least 6 min on the definite chosen power level before the next increase stepup. Considering this transient as 6 min, the stepup heating is shown in Figure 3. In this case, the obtained dose is higher due to the upfitting rule, which we applied. In case of using 10 min relaxation time, the protocol is shown in Figure 3.
The difference between the poison and medicine is only the dose. In numerous cases, people committed suicide taking medicine which would be useful in lower dosage in treatments. The dose is an important factor of efficacy safety and reproducibility too. In case of medication or radiation oncology, we know the dose units as quantitative measurable values in mg/m2 or J/kg in chemo- or radiotherapy, respectively. In hyperthermia, the temperature is overemphasized as a dose; although, it is not a quantitative parameter, it is a quality which makes the equilibrium spread all over the system. The temperature is an intensive parameter characteristic average of the individual energies of the small units in the system. In chemotherapy, the cytotoxic remedies could cease very serious side effects; their safety has an emphasized role in their applications. The chemodoses are determined by the safety (toxicity) limits, independently of the person or the size of the tumorous target. The result (efficacy) is measured a definite time later, when the result is measurable or the toxicity (by personal variability) appears. Then, the chemodose could be modified, or complete change of the medication occurs. The actual dose varies in this second line, considering more the actual person and the actual situation.
When the medication definitely has no side effects (or the side effects are controlled), then the dose role has no upper limit by their safety, and also when the dose is limited but it is too high for the actual patient due to the biovariable poisoning limit, then the actually applied dose is of course lower, trying to fit it for the actual patient.
Oncothermia is governed by a very personalized way: the patient immediately (during the treatment and not a considerable time afterwards) senses and notes the toxicity limit; the heat pain immediately limits the oncothermia dose. When the preset dose is too much, actually it has to be modified by the personal requests. On the other hand, when the preset energy dose is too small (the patients actually can tolerate more; the personalized toxicity limit is higher), then higher energy has to be applied until the personalized limit is indicated by the patient. Overheating is impossible because the surface of the skin has the highest thermal load, and the heat sensing is also there. This personalized dose regulation is the main factor of the safety and together with this for the efficacy too.
Oncothermia has formulated a new paradigm  and made a pioneering job; it was the modulated electric field application, which later had good continuation in the literature in many laboratories worldwide. Its definite breaking results were on the modulated field effect combined with the thermal actions , showing large development in the present clinical practice. The electric field action was considered in a serious manner in 2000 by Nature  and has been intensively applied in clinical practice [49, 50]. The modulated electric field actions were applied for various accepted clinical trials [50, 51].
The third new important field which was pioneered by oncothermia is the immune-stimulative applications of the modulated electric field, showing the definite natural apoptotic cell killing [54, 55] with activation of various leucocytes  to isolate  and kill the malignant lesion.
The fourth pioneering field is the  abscopal (bystander) effect of modulated electric field. According to the remark of world-famous tumor vaccination researchers in their last conference, it could be a good basis to be involved in this very modern and promising field. This effect makes a great opportunity to make the local treatment systemic , like the locally observed tumor becomes systemic by its malignant progress.
In clinical point of view, oncothermia makes also important and unique steps to go forward with proving its trustful performance . It has various levels of clinical evidence and multiple studies including phases of the data development from the toxicity measure (Phase I), [61, 62], through the efficacy (Phase II)  and the wide-range clinical applications (Phases III/IV) . Oncothermia has many retrospective studies but also many prospective ones in Phase II and Phase III categories. The retrospective data are compared to the large databases and to the multiple clinical institutions, making statistical evidence of the validity of the data.
Presently, altogether oncothermia has 54 clinical trials for malignant diseases involving 2796 patients from six countries (Germany, Hungary, Italy, South Korea, China, and Austria). These trials cover 15 localizations (see Table 1.) The patients were in advanced stages, mostly over the 3rd-line treatment. The comparison with the large databases was made in multiple clinics relations, showing extremely large (minimum 20%) enhancement of the 1st year survival percentages.
Oncothermia has good clinical achievements in the clinical studies, making a stable basis of the clinical applications in various advanced primary and metastatic malignancies and giving the long time expected stable standard on oncological hyperthermia. Oncothermia with its surface stabilized sensing (patented action) uses the personal sensing in objectivity of the actual energy dose. This makes the accurate and personalized treatment possible by this method.
The authors acknowledge the experimental work and fruitful discussions of Professor Andras Szasz.
D. W. Neber and G. Zhang, “Personalized medicine: temper expectations,” Science, vol. 337, pp. 910–919, 2012.View at: Google Scholar
N. Meggyeshazi, G. Andocs, and T. Krenacs, “Modulated electro-hyperthermia induced programmed cell death in HT29 colorectal carcinoma xenograft,” Virchows Archiv, vol. 461, supplement 1, pp. S131–S132, 2012.View at: Google Scholar
G. Hegyi, G. Vincze, and A. Szasz, “On the dynamic equilibrium in homeostasis,” Open Journal of Biophysics, vol. 2, pp. 64–71, 2012.View at: Google Scholar
W. Weibull, “A statistical distribution function of wide applicability,” Journal of Applied Mathematics, vol. 18, pp. 293–297, 1951.View at: Google Scholar
F. W. Cope, “Detection of phase transitions and cooperative interactions by Avrami analysis of sigmoid biological time curves for muscle, nerve, growth, firefly, and infrared phosphorescence of green leaves, melanin, and cytochrome C,” Physiological Chemistry and Physics, vol. 9, no. 4-5, pp. 443–459, 1977.View at: Google Scholar
F. W. Cope, “Solid state physical replacement of Hodgkin-Huxley theory. Phase transformation kinetics of axonal potassium conductance,” Physiological Chemistry and Physics, vol. 9, no. 2, pp. 155–160, 1977.View at: Google Scholar
M. Avrami, “Kinetics of phase change. I: general theory,” The Journal of Chemical Physics, vol. 7, no. 12, pp. 1103–1112, 1939.View at: Google Scholar
L. Piantanelli, “A mathematical model of survival kinetics. I: theoretical basis,” Archives of Gerontology and Geriatrics, vol. 5, no. 2, pp. 107–118, 1986.View at: Google Scholar
C. L. Weston, C. Douglas, A. W. Craft, I. J. Lewis, and D. Machin, “Establishing long-term survival and cure in young patients with Ewing's sarcoma,” British Journal of Cancer, vol. 91, no. 2, pp. 225–232, 2004.View at: Google Scholar
H. Aydin, “Strahlen-Hyperthermie bei Lebermetastasen und bei therapieresistenten Knochenmetastasen,” in Proceedings of the Hyperthermia Symposium, Cologne, Germany, October 2003.View at: Google Scholar
J. Bogovič, F. Douwes, G. Muravjov, and J. Istomin, “Posttreatment histology and microcirculation status of osteogenic sarcoma after a neoadjuvant chemo- and radiotherapy in combination with local electromagnetic hyperthermia,” Onkologie, vol. 24, no. 1, pp. 55–58, 2001.View at: Publisher Site | Google Scholar
T. Feyerabend, G. J. Wiedemann, B. Jäger, H. Vesely, B. Mahlmann, and E. Richter, “Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease,” International Journal of Radiation Oncology Biology Physics, vol. 49, no. 5, pp. 1317–1325, 2001.View at: Publisher Site | Google Scholar
P. Panagiotou, M. Sosada, S. Schering, and H. Kirchner, Irinotecan Plus Capecitabine with Regional Electrohyperthermia of the Liver as Second Line Therapy in Patients with Metastatic Colorectal Cancer, ESHO, Graz, Austria, 2005.
G. Fiorentini, U. deGiorgi, G. Turrisi et al., “Deep electro-hyperthermia with radiofrequencies combined with thermoactive drugs in patients with liver metastases from colorectal cancer (CRC): a phase II clinical study,” in Proceedings of the International Conference on Advanced Communications Technology (ICACT '06), Paris, France, January-February 2006.View at: Google Scholar
V. D. Ferrari, S. De Ponti, F. Valcamonico et al., “Deep electro-hyperthermia (EHY) with or without thermo-active agents in patients with advanced hepatic cell carcinoma: phase II study,” Journal of Clinical Oncology, vol. 25, article 15168, p. 18S, 2007.View at: Google Scholar
Z. Vigvary, E. Mako, and M. Dank, “Combined radiological and interventional treatment of non-operable rectal tumors and their liver metastases,” in Proceedings of the Regional Radiology Conference, Maribor, Slovenia, September 2002.View at: Google Scholar
E. D. Hager, H. Sahinbas, D. H. Groenemeyer, and F. Migeod, “Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia,” Journal of Clinical Oncology, vol. 26, 2047, 2008.View at: Google Scholar
A. Szasz, “Brain glioma results by oncothermia: a review,” in Proceedings of the Annual Meeting of Society of Thermal Medicine, Expanding the Frontiers of Thermal Biology, Medicine and Physics, Tucson, Ariz, USA, April 2009.View at: Google Scholar
F. Douwes, O. Douwes, F. Migeod, C. Grote, and J. Bogovic, “Hyperthermia in combination with ACNU chemotherapy in the treatment of recurrent glioblastoma,” 2006, http://www.klinik-st-georg.de/fileadmin/publikationen/en/hyperthermia_in_combination_with_ACNU_chemotherapy_in_the_treatment_of_recurrent_glioblastoma.pdf.View at: Google Scholar
A. Szasz, H. Sahinbas, and A. Dani, “Electro-hyperthermia for anaplastic astrocytoma and gliobastoma multiforme,” in Proceedings of the International Congress on Anti-Cancer Treatment (ICACT '04), Paris, France, February 2004.View at: Google Scholar
G. Fiorentini, P. Giovanis, S. Rossi et al., “A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia,” In Vivo, vol. 20, no. 6 A, pp. 721–724, 2006.View at: Google Scholar
E. D. Hager, “Response and survival of patients with gliomas grade III/IV treated with RF capacitive-coupled hyperthermia,” in Proceedings of the ICHO Congress, St. Louis, Mo, USA, 2004.View at: Google Scholar
E. D. Hager, “Clinical response and overall survival of patients with recurrent gliomas grade III/IV treated with RF deep hyperthermia—an update,” in Proceedings of the ICHS Conference, Shenzhen, China, 2004.View at: Google Scholar
H. Sahinbas and A. Szasz, “Electrohyperthermia in brain tumors, retrospective clinical study,” in Proceedings of the Annual Meeting of Hungarian Oncology Society, Budapest, Hungary, November 2005.View at: Google Scholar
H. Renner, “Simultane RadioThermoTherapie bzw. RadioChemoThermoTherapie,” in Proceedings of the Hyperthermia Symposium, Cologne, Germany, October 2003.View at: Google Scholar
H. Sahinbas, D. H. W. Grönemeyer, E. Böcher, and S. Lange, “Hyperthermia treatment of advanced relapsed gliomas and astrocytoma,” in Proceedings of the 9th International Congress on hyperthermic oncology (ICHO '04), St. Louis, Mo, USA, April 2004.View at: Google Scholar
A. Szasz, A. Dani, and A. Varkonyi, “Az elektro-hipertermia eredményei nagyszámú beteg retrospektív kiértékelésének tükrében Magyarországon,” in Magyar Klinikai Onkológiai Társaság III Kongresszusa, Budapest, Hungary, November 2004.View at: Google Scholar
E. D. Hager, H. Dziambor, D. Höhmann, D. Gallenbeck, M. Stephan, and C. Popa, “Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer,” Anticancer Research C, vol. 19, no. 4, pp. 3403–3408, 1999.View at: Google Scholar
A. Szasz, “Clinical studies evidences of modulated rf-conductive heating (mEHT) method,” in Proceedings of the 25th Annual Meeting of the European Society for Hyperthermic Oncology, ESHO, Verona, Italy, June 2009.View at: Google Scholar
A. Dani, A. Varkonyi, M. Osvath, and A. Szasz, “Treatment of non-small-cell lung cancer by electro-hyperthermia,” in Strahlenbiologie und Medizinische Physik Deutscher Kongress für Radioonkologie, DEGRO, Erfurt, Germany, June 2004.View at: Google Scholar
A. Dani, A. Varkonyi, T. Magyar, and A. Szasz, “Clinical study for advanced pancreas cancer treated by oncothermia,” Forum Hyperthermia, Forum Medizine, vol. 2, pp. 13–19, 2009.View at: Google Scholar
S. J. Haam, “Oncothermia treatment of lung carcinomas,” in Proceedings of the 1st International Oncothermia Symposium, Cologne, Germany, November 2010.View at: Google Scholar
M. D. Doo Yun Lee and M. D. Paik, “Complete remission of SCLC with chemotherapy and oncothermia (case report),” Oncothermia Journal, vol. 5, pp. 43–51, 2012.View at: Google Scholar
F. Douwes, “Thermo-Chemotherapie des fortgeschrittenen Pankreaskarzinoms,” Ergebnisse einer klinischen Anwendungsstudie, 2004, http://www.kstg.net/pdf/thermo-chemotherapie_des_fortgeschrittenen_pankreaskarzinoms.pdf.View at: Google Scholar
H. Renner and I. Albrecht, Analyse der Überlebenszeiten von Patineten mit Pankreastumoren mit erfolgter kapazitativer Hyperthermiebehandlung, STM, 2007.
A. Szasz, “Oncothermia in gynecology,” in Proceedings of the 25th Annual Meeting of Korean Society of Gynecologioc Oncology, Jeju, Korea, April 2010.View at: Google Scholar
A. Dani, A. Varkonyi, T. Magyar, and A. Szasz, “A retrospective study of 1180 cancer patients treated by oncothermia,” Forum Hyperthermia, pp. 1–11, 2010.View at: Google Scholar
G. Andocs, H. Renner, L. Balogh, L. Fonyad, C. Jakab, and A. Szasz, “Strong synergy of heat and modulated electromagnetic field in tumor cell killing, study of HT29 xenograft tumors in a nude mice model,” Strahlentherapie und Onkologie, vol. 185, no. 2, pp. 120–126, 2009.View at: Publisher Site | Google Scholar
D. De Pomerai, C. Daniells, H. David et al., “Non-thermal heat-shock response to microwaves,” Nature, vol. 405, no. 6785, pp. 417–418, 2000.View at: Google Scholar
E. D. Kirson, V. Dbal, C. Rochlitz, F. Tovary, M. Salzberg, and Y. Palti, “Treatment of locally advanced solid tumors using alternating electric fields (TTFields)—a translational study,” Clinical Research, vol. 17, article 5259, 2006.View at: Google Scholar
J. W. Zimmerman, M. J. Pennison, I. Brezovich et al., “Cancer cell proliferation is inhibited by specific modulation frequencies,” British Journal of Cancer, vol. 106, no. 2, pp. 307–313, 2012.View at: Google Scholar
A. Szasz and G. Vincze, “Dose concept of oncological hyperthermia: heat-equation considering the cell destruction,” Journal of Cancer Research and Therapeutics, vol. 2, no. 4, pp. 171–181, 2006.View at: Google Scholar
A. Szasz, “Hyperthermia, a modality in the wings,” Journal of Cancer Research and Therapeutics, vol. 3, no. 1, pp. 56–66, 2007.View at: Google Scholar
G. Andocs and N. Meggyeshazi, Revealing the Mechanism of Action of Modulated Electrothermia Experimentally in Animal Model (HT29 Colorectal Xenograft Study), ESHO, Rotterdam, The Netherland, 2010.
N. Meggyeshazi, G. Andocs, and A. Szasz, Possible Immune-Reactions with Oncothermia, ESHO, Aarhus, Denmark, 2011.
H. Saupe, “Possible activation of neutrophiles by oncothermia,” in Proceedings of the 1st International Oncothermia Symposium, Cologne, Germany, November 2010.View at: Google Scholar
G. Andocs, N. Meggyeshazi, P. Galfi et al., “Experimental oncothermia in nude mice xenograft tumor models,” in Proceedings of the 1st International Symposium of Oncothermia, Cologne, Germany, November 2010.View at: Google Scholar
N. Meggyeshazi, T. Krenacs, and A. Szasz, “Clinical studies and evidences of modulated RF conductive heating (oncothermia) method,” in Proceedings of the 1st International Oncothermia Symposium, Cologne, Germany, November 2010.View at: Google Scholar
S. M. Yoon and J. S. Lee, “Case of abscopal effect with metastatic non-small-cell lung cancer,” Oncothermia Journal, vol. 5, pp. 53–57, 2012.View at: Google Scholar
A. Szasz, A. Dani, A. Varkonyi, and T. Magyar, “Retrospective analysis of 1180 oncological patients treated by electro-hyperthermia in Hungary,” in Jahreskongress der Deutschen Gesellschaft für Radioonkologie, DEGRO 11, Karlsruhe, Germany, May 2005.View at: Google Scholar
C. Wismeth, B. Hirschmann, C. Pascher et al., “Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsing high-grade gliomas—phase I clinical results,” in Proceedings of the Annual Meeting of Society of Thermal Medicine, Expanding the Frontiers of Thermal Biology, Medicine and Physics, Tucson, Ariz, USA, April 2009.View at: Google Scholar
A. Szasz, H. Sahibas, J. Baier, D. Grohemeyer, and E. Boecher, “Retrospective clinical study for advanced brain-gliomas by oncothermia treatment,” Perspectives in Central Nervous System Malignancies II 7-8, 2006, Budapest, Hungary, http://www.escc.com.eg/docs/Retrospective%20clinical%20study%20for%20advanced%20brain-gliomas%20by%20adjuvant.pdf.View at: Google Scholar
C. Pang, “Clinical research on integrative treatment of colon carcinoma with oncothermia and clifford TCM immune booster,” Oncothermia Journal, vol. 5, pp. 24–41, 2012.View at: Google Scholar