Hyperthermia involves raising the temperature of tumor tissue to enhance the effects of radiation therapy; it can directly kill cancer cells and sensitize them to radiation, helping to overcome resistance from hypoxia and cell cycle factors. Combining hyperthermia with radiation therapy provides a thermal enhancement effect and improves clinical outcomes over radiation alone for some cancers like cervical cancer. A variety of heating methods exist to deliver hyperthermia including electromagnetic, ultrasound, and thermal conduction approaches.

1. HYPERTHERMIA IN RADIOTHERAPY
PRESENTER : DR.MOUMITA PAUL
1st Year PGT
MODERATOR : DR.RUBU SUNKU
ASSISTANT PROFESSOR
DEPT. OF RADIATION ONCOLOGY
BBCI

2. DEFINITION
Elevation of temperature to a supra-
physiologic level in the range of 39⁰C to 45⁰C.

3. HISTORY
• Ancient references to the specific use of hyperthermia (or
induced elevation of temperature above normal either
locally, in part of the body, or of the whole individual) are
found within the medical history of cultures from around
the world.
• Since the 17th century there have been numerous reports
of tumour regressions in patients suffering from infectious
fever.
• In 1866, W.Busch, described that sarcoma of face
disappeared with prolonged infection with Erysipelas.
• Westermark in 1898 deliberately used hyprthermia to
treat cancer when he used water-circulating cisterns to
treat inoperable carcinomas of the uterus with
temperatures of 42-44⁰C.

4. Rationale
Hyperthermia causes direct cytotoxicity and
also acts as a radio-sensitizer.
Mechanism of action is complementary to the
effects of RT.
Hyperthermia has effects on blood flow and
tumor physiology.

5. Effects of Hyperthermia on Cell Survival
• Cause direct cytotoxicity
• Kills cells in an exponential manner and the rate
of killing increase with temperature when
heated to a sufficient temperature and for long
enough duration.
• Initial shoulder region present.
• At lower temperatures, resistant tail at the end
of heating period due to thermotolerence.

6. Cellular response to heat

7. The Arrhenius Relationship
• Defines temperature
dependence on rate of
cell killing by heat.
• The log slope of the HT
survival curve (1/D₀) is
plotted as a function of
reciprocal of the
absolute
temperature(T).
• Biphasic curve
• It’s slope gives the
activation energy of the
chemical process
involved in cell killing.
• Breakpoint : For human
cells ,about 43⁰C.

8. The Arrhenius Relationship
• Significance :
 Above breakpoint : Temperature change of 1⁰C
doubles the rate of cell killing.
 Below breakpoint : For every drop in temperature of
1⁰C , the rate of cell killing drops by a factor of 2 to 4.
• Basis for thermal dosimetry in clinical HT
applications( as the slopes of Arrhenius plots derived
from many in vitro and in vivo studies are nearly
identical which provided long standing usefulness of
this analysis).

9. The Arrhenius Relationship
• This analysis led to the hypothesis that target for cell
killing is cellular proteins.
• Heat of inactivation for cell killing and thermal
damage is similar to protein denaturation (130-170
kcal/mol).

10. Mechanisms of Hyperthermic
Cytotoxicity
1) Cellular and tissue response
• Primary target : Proteins (Cell membrane,
cytoskeleton, nucleolus)
• Cell killing by protein denaturation : heat of
inactivation 130-170 kcal/mol
• Ultimate cell death : by apoptosis or necrosis.

11. • Predominant target molecule is protein.
• The cytoskeleton of cells is heat sensitive.
• Enzymes in the respiratory chain are more heat sensitive than
enzymes in the glycolytic pathway.
• The heat sensitivity of centriole leads to chromosomal
aberrations.
• Many DNA repair proteins are heat sensitive.
• In an organized tissues heat damage occurs more rapidly than
radiation damage, because both differentiated and dividing
cells are killed.
• Heat radio-sensitization is due to DNA damage and inhibition
of its repair.
• The role of heat is to block the repair of radiation-induced
lesions.

12. Effects of Hyperthermia

13. Mechanisms of Hyperthermic
Cytotoxicity
2) Physiological response

15. Thermal Enhancement Ratio(TER)
• TER is defined as the ratio of the doses of X-rays required
to produce a given level of biological damage with
radiation dose alone to that for combination of radiation
and heat.
TER = ratio of doses with RT alone / RT+HT to
achieve issoeffect
• TER increases with increasing temperature , upto a value
of about 2 for a 1-hour heat treatment at 43⁰C.
• Typical TER values : 1.4 at 41⁰C, 2.7 at 42.5⁰C and 4.3 at
43⁰C.
• In canine oral squamous cell carcinomas,it was estimated
to be approximately 1.15 , when HT was administered
twice a week during a course of fractionated RT.

16. Thermotolerance
• Also known as thermal resistance, is the transient
adapatation to thermal stress that renders surviving
heated cells more resistant to additional stress.
• May take few hours to a week to decay.
• Mechanisms: Repair of protein damage via heat shock
proteins(HSP) 70-90 kd(HSP has been proposed to be the
mediators of thermotolerance in humans).
• 2 ways of thermotolerance development : At low
temp.39-42⁰C – during heating period after an exposure
of 2-3 hrs and above 43⁰C—after heating stopped.
• 1st heat dose kills a substantial fraction of cells but daily
treatment becomes less effective because of
thermotolerance.

18. Thermotolerance
Modifiers of the thermotolerance response :
• Thermal exposure above 43⁰C : Thermotolerance during the
heating period is prevented.
• Step down heating :
-- It is an initial short heat shock above 43⁰C, followed by a drop in
temperature below this threshold, delays Thermotolerance.
-- Difficult to achieve clinically
• Acute reduction in pH, delays thermotolerance.
--Acute acidification is brought about by-
(i) induction of hyperglycemia
(ii) glucose combined with respiratory inhibitors MIBG (meta iodo
benzyl guanidine)
(iii) pharmacological agents that block the extrusion of hydrogen ions
from cells.

19. Thermal Dose
• Sapareto and Dewey proposed the concept of “Cumulative Equivalent
Minutes” (CEM).
• Normalise thermal data from hyperthermia treatments using this
relationship
CEM 43⁰C = t R˄(43-T)
 Where CEM 43⁰C is the cumulative equivalent minutes at 43⁰C(the
temp.suggested for normalisation)
 t is the time of treatment
 T is the average temperature during desired interval of heating
 R is a constant. (Above breakpoint R=0.5 and below 0.25)
• For complex time-temperature history, heating profile is broken into
intervals of time “t” length, where the temperature remains relatively
constant.
CEM 43⁰C = Σ t R˄(43-Tavg)

20. Immunological effect of HT:
Enhanced immunogenicity and HSP expression.
Increased T-cell, NK cell and dendritic cell maturation
and activity.
Enhanced trafficking of immune effector cells into
tumors. (mediated by cytokines such as interleukin 6)

21. Factors affecting response to HT
• Temperature
• Duration of heating
• Rate of heating
• Temporal fluctuation in temperature
• Spatial distribution of temperature
• Environmental factors (pH and nutrient levels)
• Combination with radiotherapy, chemotherapy,
immunotherapy, etc.
• Intrinsic sensitivity

22. Rationale for combining RT+HT
• Cell in late S phase of cell cycle and hypoxic cells are
radioresistant but are most sensitive to
hyperthermia.
• Hyperthermia can lead to reoxygenation which
improves radiation response(Radiosensitisation).
• Inhibits the repair of sub-lethal and potentially lethal
damage.

23. HT in Chemotherapy
• Mechanisms:
1.Increased cellular uptake of drug
2. Increased oxygen radical production
3. Increased DNA damage and inhibition of repair
• Eg.including Cisplatin and related
compounds,melphalan, cyclophosphamide, nitrogen
mustards, anthracyclines, nitrosoureas, bleomycin,
mitomycin C, and hypoxic cell sensitisers.

24. Modalities of Hyperthermia
• 1)Superficial RT
• 2)Deep/Regional HT
• 3)Interstitial RT
• 4)Whole body RT

26. Methods of Heating
• Electromagnetic heating
• Ultrasound heating
• Interstitial hyperthermia
• Thermal conduction

27. Problems in delivery of clinical hyperthermia:
Irregularities of patient anatomy and tissue
interfaces
Blood perfusion which varies among tissue types
and function of time and local temperature.
Continuous monitoring during treatment to
readjust the heating pattern for uniform temp. as
blood flow changes rapidly.

28. ELECTROMAGNETIC HEATING
• Mechanism:
 Electric field passes through material : resistant heating occurs
 Focus of heating broad : with low frequency and high wavelength
 Can be invasive or non invasive
superficial heating deep heating
1.Superficial heating-effective
penetration of 2 to 5 cm.
1.Deep heating- penetration >5 cm
2.Operate in microwave band at 433,
915 and 2450 MHz.
2.Use lower EM frequencies in the RF
band 5 to 200 MHz
3.Waveguides, microstrip or patch
antennas
3.Three techniques-
Magnetic induction
Capacitive coupling
Phased array fields

29. Superficial Heating
• The frequency of
microwave hyperthermia
used are 430 MHz, 915
MHz and 2450 MHz.
• Rectangular or circular
metal structure that
guides EM waves from a
single monopole.

32. BSD 2000 Sigma (deep heat system)

33. BSD-2000/3D
• Designed particularly for treating tumours in hard-to-
reach locations.
• The targeted treatment area is enclosed by an eye-
shaped applicator.
• Phase and amplitude steering is used to create the
heating focus within the applicator.
• The 3D technology uses 24 dipole antennas of the Sigma
Eye driven by 12 RF power channels to optimise the
targeted heating.
• The 24 dipoles are arranged in three rings of 8 antennas
each.
• By varying the phase and the amplitude of each of the 12
input channels, the operator can enhance the heating in
the tumour and reduce the heating in non-target tissues.

34. Thermotron RF-8;

35. Thermotron RF-8
• It uses electromagnetic waves to reach tumour tissue
wherever it is located in the body.
• It works by heating a region of the body between a
pair of parallel-opposed circular electrodes.
• Possible to selectively heat regions of different depth
by using combination of large and small electrodes.
• Deep seated tumours can be heated uniformly.
• Presence of self-excited oscillator that is used to
adapt the fluctuation of the specific frequency of the
target lesion.

36. Ultrasound Heating
• Mechanism: Acoustic field transfer energy with
viscous friction.
• Penetration of US field decreases with increasing
frequency.
• But,anatomic geometry and tissue heterogeneity (air
reflects,bone preferentially absorbs) severely limit
the utility of US.
• Useful in intact breast and non bony soft tissue sites.
• Include single transducer and multiple transducer
devices for superficial tumours (2-5cm)heating.
• Operate in 1-3 MHz range.

37. Ultrasound Heating
• Coupled into tissue
using a water bolus
which is temperature
controlled.
• Bolus water is
degassed since US
cannot propagate in
air.(i.e., air has to be
removed)
• Good surface contact
achieved by using a
coupling gel.

38. Interstitial Hyperthermia
• Principle: Usually combined with brachytherapy : double
use of the implant for both HT and RT.
• Ways:
(i) Simultaneous delivery
(ii) Sequential heat and radiation(most clinical experience)
• Interstitial heating techniques :
a)Low frequency RF electrode system (0.2 to 30 MHz)
b)High frequency MW antennas (300- 1000 MHz)
c)Hot source techniques
•Lost its popularity due to decline in brachytherapy use and
non-uniform distributions.

40. Thermal conduction:
Simplest method of heating; e.g. hot water baths,
circulating hot water in a needle, a catheter or a
surface pad.
Limitations:
The tumor may not be at the same temp. as the
skin (in case of hot water baths).
Limited penetration of heat from a hot source.
Restricted to interstitial applications.

41. Whole Body RT
• A technique to heat whole body either up to 41-42°C
for 60 minutes (extreme WBHT) or only 39.5-41°C for
longer time, e.g.3 hours (Moderate WBHT).
• In carcinomas with distant metastasis, a steady state
of maximum temperatures of 42°C can be
maintained for 1 hour with acceptable adverse
effects.
• Intended for activation of drugs or enhancement of
immunologic response.

42. Isolated Limb Perfusion
• Hyperthermic Limb perfusion
involves isolation of the limb
from systemic circulation.
• CT is administered often in the
range of 60 mins with
extracorporeal circulation.
• At the beginning of perfusion
phase , the blood in the limb is
heated after which CT infusion
begins.
• High concentration of CT can
be delivered to the targetted
limb while minimising
cytotoxicity.

43. Hyperthermic Intraperitoneal
Chemoperfusion(HIPEC)
• Hyperthermia therapy used in combination with surgery in
treatment of advanced abdominal cancers.
• Used for treating cancers that have spread to the lining of
abdominal cavity(Ca appendix, Ca colon, Ca stomach and Ca
ovaries).
• Delivers CT directly to cancer cells unlike systemic CT.
• After debulking/macroscopic tumour removal, the abdominal
cavity is rinsed with a heated chemotherapy solution(usually
approx.at 40⁰C).
• Heat potentiates the effect of CT by reducing tumour cell
resistance.
• Mitomycin-C and Oxaliplatin for colorectal cancer, amd
Cisplatin for ovarian cancer.
• Decreases systemic side effects.

44. Hyperthermic Intraperitoneal
Chemoperfusion(HIPEC)

45. Trials on HIPEC
• Phase III trial by Willemian J.van Driel et al. (The New
England Journal of Medicine) to see the overall survival
and the side effect profile of patients in stage III epithelial
Ovarian cancer.245 patients were randomly assigned
who had atleast stable disease after 3 cycles of
carboplatin and paclitaxel to undergo cytoreductive
surgery either with or without administration of HIPEC
with cisplatin
Results: The median overall survival was 33.9 months in the
surgery group and 45.7 months in the surgery+HIPEC
group.The percentage of patients who had adverse events
of grade 3 or 4 was similar in the two groups.

46. Randomized Trial: Cytoreduction and Hyperthermic
Intraperitoneal Chemotherapy Versus Systemic
Chemotherapy in Patients with Peritoneal
Carcinomatosis of Colorectal Cancer
• The median progression-free survival was 7.7 months
in the control arm and 12.6 months in the HIPEC arm
(P = 0.020). The median disease-specific survival was
12.6 months in the control arm and 22.2 months in
the HIPEC arm (P = 0.028). The 5-year survival was
45% for those patients in whom a R1 resection was
achieved.

47. Thermometry
• Thermometry : procedure to measure intra-tumoral temperature
• For superficial tumours (0.5 cm) : probes attached on skin surface
or mapped through catheters lying on skin
• For deep tumours : Invasive thermometry is standard.
Angiocatheter inserted in tumour at a point, perpendicular to the
direction of electric flow.
Temp.is measured by putting a thermocouple probe in
angiocatheter
• Record : lowest thermal dose (lowest temp*time)
highest thermal dose(highest temp*time)
NON INVASIVE THERMOMETRY :
MRI is preferred technology – the MR parameters sensitive to
temperature changes are : relaxation times T1 & T2, bulk
magnetisation, resonance frequency of water atoms.

48. Hyperthermia Toxicity
• HT toxicities (studies) with or without radiation is
minor only.
• Doesn’t result in treatment interruption.
 Thermal burns-generally grade I
 Pain
 Systemic stress

50. • CR rates were 39% after RT alone and 55% after RT+HT.
•The duration of local control was significantly longer with
RT+HT than RT alone.
•For cervical cancer, for which the CR rate with RT+HT was
83% compared with 57% after Rt alone.

51. •At 12 year follow-up, local control remained better
in RT+HT group(37% vs 56%).
•Survival was persistently better after 12 years :
20%(RT) and 37%(RT+HT)
•Hyperthermia did not significantly add to radiation-
induced toxicity compared with RT alone.
Study by Franckena et al; IJROBP 2008

52. Trials(Phase III) showing compatibility of RT alone VS
RT+HT
In general,
clinical
response rates
with the
addition of HT
to RT have
approx.double
d from 25-35%
with RT alone
to 50-70%.

53. Chemotherapy Trials
• The Rotterdam group treated 19 patients with
locally recurrent Ca cervix post RT with a
combination of HT and Cisplatin (overall response
rate was 53% with 1 complete response).
• Another phase I/II trial by Hilderbrandt et al, in
which nine patients with locally advanced rectal
carcinoma having failed RT with/without surgery
were treated with CT(oxaliplatin, folinic acid and 5-
FU) in combination with HT, was well tolerated and
quite feasible.

54. Trimodality Therapy Trials
• The combination of CT, RT, and HT was explored in an international
collaborative study for locally advanced cervical carcinoma.
[ 68 patients, all patient received 45-50Gy WP-RT followed by
brachytherapy boost with a total dose to point A- 86Gy with weekly
concurrent cisplatin, external HT was delivered weekly.]
The 2 year survival was 78% and DFS was 71%.
• Rau and colleagues from Berlin also explored the use of
preoperative trimodality therapy for locally advanced untreated
rectal carcinoma.(RT, HT, and 5-FU/leucovorin)
[36 patients, RT to 45Gy with weekly HT] [32 patients were
surgically resectable, 5 patients with CR] After surgery OS was 86%
at 38 months with no local recurrence.

55. •The use of trimodality therapy also reported for
locally recurrent breast cancer.
[23 patients were treated with superficial HT and
RT to a dose of 45Gy and capecitabine CT in 21,
vinorelbine in 2 and paclitaxel in 4 patients.] [ 23
of whom previously irradiated and 22 had
received prior CT]
80% of patients achieved a CR with 76% locally
controlled at 1 year.

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57. Meta-analysis
• Datta NR, et al. Int J Hyperthermia.2016 (Hyperthermia
and radiotherapy in the management of head and neck
cancers : A systematic review and meta-analysis)
A total of 498 abstracts were screened from four
databases and hand searched as per the PRISMA
guidelines.CR was evaluated in patients of head and neck
cancers treated with either RT alone, or RT+HT without
concurrent CT or surgery.
Results : Overall CR with RT alone was 39.6% whereas with
RT+HT it was 62.5%. Acute and late grade III/IV toxicities
were reported to be similar in both the groups.

58. Meta-analysis
• Datta NR, et al. Int J Radiat Oncol Biol Phys.2016
(Hyperthermia and Radiation Therapy in Locoregional Recurrent
Breast Cancers : A Systematic Review and Meta-analysis)
CR was evaluated in patients of locally recurrent breast cancers.A
total of 708 abstracts were screened from 8 databases according to
PRISMA guidelines.Single arm and 2-arm studies, treating LRBCs
with HT and RT but without surgery(for local recurrence) or
concurrent chemotherapy were considered.
Results: In the 2-arm studies, A CR of 60.2% was achieved with RT+HT
vs 38.1% with RT alone.In 26 single arm studies, RT+HT attained a
CR of 63.4%. A Cr of 66.6% was achieved with HT and re-irradiation
in previously irradiated patients.
Mean acute and late grade3/4 toxicities with RT+HT were
14.4% and 5.2% respectively.

59. Conclusion
• Hyperthermia is an useful adjuvant to radiotherapy and
chemotherapy.
• Associated with increased local control rates with
comparable acute side effects and no late toxicity.
• Major drawbacks:
 Cannot treat all sites;difficult for deep seated tumours
 Cannot deliver exact dose
 Non uniformity in doses
 Difficult/variable thermometry
 Difficult to set up and delivery in some positions
 Uncomfortable for patients

60. THANK YOU