This document discusses hyperthermia in radiotherapy. It provides an overview of the history and biology of hyperthermia, including direct and indirect effects on cells. Temperatures between 41-44°C are used, depending on the region. Hyperthermia enhances radiation therapy by sensitizing cells to radiation, improving oxygenation, and inhibiting DNA repair. Phase III clinical trials have demonstrated improved outcomes when hyperthermia is combined with radiation therapy for various cancers. Challenges include achieving uniform heating and standardizing equipment and dosimetry.
2. INTRODUCTION
Elevation of temperature to a
supraphysiologic level
USA & Europe- 41.8–42 °C (107.2–107.6 °F)
Japan & Russia- 43–44 °C (109–111 °F)
Maintain the temperature about 1 hour
7. 400 – 300 B.C
"What medicines do not heal, the lance will;
what the lance does not heal, fire will"
8. 100 A.D – 140 A.D
"If indeed any were so
good a physician as to be
able to produce fever, it
would not be necessary to
look for any other remedy
in sickness."
10. 1600’S
“Fever is a mighty
engine, which nature
brings into the world
for the conquest of her
enemies”
11. THE MODERN ERA
Inhibition of tumor growth by high fever
caused by malaria - de Kizowitz (France) in
1779
12. Complete remission of histologically
confirmed face sarcoma after two erysipelas
infections with subsequent 2-year disease-
free survival - Busch (Germany) in 1866
13. George W. Crile Jr.
Long-lasting increase of the temperature of
some tumors to 42 – 50°C could selectively
destroy them without damaging the healthy
tissues.
17. DIRECT EFFECTS
When cells are heated in vitro to a
sufficient temperature and for a long
enough duration, they die in a predictable,
exponential manner, and the rate of killing
increases with temperature
The cell survival curves for heat are
similar in shape to those obtained for x-
rays
18. Different cell lines differ in their
sensitivity to hyperthermia
There is NO consistent difference between
normal and malignant cells heated in
vitro.
22. Temperature dependence of the rate of
cell killing by heat
Plots the log of the slope (1/Do) of cell
survival curves as a function of
temperature
Slope gives the activation energy of the
chemical process involved in the cell
killing
Arrhenius plots have a biphasic curve
Slope changes at the BREAK POINT(43
degrees for human cells)
23. 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
24. WHY DOES BREAK POINT
OCCUR?
Different mechanisms of cell killing above
and below BP
Development of thermotolerance within
cells
25. ARE PROTEINS THE TARGETS
FOR HEAT KILLING?
Activation energy for protein denaturation
to the activation energy for heat
cytotoxicity are similar
Heat of inactivation for cell killing and
thermal damage is similar to the energy
needed for protein denaturation (130–170
kcal/mol)
Increased expression of Heat Shock
Proteins
26. INDIRECT EFFECTS
Changes in the tumor microenvironment
42 to 44° C
Damage to tumor vascular endothelium
Decreased pO2,pH and nutrient status
Increased heat sensitivity but decreased
radiosensitivity
27. 41 to 41.5° C
Damage to respiratory enzymes
Shift to anaerobic pathways
Increased oxygen tension in the tissues &
increased radiosensitivity
(Brezel et al., Jones et al)
29. EFFECT ON PERFUSION
Increased tissue perfusion (41 – 41.5°C)
Changes in vascular permeability
Vascular stasis and hemorrhage (42 - 44°C)
The increase in liposomal extravasation can
be exploited as a drug delivery vehicle
35. Enhanced immunogenicity and HSP
expression seen after tumor cells heating
Thermally enhanced immune effector cell
activation and function
Thermally enhanced vascular perfusion
and delivery or trafficking of immune
effector cells to tumors
39. THERMAL CONDUCTION
Circulating hot water in a needle, a
catheter, surface pad
Limited penetration of heat
Restricted to interstitial applications with
closely spaced implant arrays
40. ELECTROMAGNETIC HEATING
Heating from resistive losses as a result of
electric current in a resistive media (tissue)
At higher microwave frequencies, heat is
generated from mechanical interactions
between adjacent polar water molecules
aligning to the alternating EM field
Superficial applicators – penetration 1 – 4 cm
Deep HT devices – penetration more than 4
cm
41.
42. ULTRASOUND HEATING
Energy transfer results from the
mechanical losses of viscous friction
Wavelength of US is orders of magnitude
smaller than that of an EM field of similar
penetration capabilities
So, US energy can be focused into small
tissue volumes
43.
44. DOSIMETRY
Sapareto and Dewey - “cumulative
equivalent minutes” (CEM) at 43° C
Break point is set at 43° C
Above the break point,
t1/t2 = 2T1-T2
Below the break point,
t1/t2 = (4 to 6)T1-T2
CEM 43°C = tR(43-T)
R above BP – 0.5
below BP – 0.25
45. For a complex time–temperature history,
the heating profile is broken into short
intervals of time “t” length (typically 1 to 2
minutes), where the temperature remains
relatively constant
CEM 43° C = 𝒕R(43-avgT)
48. RATIONALE IN RT
Sensitizes the cells in S phase to RT
No difference in sensitivity to aerobic and
anaerobic cells
HT can lead to reoxygenation, which will
improve RT response
HT inhibits the repair of both sub lethal
and potentially lethal damage via its
effects in inactivating crucial DNA repair
pathways
49. 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
50. IS IT A PROBLEM???
NObecause
Radio sensitization by blood flow &
oxygenation inhibition of thermal
killing by thermotolerance
Heat-induced radio sensitization is not
subject to thermotolerance
51. THERMAL ENHANCEMENT
RATIO
Ratio of doses of x-rays required to
produce a given level of biologic damage
without and with the application of heat
RT/RT+HT
Data shows consistent pattern of
increasing TER with increasing
temperature, up to a value of 2 for a 1-
hour heat treatment (HT) at 43° C
52. Typical TER values
1.4 at 41° C
2.7 at 42.5° C
4.3 at 43° C
Canine oral squamous cell carcinomas –
1.15
Superficial human tumor types – 1.5
54. PHASE III CLINICAL TRIALS
TESTING
BENEFIT OF HYPERTHERMIA
FOR ENHANCING RADIATION
THERAPY
55. Carcinoma Cervix
Dutch group
The complete response (CR) rate following
RT +HT was 83% vs. 57% after RT alone
Three-year survival - 27% in the RT-alone
group vs. 51% in the RT+HT group
(p=0.003)
Recent long-term following continues to
demonstrate significant survival benefit in
the patients who received hyperthermia
56. Recurrent Chest Wall Breast
Cancer
Five separate phase III trials have been
conducted, which were eventually
combined as an international collaborative
study
Significant improvement in CR rate was
seen for patients receiving HT+RT
compared with RT alone (67% vs. 31%)
57. Superficial Malignancies
Single institution prospective randomized
trial conducted by Jones et al.
The complete response rate in the
hyperthermia/ radiation group was 66%
versus 42% in the radiation-alone group
Previously irradiated patients had the
greatest benefit, enjoying a 68.2% response
rate in the hyperthermia/radiation group
versus 23.5% in the radiation alone group
58. Head and neck cancer
Valdagni et al., showed patients in stage
III receiving RT+HT had a 58% CR
compared with 20% in the RT group
Patients with stage IV disease achieved a
CR of 38% compared with 7% for those
receiving RT alone
59. Glioblastoma multiforme
Sneed et al. – time to tumor progression
and 2-year survival were significantly
improved for patients who received
hyperthermia compared with those
treated with brachytherapy alone (31% vs.
15%)
60. ADVERSE EFFECTS
External application of heat may cause
surface burns
Whole body hyperthermia can cause
swelling, blood clots, and bleeding
Systemic shock
61. CHALLENGES IN
IMPLEMENATAION
It is difficult to heat tumor tissue volumes
with uniformity and precision
There is no standardized equipment to
effect loco regional HT
Techniques for measuring temperature
and the actual definition and calculation
of thermal dose remain significant
problems