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Thermo-sensitization of tumor to radiation therapy through a process now as Radio-thermotherapy (hyperthermia and radiation therapy) to treat cancer cells.

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  2. 2. PRESENTATION OUTLINE  Introduction  Definition of Terms  Methods and Types of hyperthermia therapy  Mechanism of Action-Cellular changes during hyperthermia  Clinical Studies and Results  Discussion of Findings  Benefits of combination therapy  Limitations of clinical use of hyperthermia  Conclusion  References
  3. 3. INTRODUCTION-Definitions  Hyperthermia (Oncothermia or thermal therapy) is a type of medical treatment in which body tissues are exposed to slightly higher temperatures (39.0®C-45®C) to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anti-cancer drugs.  Thermoradiosensitization is the phenomenon by which heat is used to sensitize cancer cells to radiation therapy. This protocol is known as ”Thermo-radiotherapy”.
  4. 4. Treatment Methods Hyperthermia therapy can be delivered;  Local hyperthermia: Heat is applied externally with high-frequency waves to a small area or directly to a tumor through the use of implanted microwave antenna, radiofrequency electrodes or probes, and ultrasound. Mostly used for solid tumors.  Regional (Perfusion) hyperthermia: Heat is applied to large tissue areas or body cavity where the entire area or region is targeted and treated using microwave or radiofrequency energy that raises the temperature to the area.  Whole body hyperthermia: Done for patients with metastatic cancer. Heat is given at 41.8 to 42®C.
  5. 5. Radiofrequencies, Microwaves, Lasers, Nano magnetics, Ultrasounds and Scanning Ultrasound Reflector Linear Arrays System (SURLAS). Current Typerthermia Technologies
  6. 6. Perfusion Hyperthermia (+ Chemotherapy) -Heating the Blood
  9. 9. Van der Zee J. (2002). Heating the Patient: a promising approach (Review). Annals of Oncology 13: 1173-1184.
  10. 10. James I. Bicher (2006) Thermoradiotherapy with curative intent. German Journal of Oncology, (Deutsche Zeitschrift für Onkologie). 38: 116-122.
  11. 11. Edward et al., 2010. Hyperthermia as treatment for bladder cancer Hyperthermia-induced Cell death is Time and Temperature Dependent
  12. 12. Ref : Edward et al., 2010. Hyperthermia as treatment for bladder cancer
  13. 13. Cell cycle checkpoints cycle/image RT = M-> G2-> G1->S HT = S-> M-> G2-> G1
  14. 14. Comparison of Cell cycle phase sensitivities to RT and HT
  15. 15. BENEFITS  The response of hypoxic cells constitutes a vital difference between X- rays and hyperthermia. Hypoxia protects cells from killing by X-rays.  By contrast, hypoxic cells are not more resistant than aerobic cells to hyperthermia;  Cells made acutely hypoxic and then treated with heat have a sensitivity similar to aerated cells;  Cells subject to chronic hypoxia show a slightly enhanced sensitivity to heat. This may be a consequence of the lowered pH and the nutritional deficiency as a result of prolonged hypoxia.
  16. 16. - Cells at acid (low) pH appear to be more sensitive to killing by heat; - Cells deficient in nutrients are certainly heat sensitive. - The role of heat is to block the repair of radiation-induced lesions. - In organized tissues heat cell damage occurs more rapidly than radiation damage, because differentiated cells are killed as well as dividing cells. - Increases perfusion, permeability,pO2 (oxygenation) NB: Heat and X-rays appear to be complementary in their action. BENEFITS Cont’d
  17. 17. Limitations and Current position on hyperthermia 1. Limited availability of equipment for regulated heating of tumor. 2. It is still difficult to achieve uniform heating of a volume deep within the body. 3. The question of a therapeutic gain factor is complicated in the case of heat because the tumor and normal tissues are not necessarily at the same temperature. 4. Thermotolerance
  18. 18.  Temperatures in the range of moderate hyperthermia can be non-lethal (39 to 42°C) or lethal (>42°C). Temperatures above 42°C were shown to kill cancer cells in a time- and temperature-dependent manner that was measured by the clonogenic cell survival assay.  Hyperthermia’s ability to affect cells in S phase, inhibit sub-lethal damage repair, and improve oxygenation make it an attractive therapy to combine with radiation and/or chemotherapy in the hopes of synergy. CONCLUSION  Biologic effect of the combination of heat and radiation: 1. Additive cytotoxic effect. 2. Sensitization of the radiation cytotoxicity by heat.
  19. 19.  Andocs G, Szasz O, Szasz A (2009). "Oncothermia treatment of cancer: from the laboratory to clinic".ElectromagnBiol Med 28 (2): 148–65. PMID 19811397.  Bettaieb et al. (2013). Hyperthermia: Cancer treatment and Beyond.  Dan A. (2003). Clinical experience of electro-hyperthermia for advanced lung tumors, ESHO Conference, Munich.  Edward et al. (2010) hyperthermia as treatment of bladder cancer.  James I. Bicher (2006) Thermoradiotherapy with curative intent. German Journal of Oncology, (Deutsche Zeitschrift für Onkologie). 38: 116-122.  Szasz, Andras; Szasz, Nora; Szasz, Oliver (2011). Oncothermia: Principles and Practices.Springer.ISBN 978-90-481-9497-1. 2nEe1HpwC.  Van der Zee J. (2002). Heating the Patient: a promising approach (Review). Annals of Oncology 13: 1173-1184. References
  20. 20. Thermal enhancement ratio In the case of either normal tissues or transplantable tumors in experimental animals, the extent of the interaction of heat and radiation is expressed in terms of the: Thermal enhancement ratio (TER), defined as the ratio of doses of X- rays required to produce a given level of biological damage with and without the application of heat. TER = Radiation dose for a specified effect Radiation dose with heat for a specific effect The TER has been measured for a variety of normal tissues, including skin, cartilage, and intestinal epithelium. The data form a consistent pattern of increasing TER with increasing temperature, up to a value of about 2 for 1-hour heat treatment at 43°.
  21. 21. Heat and the therapeutic gain factor  The therapeutic gain factor can be defined as the ratio of the TER in the tumor to the TER in the normal tissues. TGF= TER for tumor TER for normal tissue NB: There is no advantage to using heat plus lower doses of X-rays, if there is no therapeutic gain compared with the use of higher doses of X-ray alone. Generally speaking, there are good reasons to believe that the effects of heat, alone or in combination with X-rays, may be greater on tumors than on normal tissues.
  22. 22. Heat and tumor vasculature The capacity of tumor blood flow to increase during heating appears to be limited in comparison with normal tissues. A postulated mechanism for the selective solid tumor heating is shown in Figure.
  23. 23. Thermal Dosimetry Thermal dosimetry (thermometry) is critical to the optimization of hyperthermia treatment as well as to the minimization of potential heat-related toxicity. Although delivery standardization is difficult to implement because of varying target locations and clinical circumstances, Oleson and colleagues created the concept of the “thermal isoeffect dose,” which is used to quantitate a given thermal dose as “equivalent heating minutes” at 43°C.[35,36] Each additional 1°C doubles the equivalent number of minutes at 43°C. Each 1°C below 43°C effectively decreases the 43°C-equivalent time-dose by a factor of 4. - See more at: cancer/hyperthermia-treatment-bladder- cancer/page/0/2#sthash.m620K89s.dpuf
  24. 24. Thermotolerance Thermotolerance is a serious problem in the clinical use of hyperthermia. Figure on the left illustrates why by contrasting heat and radiation: -top graph-X-ray, -bottom graph- hyperthermia
  25. 25. Thermo-tolerance The development of a transient and non-heritable resistance to subsequent heating by an initial heat treatment has been described variously as induced thermal resistance, thermal tolerance, or most commonly, thermo- tolerance
  26. 26. Thermal dose Non-uniform temperature distribution in a tumor. It stems from two sources: -power deposition, and -tumor blood perfusion, which carries the heat away. The formal definition of thermal dose: “the time in minutes for which the tissue would have to be held at 43°C to suffer the same biologic damage as produced by the actual temperature, which may vary with time during a long exposure”
  27. 27. Thermal dose Although the concept of thermal dose is attractive, there are problems in its implementation: - Non-uniformity of temperature occurs throughout the tumor. - The concept relates only to cell killing by heat and does not include radiosensitization - It relates to one heat treatment, so it is not possible to add one treatment to the next given a few days later, because of the problem of Thermotolerance.