BY:

SAHEED OLUWASINA OSENI (DVM)

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

INTRODUCTION-Definitions

Hyperthermia (Oncothermia or thermaltherapy) is a type of medical treatment inwhich body tissues are exposed to slightlyhigher temperatures (39.0®C-45®C) to damageand kill cancer cells or to make cancer cellsmore sensitive to the effects of radiation andcertain anti-cancer drugs.

Thermoradiosensitization is the phenomenonby which heat is used to sensitize cancer cells toradiation therapy. This protocol is knownas ”Thermo-radiotherapy”.

Treatment MethodsHyperthermia therapy can be delivered; Local hyperthermia: Heat is applied externally

with high-frequency waves to a small area ordirectly to a tumor through the use of implantedmicrowave antenna, radiofrequency electrodes orprobes, and ultrasound. Mostly used for solidtumors.

Regional (Perfusion) hyperthermia: Heat isapplied to large tissue areas or body cavity wherethe entire area or region is targeted and treatedusing microwave or radiofrequency energy thatraises the temperature to the area.

Whole body hyperthermia: Done for patientswith metastatic cancer. Heat is given at 41.8 to42®C.

Radiofrequencies, Microwaves, Lasers, Nano magnetics, Ultrasounds and Scanning Ultrasound Reflector Linear Arrays System (SURLAS).

www.google.com/hyperthermia/images

Current Typerthermia Technologies

Perfusion Hyperthermia (+ Chemotherapy) -Heating the Blood

http://www.valleyhealthcancercenter.com/Cancer-Services/Surgical-Oncology/HIPEC-Hyperthermic-IntraPEritoneal-Chemotherapy

CLINICAL SIGNIFICANCE OF HYPERTHERMIA

CELLULAR CHANGES IN HYPERTHERMIA

S

Van der Zee J. (2002). Heating the Patient: a promising approach (Review). Annals of Oncology 13: 1173-1184.

James I. Bicher (2006) Thermoradiotherapy with curative intent. German Journal of Oncology, (Deutsche Zeitschrift für Onkologie). 38: 116-122.

Edward et al., 2010. Hyperthermia as treatment for bladder cancer

Hyperthermia-induced Cell death is Time and Temperature Dependent

Ref : Edward et al., 2010. Hyperthermia as treatment for bladder cancer

Cell cycle checkpoints

www.google.com/cell cycle/image

RT = M-> G2-> G1->S

HT = S-> M-> G2-> G1

Comparison of Cell cycle phase sensitivities to RT and HT

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 tohyperthermia;

Cells made acutely hypoxic and then treated with heat have asensitivity similar to aerated cells;

Cells subject to chronic hypoxia show a slightly enhanced sensitivityto heat. This may be a consequence of the lowered pH and thenutritional deficiency as a result of prolonged hypoxia.

- 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 thanradiation damage, because differentiated cells are killed as well asdividing cells.

- Increases perfusion, permeability,pO2 (oxygenation)

NB: Heat and X-rays appear to be complementary in their action.

BENEFITS Cont’d

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 deepwithin the body.

3. The question of a therapeutic gain factor is complicated in the caseof heat because the tumor and normal tissues are not necessarilyat the same temperature.

4. Thermotolerance

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 tokill cancer cells in a time- and temperature-dependent manner that wasmeasured by the clonogenic cell survival assay.

Hyperthermia’s ability to affect cells in S phase, inhibit sub-lethal damagerepair, and improve oxygenation make it an attractive therapy to combinewith 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.

Andocs G, Szasz O, Szasz A (2009). "Oncothermia treatment of cancer: from thelaboratory to clinic".ElectromagnBiol Med 28 (2): 148–65. PMID 19811397.

Bettaieb et al. (2013). Hyperthermia: Cancer treatment and Beyond.http://dx.doi.org/10.5772/55795.

Dan A. (2003). Clinical experience of electro-hyperthermia for advanced lungtumors, 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 andPractices.Springer.ISBN 978-90-481-9497-1. http://books.google.com/books?id=Ek-2nEe1HpwC.

Van der Zee J. (2002). Heating the Patient: a promising approach (Review). Annalsof Oncology 13: 1173-1184.

References

Thermal enhancement ratio

In the case of either normal tissues or transplantable tumors inexperimental animals, the extent of the interaction of heat andradiation 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 andwithout 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, includingskin, cartilage, and intestinal epithelium. The data form a consistentpattern of increasing TER with increasing temperature, up to a value ofabout 2 for 1-hour heat treatment at 43°.

Heat and the therapeutic gain factor

The therapeutic gain factor can be defined as the ratio of the TER inthe 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, ifthere is no therapeutic gain compared with the use of higher doses ofX-ray alone.

Generally speaking, there are good reasons to believe that the effects ofheat, alone or in combination with X-rays, may be greater on tumorsthan on normal tissues.

Heat and tumor vasculatureThe capacity of tumor blood flow to increase during heating appears tobe limited in comparison with normal tissues. A postulated mechanismfor the selective solid tumor heating is shown in Figure.

Thermal Dosimetry

Thermal dosimetry (thermometry) is critical to the optimizationof hyperthermia treatment as well as to the minimization ofpotential heat-related toxicity. Although delivery standardizationis difficult to implement because of varying target locations andclinical circumstances, Oleson and colleagues created the conceptof the “thermal isoeffect dose,” which is used to quantitate a giventhermal dose as “equivalent heating minutes” at 43°C.[35,36] Eachadditional 1°C doubles the equivalent number of minutes at 43°C.Each 1°C below 43°C effectively decreases the 43°C-equivalenttime-dose by a factor of 4.

- See more at: http://www.cancernetwork.com/bladder-cancer/hyperthermia-treatment-bladder-cancer/page/0/2#sthash.m620K89s.dpuf

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

Thermo-tolerance

The development of atransient and non-heritableresistance to subsequentheating by an initial heattreatment has been describedvariously as induced thermalresistance, thermal tolerance,or most commonly, thermo-tolerance

Thermal dose

Non-uniform temperature distribution in a tumor. It stems from twosources:

-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°Cto suffer the same biologic damage as produced by the actualtemperature, which may vary with time during a long exposure”

Thermal dose

Although the concept of thermal dose is attractive, there areproblems 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 theproblem of Thermotolerance.