Lecture 25 Hyperthermia Lecture 25 Ahmed Group Lecture

Lecture 25 Hyperthermia Lecture 25 Ahmed Group

• • • Lecture 25 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: - Lecture 25 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 Ahmed Group

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 Lecture 25 Ahmed Group

• • • Lecture 25 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

Methods of Heating 1) 2) 3) 4) Lecture 25 shortwave diathermy radiofrequency-induced currents microwaves ultrasound Ahmed Group

Methods of Heating Limitations Heating by hot water baths - simple in a Petri dish; - more problematic with transplanted tumorthe temperature would nto be the same as the skin Lecture 25 Ahmed Group

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. Lecture 25 Ahmed Group

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. Lecture 25 Ahmed Group

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. Lecture 25 Ahmed Group

• • • Lecture 25 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

Cellular response to heat Heat kills cells in a predictable and repeatable way. Lecture 25 Ahmed Group

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 Lecture 25 Ahmed Group

Cellular response to heat Arrhenius plot Lecture 25 Ahmed Group

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 p. H of the cells raises the curves, and the break point occurs at a higher temperature. Lecture 25 Ahmed Group

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

Cellular response to heat Effect of p. H and nutrient deficiency on sensitivity to heat - Cells at acid p. H 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 p. H 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. Lecture 25 Ahmed Group

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 p. H and the nutritional deficiency as a result of prolonged hypoxia. Lecture 25 Ahmed Group

• • • Lecture 25 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. Lecture 25 Ahmed Group

Heat-shock proteins If cells are exposed to heat, proteins of a defined molecular weight (mainly 70 or 90 k. Da) 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. Lecture 25 Ahmed Group

Heat-shock proteins are identified by gel electrophoresis, in which they show up as clearly defined bands of specific MW. Lecture 25 Ahmed Group

Lecture 25 Ahmed Group

Lecture 25 Ahmed Group

• • • Lecture 25 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

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 Lecture 25 Ahmed Group

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 graphhyperthermia Lecture 25 Ahmed Group

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” Lecture 25 Ahmed Group

Thermal dose Although the concept of thermal dose is attractive, there are problems in its implementation: - Lecture 25 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. Ahmed Group

• • • Lecture 25 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. Lecture 25 Ahmed Group

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. Lecture 25 Ahmed Group

Heat and tumor vasculature The microcurculation of tumors after hypothermia. At the higher temperatures compression, occlusion, hemorrhage, and stasis thrombosis were observed. Lecture 25 Ahmed Group

Heat and tumor vasculature There is a complex interplay in tumors between hyperthermia, blood flow, and cell killing; this is illustrated in Figure. Lecture 25 Ahmed Group

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 reoxygenation correlating with the level of cytotoxicity. Lecture 25 Ahmed Group

• • • Lecture 25 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). Lecture 25 Ahmed Group

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. Lecture 25 Ahmed Group

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 Lecture 25 Ahmed Group

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°. Lecture 25 Ahmed Group

Heat and 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. Lecture 25 Ahmed Group

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. Lecture 25 Ahmed Group

Heat and chemotherapeutic agents Table below is a listing of drugs that are potentiated by heat and those that are not. Lecture 25 Ahmed Group

Heat and chemotherapeutic agents There are several different mechanisms that may be involved, some of which are listed in the table below. Lecture 25 Ahmed Group

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 Lecture 25 Ahmed Group

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 Lecture 25 Ahmed Group

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. Lecture 25 Ahmed Group