1. Lecture 25
Hyperthermia

2. Delivery modalities
Cellular response to heat
Heat shock proteins
Thermo-tolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy

3. The use of hyperthermia as a medical treatment:
- First case describing a patient with a breast tumor treated with
hyperthermia is more than 5,000 years old;
- Heat was used in all cultures for almost any disease including
cancer;
- In 1866 a case was described where sarcoma disappeared after
prolonged infection with a high fever causing bacteria;
– marked regression of carcinomas of the uterine cervix
after local hyperthermia;
- Use of hyperthermia alone or in combination with radiation has
been attempted over the years

4. The interest in hyperthermia at the present time is based on documented clinical evidence of tumor regression as well as a biologic rationale and encouraging results from laboratory experiments

5. Delivery modalities
Cellular response to heat
Heat shock proteins
Thermo-tolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy

6. Methods of Heating shortwave diathermy radiofrequency-induced currents
microwaves
ultrasound

7. Methods of Heating Limitations Heating by hot water baths
- simple in a Petri dish;
- more problematic with transplanted tumor-
the temperature would nto be the same as the skin

8. Methods of Heating Limitations Heating by microwaves
- good localization at shallow depths;
- at greater tumor depths, even with lowered frequency, the
localization is much poorer and surface heating limits
therapy.

9. Methods of Heating Limitations Heating by ultrasound
- the presence of bone or air cavities causes distortions of the
heating pattern;
- good penetration and temperature can be achieved in soft
tissues, particularly with ultrasound in focused arrays.

10. Methods of Heating Limitations
One method that suffers from fewer problems is the use of implanted microwave or radiofrequency sources. Good temperature distributions can be achieved and maintained if radiofrequency-induced currents or microwaves are applied to an array of wires actually implanted in the tumor and surrounding tissues. The “wires” used are frequently radioactive sources, so that heat and radiation can be combined.

11. Delivery modalities
Cellular response to heat
Heat shock proteins
Thermo-tolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy

12. Cellular response to heat
Heat kills cells
in a predictable
and repeatable
way.

13. Cellular response to heat
Families of survival curves similar to this have been obtained for many different cell types, and it is clear that cells differ widely in their sensitivity to hyperthermia. Survival data for cells exposed to various levels of hyperthermia (taken from the figure) are re-plotted on the next slide

14. Cellular response to heat
Arrhenius plot

15. Cellular response to heat
Arrhenius plot
The Arrhenius plot for a given cell line can be modified by a number of things. For example, altering the pH of the cells raises the curves, and the break point occurs at a higher temperature.

16. Cellular response to heat
Cellular response to heat. Sensitivity to heat as a function of cell age in the mitotic cycle

17. Cellular response to heat
Effect of pH and nutrient deficiency on sensitivity to heat
Cells at acid pH appear to be more sensitive to killing by heat;
Cells deficient in nutrients are certainly heat sensitive;
Conclusion: cells in tumors that are nutritionally deprived and at acid pH because of their location remote from a blood capillary may be particularly sensitive to heat. In addition, these cells are out of cycle and possibly hypoxic too. This correlates with the observation that large necrotic tumors shrink darmatically after a heat treatment.
Heat and X-rays appear to be complementary in their action.

18. Hypoxia and hyperthermia
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.

19. Delivery modalities
Cellular response to heat
Heat shock proteins
Thermo-tolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy

20. Mechanisms of action of hyperthermia
Hyperthermia induces effects in both the nucleus and cytoplasm.
Heat killing appears to be associated with degradation or denaturation
of proteins. It is different from that for radiation killing, which
clearly involves primarily damage to DNA;
Although the intermediate steps may be different, the ultimate
cytotoxic effect of both heat and radiation is at the DNA level;
-In organized tissues heat damage occurs more rapidly than radiation
damage, because differentiated cells are killed as well as dividing cells;
-The events associated with heat radiosensitization involve DNA
damage and the inhibition of its repair. The role of heat is to block
the repair of radiation-induced lesions.

21. Heat-shock proteins
If cells are exposed to heat, proteins of a defined molecular
weight (mainly 70 or 90 kDa) are produced. The appearance
of these heat-shock proteins tends to coincide with the
development of thermotolerance and their disappearance
with the decay of thermotolerance.
Even though they have been given the name heat-shock proteins,
they are produced after treatment with other agents, including
arsenic and ethanol.
Heat-shock proteins are well conserved, they are found in cells
of many species.

22. Heat-shock proteins Heat-shock proteins are
identified by gel electrophoresis,
in which they show up as clearly
defined bands of specific MW.

25. Delivery modalities
Cellular response to heat
Heat shock proteins
Thermo-tolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy

26. 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

27. 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

28. 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”

29. Thermal dose
Although the concept of thermal dose is attractive, there are
problems in its implementation:
Nonuniformity of temperature occures 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.

30. Delivery modalities
Cellular response to heat
Heat shock proteins
Thermo-tolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy

31. 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.

32. Heat and tumor vasculature
Heat appears to preferentially damage the fragile vasculature of tumors; as a consequence, the heat-induced change in blood flow is different from that in normal tissues.

33. Heat and tumor vasculature The microcurculation
of tumors after hypothermia.
At the higher temperatures
compression, occlusion,
hemorrhage, and stasis thrombosis were observed.

34. Heat and tumor vasculature
There is a complex interplay in tumors between hyperthermia,
blood flow, and cell killing; this is illustrated in Figure.

35. Hyperthermia and tumor oxygenation
In transplanted tumors in rodents heat causes vascular damage; however, in spontaneous human tumors the vasculature is considerably more resistant to thermal damage.
It now is recognized that mild hyperthermia actually can promote tumor re-oxygenation, with the degree of re-oxygenation correlating with the level of cytotoxicity.

36. Delivery modalities
Cellular response to heat
Heat shock proteins
Thermo-tolerance
Response of tumors and normal tissues to heat
Combination with radiation therapy

37. The interaction between heat and radiation
Biologic effect of the combination of heat and radiation:
Additive cytotoxic effect.
Sensitization of the radiation cytotoxicity by heat.
Additive cytotoxic effect takes place in a practical situation in clinic-synergistic interaction of the two modalities.
There are differences between different heat treatments
acute hyperthermia (45°C)
more modest level of hyperthermia (40-43°C).

38. The interaction between heat and radiation
If heat and radiation are combined, an important consideration
is sequencing. Picture on this slide shows sequencing in vitro.

39. The interaction between heat and radiation
Comparable data for mouse skin are shown here.
There was a marked
variation in the normal
tissue response after a
given dose of X-rays,
depending on the time
interval, and the order in
which the two treatments
were given

40. 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.
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°.

41. 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.
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.
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.
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.

42. Heat and chemotherapeutic agents
The cell-killing potential of
some but not all
chemotherapeutic agents is
enhanced substantially by a
temperature elevation of
even a few degrees.

43. Heat and chemotherapeutic agents
Table below is a listing of drugs that are potentiated by heat and
those that are not.

44. Heat and chemotherapeutic agents There are several
different mechanisms
that may be involved,
some of which are
listed in the table
below.

45. Hyperthermia and implants
Good results have been claimed for the combination of hyperthermia and high dose rate implants. The success is a result of the favorable physical distribution of both heat and radiation that are possible with implants rather than of any particular biologic advantage

46. Heat plus radiation: current status of clinical studies
Hyperthermia has
been used extensively
as an adjuvant to
radiation in the
treatment of local
and regional
cancer

47. Current position on hyperthermia
The biologic properties of hyperthermia make it an attractive
modality for the treatment of cancer
It is still difficult to achieve uniform heating of a volume deep
within the body. The basic laws of physics make the desired
end difficult to achieve.
The clinical value of hyperthermia in the routine treatment of
cancer is still not clear, despite its proven efficiency in a few
specific instances. Hyperthermia is most effective in situations that
involve either combination with external-beam radiotherapy or
with brachytherapy.