Lecture 25

Lecture 25

Hyperthermia

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Lecture 25

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

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; 1898 – 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

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Lecture 25 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 Ahmed Group

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

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Methods of Heating

1) shortwave diathermy 2) radiofrequency-induced currents 3) microwaves 4) ultrasound Ahmed Group

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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

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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.

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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.

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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.

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Lecture 25

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

Lecture 25

Cellular response to heat

Heat kills cells in a predictable and repeatable way.

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Lecture 25

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

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Lecture 25

Cellular response to heat

Arrhenius plot Ahmed Group

Lecture 25

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 temperature.

higher Ahmed Group

Lecture 25 Cellular response to heat. Sensitivity to heat as a function of cell age in the mitotic cycle Ahmed Group

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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.

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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.

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Lecture 25

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

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.

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Lecture 25

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.

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Lecture 25

Heat-shock proteins

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

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Lecture 25 Ahmed Group

Lecture 25

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

Lecture 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

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Lecture 25

Thermotolerance

Thermotolerance serious problem clinical use of hyperthermia. Figure on the left illustrates is in why a the by and contrasting radiation: heat -top graph-X-ray, -bottom graph hyperthermia

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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” Ahmed Group

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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.

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Lecture 25

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

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.

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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.

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Lecture 25

Heat and tumor vasculature

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

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Lecture 25

Heat and tumor vasculature

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

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Lecture 25

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.

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Lecture 25

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

The interaction between heat and radiation

Biologic effect of the combination of heat and radiation: 1. Additive cytotoxic effect. 2. 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).

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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

.

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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

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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°.

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Lecture 25

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.

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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.

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Heat and chemotherapeutic agents

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

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Heat and chemotherapeutic agents

There are several different mechanisms that may be involved, some of which are listed in the table below.

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Lecture 25

Hyperthermia and implants

Good results have been claimed for the combination hyperthermia of and high implants.

dose rate The success is a result of the favorable physical distribution of both heat and radiation possible that are with implants rather than of any particular biologic advantage

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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

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Current position on hyperthermia

1. The biologic properties of hyperthermia make it an attractive modality for the treatment of cancer 2. 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.

3. 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.

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