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

1. BY:
SAHEED OLUWASINA OSENI (DVM)

3. 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

4. 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”.

5. 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.

6. Radiofrequencies, Microwaves, Lasers, Nano magnetics, Ultrasounds and
Scanning Ultrasound Reflector Linear Arrays System (SURLAS).
www.google.com/hyperthermia/images
Current Typerthermia Technologies

7. Perfusion Hyperthermia (+ Chemotherapy) -Heating the Blood
http://www.valleyhealthcancercenter.com/Cancer-Services/Surgical-Oncology/HIPEC-Hyperthermic-IntraPEritoneal-Chemotherapy

8. CLINICAL SIGNIFICANCE OF HYPERTHERMIA

9. CELLULAR CHANGES IN HYPERTHERMIA
S

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

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

13. Edward et al., 2010. Hyperthermia as treatment for bladder cancer
Hyperthermia-induced Cell death is Time and Temperature Dependent

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

15. Cell cycle checkpoints
www.google.com/cell cycle/image
RT = M-> G2-> G1->S
HT = S-> M-> G2-> G1

16. Comparison of Cell cycle phase sensitivities to RT and HT

17. 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.

18. - 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

19. 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

20.  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.

21.  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.
http://dx.doi.org/10.5772/55795.
 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. http://books.google.com/books?id=Ek-
2nEe1HpwC.
 Van der Zee J. (2002). Heating the Patient: a promising approach (Review). Annals
of Oncology 13: 1173-1184.
References

25. 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°.

26. 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.

27. 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.

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

29. 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

30. 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

31. 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”

32. 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.