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.

1. HYPERTHERMIA IN
RADIOTHERAPY
DR.JEWELL JOSEPH

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

3. OVERVIEW
HISTORY OF MEDICAL HT
BIOLOGY OF HT
PHYSIOLOGICAL EFFECTS
PHYSICS
APPLICATIONS IN RADIOTHERAPY

5. 700 - 600 BC
Western Zhou Dynasty – China

6. 500 – 400 B.C
GREEKS
EGYPTIANS

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."

9. 1400 – 1500 A.D
NATIVE AMERICANS

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.

14. James Fulton Percy
3–7-year survival of
inoperable cancer of the
uterus after local
hyperthermia above 45°C

15. The first International
Symposium on Cancer Therapy by
Hyperthermia and Radiation
Washington D.C in 1975

16. BIOLOGY OF HT
DIRECT EFFECTS INDIRECT EFFECTS

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.

21. Thermal Isoeffect Dose:
The Arrhenius Relationship

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)

28. PHYSIOLOGIC EFFECTS

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

30. EFFECT ON OXYGENATION

31. EFFECT OF pH

32. Tumor cells
Decrease in extracellular pH
Cannot increase proton pumping
Increase in intracellular pH

33. APPLICATIONS
Reduction in pH by hyperglycemia,
glucose + metaiodobenzylguanidine
Vasoactive agents to reduce the blood
flow

34. IMMUNOLOGIC EFFECTS

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

36. HYPERTHERMIA PHYSICS

37. CHALLENGES IN DELIVERING
HT
Anatomical variations
Varying tissue interfaces
Blood perfusion

38. MODALITIES
Thermal conduction
Nonionizing electromagnetic radiation
Ultrasound

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

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

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)

46. MEASURING LOCAL
TEMPERATURE
INVASIVE METHODS
Electrically conducting
Minimally conducting
Non conducting (optic)

47. NON-INVASIVE METHODS
Infrared thermography
Thermal monitoring sheet fiber optic
arrays
Electrical impedance tomography
Microwave tomography
Microwave radiometry
Ultrasonic temperature estimation
techniques
Magnetic resonance thermal imaging
(MRTI)

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

53. THERAPEUTIC GAIN FACTOR
Ratio of the TER in the tumor to the TER
in normal tissues

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