Lecture 25
Hyperthermia
Lecture 25
Ahmed Group
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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:
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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
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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
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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
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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.
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
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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 pH 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 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.
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 pH
and the nutritional deficiency as a result of prolonged hypoxia.
Lecture 25
Ahmed Group
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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 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.
Lecture 25
Ahmed Group
Heat-shock proteins
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
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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
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:
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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
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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 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.
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