Leveraging the Laws of Nature
Capacitive Coupled Loco-Regional Hyperthermia
The schematic illustrates the application of LRHT. A mobile electrode is positioned in accordance with the body area being treated, while a second stationary electrode remains in a fixed position below the patient, integrated within the therapy bed. The modulated radio frequency-RF field (represented by the red lines) emitted by the electrodes, passes through the patient's body. The RF field tends to move predominantly through the cellular pathways with the highest conductivity, i.e. through malignant tissue (tumour).
RF Field Focus
A cross sectional view (left) of the patient’s body showing the location of the targeted tumour treatment area.
Modulated Radio Frequency Energy (13.56 MHz RF) is directed to the area of the malignancy to affect energy transfer and induce heating.
Each small circle (right) represents an individual cell within the malignant tumour. The red lines depict the modulated electric RF transmission selectively focusing on the more conductive malignant environment.
Large circle (left) represents an individual malignant cell. Illustration shows the RF field concentrating along the cell membrane. Thermodynamic (heat) flow triggers biochemical processes in the cell membrane.
Thick white line (right) represents the malignant cell membrane. The electric field heating effect has created a temperature gradient between the extracellular and intracellular matrices (fluid). This effect changes the membrane's potential, thereby initiating reactions within those domains. These include heat flow across the membrane, an increased intracellular sodium concentration, an efflux of potassium, and water osmosis. The combined effect drives apoptosis.
Restored Inter-cellular Process
Thick vertical white lines represent the intra- and extra-cellular membrane barriers of adjacent cells. Red lines represent electric field density. The precisely modulated electric field, and the previously described change in membrane potential, cause dysfunctional E-cadherins & β-catenins (protein complexes integral to the immune system) within the cell membrane to reconnect. This restores critical inter-cellular connections that drive apoptosis and mitigate malignant cell proliferation.
Science Based Medicine
The Result…. Localized Heating and Tumor Cell Membrane Degradation
The Benefit…. Chemo & Radio-Sensitization, Immune Response and Apoptosis
Targeted RF therapy
Unique malignant cellular environment
Energy absorption & Heat
Loco-Regional Hyperthermia-LRHT (with the Oncotherm EHY-2000 Plus) is based on the classical method of Hyperthermia (high-heat) but does more than just randomly heat layers of tissue. LRHT employs a modulated electric field current to selectively deliver a controlled energy dose to a localized treatment area. A mobile electrode is positioned on the treatment area, while a second stationary electrode remains in a fixed position below the patient, integrated within the therapy bed. Operating at a carrier frequency of 13.56 MHz, this capacitive coupled impedance matching circuit delivers energy directly to the malignant cells.
Microbiological tests have demonstrated that higher ionic/electrolyte concentrations exist in the more metabolically active malignant cellular environment (Warberg Effect). Consequently, the extracellular matrix of malignant cells inherently has greater conductivity and permittivity than healthy cells. This difference facilitates selective radio-frequency-RF focusing on malignant cells even in highly mixed tissue containing large numbers of healthy and malignant cells. The derived advantage is the RF field current tends to flow predominantly through the tumour environment. The resulting concentration of focused RF field, and the subsequent extra-cellular absorption of imparted energy, selectively heats the malignant cells.
This process of natural selection is further enhanced by the electric-field modulation, which addresses the autonomous, non-collective behavior of individual malignant cells and reengages the body’s inherent immune response. Malignant tumour cells then die via a natural process known as “apoptosis”.
This effect of modulated electric field is prominent in LRHT therapy using modulated electro-hyperthermia. LRHT treatment using modulated electro-hyperthermia is thus based on two key effects: cellular-level selection and energy absorption induced heating.
HT & CT
HT & RT
Oncotherm kft. of Germany/Hungary designs and manufactures a range of loco-regional hyperthermia devices utilizing modulated electro-hyperthermia (mEHT). mEHT is the application of modulated, capacitive coupled, radio frequency, electro-hyperthermia in the treatment of solid tumours. The following references provide information on the development and implementation of the Oncotherm devices.
Please click the Oncotherm kft. logo (left) to visit their website.
References below are downloadable. Click on the red arrow.
2. Andocs G, et al. Oncothermia Treatment of Cancer: From the Laboratory to Clinic. Electromagnetic Biology and Medicine, Volume 28, Issue 2 June 2009, pages 148 - 165.
3. Hager E.D, et al. Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia. ASCO 2008.
4. Sahinbas H, et al. Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas. Deutsche Zeltschrift fur Oncologie 2007; 39: 154-160.
5. Gian Franco Baronzio, et al. Hyperthermia in Cancer Treatment: Chapter 3. Springer Science and Business Media Inc, New York, 2006.
6. McCaig C.D, et al. Controlling Cell Behavior Electrically: Current Views and Future Potential. Physiol Rev 85: 943–978, 2005; doi:10.1152/physrev. 00020.2004.
7. Szasz A, et al. Electro-hyperthermia: a new paradigm in cancer therapy. Deutsche Zeitschrift fur Oncologie, 2001; 33:91-99.
In oncology, the term ‘hyperthermia’ refers to the treatment of malignant diseases by administering heat in various ways. The results from experimental studies indicate that hyperthermia is both an effective complementary
treatment to, and a strong sensitizer of, radiotherapy and chemotherapy. The aim of loco-regional hyperthermia is to achieve the optimal thermal dose in the tumour tissue. This is generally defined as a modest elevation of
temperature to a range of 40° to 45°C. without exceeding the tolerance limits of the surrounding normal tissues.
Hyperthermia is a treatment modality now based on a considerable amount of good experimental data, and there is a clear rationale for using hyperthermia in cancer treatment. Hyperthermia is a promising approach and deserves consideration as part of standard treatment in tumour sites for which its efficacy has been demonstrated.
Supportive references cited below.
1. Benjamin Frey, et al. Old and new facts about hyperthermia-induced modulations of the immune system. Int. J. Hyperthermia, 2012, 1–15, Early Online.
2. Yue Zhang & Stuart K. Calderwood. Autophagy, protein aggregation and hyperthermia: A mini-review. Int. J. Hyperthermia, August 2011; 27(5): 409–414.
3. Gianfranco Baronzio, et al. Current Role and Future Perspectives of Hyperthermia for Prostate Cancer Treatment. in vivo 23: 143-146 (2009).
4. J. van der Zee, et al. The Kadota Fund International Forum 2004-Clinical Group Consensus. Int J Hyperthermia. 2008 March ; 24(2): 111–122.
5. Giammaria Fiorentini, et al. A Phase II Clinical Study on Relapsed Malignant Gliomas Treated with Electro-hyperthermia. in vivo 20: 721-724 (2006).
6. Seegenschmiedt, et al. A Historical Perspective on Hyperthermia. Lepock JR. Cellular effects of hyperthermia: relevance to the minimum dose for thermal damage. Int J Hyperthermia. 2003;19:252–266.
7. Hildebrandt B, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol. 2002 Jul;43(1):33‐56.
8. J. van der Zee. Heating the Patient: a promising approach? Annals of Oncology 13: 1173-1184, 2002.
9. Hager E.D, et al. Deep Hyperthermia with Radiofrequencies in Patients with Liver Metastases from Colorectal Cancer. Anticancer Research 19: 3403-3408 (1999).
10. Coss RA, Linnemans WA. The effects of hyperthermia on the cytoskeleton: a review. Int J Hyperthermia. 1996;12:173-196.
11. Vidair CA, Dewey WC. Division-‐associated and division-‐independent hyperthermic cell death: comparison with other cytotoxic agents. Int J Hyperthermia. 1991;7:51–60.
12. Streffer C. Metabolic changes during and after hyperthermia. Int J Hyperthermia. 1985;1:305–319.
13. John L.Meyer. The Clinical Efficacy of Localized Hyperthermia. [Cancer Research (Suppl.) 44, 4745s-4751s, October 1984].
14. Bleehen N.M, Hyperthermia in the Treatment of Cancer. Br. J. Cancer (1982) 45, Suppl. V, 96.
HT can make many chemotherapy and molecularly targeted agents more effective, mainly by accelerating their primary mode of action;
I. Improves the Alkylating action of this class of drugs
II. Induces protein damage & DNA strand breaks
III. Production of oxygen radicals
HT improves the vascular perfusion of tumours as well as the oxygenation of the tissue. Since the blood vessels grown in tumours are weak and disordered, HT causes the drugs to “leak” out into the tumour. This improves delivery of the drug into target tissue, and the improved oxygenation allows the drugs to work better.
Many CT agents have been shown to have improved effects when combined with HT, including; melphalan, cyclophosphamide, nitrogen mustards, anthracyclines, nitrosureas, bleomycin and mitomycin C.
Supportive references cited below.
1. Issels RD, et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70.
2. Jones EL, et al. A pilot Phase II trial of concurrent radiotherapy, chemotherapy, and hyperthermia for locally advanced cervical carcinoma. Cancer. 2003;98:277–282.
3. Issels RD, Abdel-Rahman S, Wendtner C, et al. Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft- tissue sarcomas (STS) of adults: long-term results of a phase II study. Eur J Cancer. 2001;37:1599–1608.
4. Rau B, et al. Phase II study on preoperative radio-chemo- thermotherapy in locally advanced rectal carcinoma. Strahlenther Onkol. 1998;174:556–565.
5. Sneed PK, Stauffer PR, McDermott MW, et al. Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/- hyperthermia for glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 1998;40:287–295.
6. Bornstein BA, et al. Pilot study of local hyperthermia, radiation therapy, etanidazole, and cisplatin for advanced superficial tumours. Int J Hyperthermia. 1995;11:489–499.
7. Vaden SL, et al. Effect of hyperthermia on cisplatin and carboplatin disposition in the isolated, perfused tumour and skin flap. Int J Hyperthermia. 1994;10:563–572.
8. Herman TS, et al. Effect of hypoxia and acidosis on the cytotoxicity of mitoxantrone, bisantrene and amsacrine and their platinum complexes at normal and hyperthermic temperatures. Anticancer Res. 1992;12:827–836.
9. Urano M, et al. The effect of 5-fluorouracil at elevated temperatures on a spontaneous mouse tumour: Arrhenius analysis and tumour response. Int J Radiat Biol. 1991;59:239–249.
10. Herman TS, et al. Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies. Int J Hyperthermia. 1988;4:143–158.
11. Dahl O. Interaction of heat and drugs in vitro and in vivo. In: Seegenschmiedt M, Fessenden P, Vernon C, eds. Thermoradiotherapy and Thermochemotherapy. Berlin: Springer Verlag; 1995:103–155.
12. Herman TS, et al. Effect of hypoxia and acidosis on the cytotoxicity of mitoxantrone, bisantrene and amsacrine and their platinum complexes at normal and hyperthermic temperatures. Anticancer Res. 1992;12:827–836.
13. Herman TS, Teicher BA, Jochelson M, Clark J, Svensson G, Coleman CN. Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human malignancies. Int J Hyperthermia. 1988;4:143–158.
There are a number of complimentary effects associated with the use of HT in conjuntion with RT. The following is supported in the cited references below;
1. Cancer cells in S-phase are relatively resistant to RT, but are also the most sensitive to HT. The combination therefore allows more cells, in various stages of their life cycles, to be killed.
2. Hypoxic cells are 3 times more resistant to RT than aerobic cells. This means that if cells are not receiving adequate oxygen through adequate circulation and other factors, they do not respond as well to RT. Conversely, there is no difference in the thermal sensitivity to HT between aerobic and hypoxic cells.
3. There is good evidence in human soft tissue sarcoma and locally advanced breast cancer, that HT causes the re-oxygenation of the target tissue, further improving RT response.
4. HT inhibits the repair of protein damage caused by itself, RT or CT, by inactivating crucial DNA repair pathways and mechanisms.
Supportive references cited below.
1. Van der Zee J, et al. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet. 2000;355:1119–1125.
2. Prosnitz LR, et al. The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys. 1999;45:941–949
3. Vernon CC, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys. 1996;35:731– 744.
4. Emami B, et al. Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group. Int J Radiat Oncol Biol Phys. 1996;34:1097–1104.
5. Overgaard J, et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European Society for Hyperthermic Oncology. Lancet. 1995;345:540–543.
6. Perez CA, et al. Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group. Am J Clin Oncol. 1991;14:133– 141.
7. Datta NR, et al. Head and neck cancers: results of thermoradiotherapy versus radiotherapy. Int J Hyperthermia. 1990;6:479–486.
8. Raaphorst GP, Ng CE, Yang DP. Thermal radiosensitization and repair inhibition in human melanoma cells: a comparison of survival and DNA double strand breaks. Int J Hyperthermia. 1999;15:17–27.
9. Overgaard J. The current and potential role of hyperthermia in radiotherapy. Int J Radiat Oncol Biol Phys. 1989;16:535–549.
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