HYPERTHERMIA

MODERATOR: Dr.RASHI AGRAWAL

PRESENTOR: Dr.SHREEBHA HARI

Hyperthermia
OElevation of
temperature to a
supraphysiological level,
between 40 to 45 C
HISTORY
HISTORY
Mid to Late 1970’s- Modern discipline of
Thermal therapy emerged
RESPONSE TO HEAT AT
CYTOTOXIC
TEMPERATURES
 Hypoxia and Hyperthermia
 Hypoxia protects cells from killing by
x-rays
 Hypoxic cells may be slightly more sensitive to
hyperthermia
 Effect of pH and Nutrient
Deficiency
 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
Response of Normal Tissues to
Heat
 After irradiation, cells die only in
attempting the next or a subsequent
mitosis ,whereas heated cells die by
apoptosis so that heat damage is
expressed early
 Heat affects differentiated as well
as dividing cells.ie. all cells are
affected
 The damage to the tissue is
expressed immediately
THERMOTOLERENCE
 Development of a transient and
nonhereditary resistance to
subsequent heating by an initial HT
 Begins a few hours after the first
treatment and takes up to a week to
decay
 Clonogenic assays reveal that although
one dose of heat kills a substantial
fraction of cells, subsequent daily
treatments are comparatively ineffective
 Thermotolerance is a serious
problem in the clinical use of
hyperthermia
 It imposes a limit of one or two
HTs per week
Heat and Tumor Vasculature
 Tumors have a less organized and
less efficient vasculature
 All functional capillaries in tumors are
open and used to capacity, even under
ordinary conditions
 Heat dissipation by blood flow is
slower in tumors than in normal tissues
 Temperature within a tumor is
higher than in the surrounding normal
tissues
 Dose Response
 When cells are heated in vitro to a
sufficient temperature and for a
long
enough duration, they die in a
predictable,
exponential manner
 Rate of killing increases with
temperature
 The cell survival curves for heat are
similar in shape to those obtained for
xrays
 Different cell lines differ in their
sensitivity to hyperthermia
 There is NO consistent difference between
normal and malignant cells heated in vitro
 ARRHENIUS PLOT
O Arrhenius plots have a biphasic curve
Slope changes at the BREAK POINT
(43 degrees for human cells)
O Above this temperature, an
increase of 1°C
doubles the rate of cell killing
Below the breakpoint, the rate of cell
killing by heat drops by a factor of 2 to 4
for each drop of 1° C
 WHY DOES BREAK POINT
OCCUR?
O Different mechanisms of cell killing
above
O and below BP
O Development of thermotolerance
within
O cells
 ARE PROTEINS THE TARGETS
FOR HEAT KILLING?

O Activation energy for protein denaturation

to the activation energy for heat
cytotoxicity are similar
O Heat of inactivation for cell killing and
thermal damage is similar to the energy
needed for protein denaturation (130–170
kcal/mol)
O Increased expression of Heat Shock
Proteins
METHODS OF HEATING AND THE IMPACT
ON CLINICAL
HYPERTHERMIA
 Methods of Heating in
Experimental Systems
O Most reliable way to heat to heat a
petri dish or a tumor transplanted
into the leg of a mouse is to-
immerse it totally in a
thermostatically controlled bath
of water
Methods of Heating in Patients
 Microwaves
O Good at shallow depths,
O ocalization is much
poorer at deeper depths
O Surface heating limits
therapy

O Recurrent chest wall

tumors can be treated
adequately with
microwaves
 Ultrasound

O Presence of bone or air cavities causes distortions

of the heating pattern

O Adequate penetration and reasonably good

temperature distributions can be achieved in soft
tissues-with ultrasound in focused arrays
Magnetic Hyperthermia
O Magnetic nanoparticles, when subjected
to an alternating magnetic field, generate
a great deal of heat
O patents with prostate cancer and glioma
multiforme- the iron nanoparticles were
injected directly into the tumors
O Variable temperatures between 40° and
48° C were reported in prostate patients
O This HT was combined with radiation
therapy
O When the nanoparticles
have accumulated in
the tumor, the
alternating magnetic
field is applied
O It may prove to be an
ideal way to treat
deep-seated tumors
that are difficult to heat
adequately with
conventional methods.
Thermal Ablation
 Thermal Ablation
O Thermal ablation refers to the destruction
of tissue by extreme hyperthermia
O (elevated tissue temperatures) and is a
minimally invasive treatment option for
O cancer. The temperature change is
concentrated to a focal zone in and
around the
O tumor. At 50° C, it takes a few minutes to
kill cells, at 60° C, it takes only
O seconds.
O Ablative heating is produced by
needle-type radiofrequency (RF) or
O microwave applicators, 1.5 mm in
diameter, which are inserted into the
tumor
O under computed tomography (CT) or
ultrasound imaging guidance.
O Most common anatomic site is the
liver, which may involve primary or
metastatic cancers
O Treatment of choice
O Osteoid osteomas, esp- in pediatric
patients
O Large proportion of primary kidney
tumors
O inoperable pulmonary nodules
THERMAL ENHANCEMENT
RATIO
O Ratio of doses of x-rays required to
produce a given level of biologic damage
without and with the application of heat
Typical TER values
O 1.4 at 41° C
O 2.7 at 42.5° C
O 4.3 at 43° C

Superficial human tumor

types – 1.5
THERAPEUTIC GAIN FACTOR
O Ratio of the TER in the tumor to the
TER in normal tissues
 MEASURING LOCAL
TEMPERATURE
INVASIVE METHODS
 Electrically conducting
 Minimally conducting
 Non conducting (optic)
NON-INVASIVE METHODS
O Infrared thermography
O Thermal monitoring sheet fiber optic
O arrays
O Electrical impedance tomography
O Microwave tomography
O Microwave radiometry
O Ultrasonic temperature estimation
techniques
O Magnetic resonance thermal imaging
(MRTI)
 PHASE III CLINICAL TRIALS
TESTING
BENEFIT OF HYPERTHERMIA
FOR ENHANCING RADIATION
THERAPY
O Dutch group
The complete response (CR) rate
following
RT +HT was 83% vs. 57% after RT
alone
O Three-year survival - 27% in the
RT-alone
group vs. 51% in the RT+HT group
(p=0.003)
Recurrent Chest Wall Breast
Cancer
O Five separate phase III trials have
been conducted, which were
eventually
combined as an international
collaborative
study
O Significant improvement in CR rate
was
seen for patients receiving HT+RT
compared with RT alone
Head and neck cancer
O Valdagni et al, showed patients in
O Stage III receiving RT+HT had a 58%
CR
compared with 20% in the RT group
Glioblastoma multiforme
O Sneed et al.
O Time to tumor progression
2-year survival were significantly
improved for patients who received
hyperthermia compared with those
treated with brachytherapy alone
(31% vs. 15%)
Superficial Malignancies
O Single institution prospective randomized
trial conducted by Jones et al
O The complete response rate in the
hyperthermia/ radiation group was 66%
versus 42% in the radiation-alone group
O Previously irradiated patients had the
greatest benefit, enjoying a 68.2%
response rate in the
hyperthermia/radiation groupversus
23.5% in the radiation alone group
 CHALLENGES IN
IMPLEMENATAION
O It is difficult to heat tumor tissue
volumes
with uniformity and precision
O There is no standardized equipment
to
effect loco regional HT
O Techniques for measuring
temperature
and the actual definition and
calculation
of thermal dose remain significant