Hyperthermia, defined as elevating temperature above normal physiological levels, can be used to directly kill cancer cells or sensitize them to radiation and chemotherapy. Key points: - Temperatures of 40-45°C can directly kill cells in a time and temperature dependent manner. - Lower temperatures of 40-43°C do not directly kill cells but can sensitize them to radiation by improving oxygenation and inhibiting DNA damage repair. - Hyperthermia can also sensitize cells to chemotherapy by increasing drug uptake and oxygen radical production. - The combination of hyperthermia with radiation and chemotherapy has shown improved local tumor control compared to these treatments alone.

1. PRINCIPLES OF HYPERTHERMIA
& CLINICAL APPLICATION
MODERATOR : PROF. S.C.SHARMA

2. Definition
 Hyperthermia means elevation of temperature to a supraphysiological
level, between 40 to 45 C
 Effects of Hyperthermia on Cell Survival :
- cause direct cytotoxicity
- kills cells in a log-linear fashion depending on
the time at a defined temperature
- initial shoulder region
- followed by exponential portion
- At lower temperatures,
resistant tail at end of heating period

3. The Arrhenius Relationship
 Defines temp dependence on rate of cell killing.
 Temp vs log of slope (1/Do) of cell survival curve
 biphasic curve
 break point : For human cells : near 43.5 C
 Significance :
above bk pt : temp Δ of 1 C , doubles rate of
cell killing
below bk pt : rate of cell killing drops by a factor of
4 to 8 for every drop in temp of 1 C
 Basis for thermal dosimetry

4.  Tumor temp varies during t/t
 Formula to convert all time temp data to equiv no. of minutes at a standard temp:
CEM 43 C = tR (43-T)
where CEM 43 C = cumulative equivalent minutes at 43 C /thermal isoeffect dose
defined as time in minutes for which the tissue would have to be held at 43 C ,to suffer the same
biologic damage as produced by actual temp, which may vary with time during a long exposure
t = time of treatment
T = avg temp during desired interval of heating
R = 0.5 if temp >43 C & 0.25 if < 43 C
 used to assess efficacy of heating
 above 43 C : 1 C rise in temp: decreases time by a factor of 2:
so, t2/t1 = 2 (T1 – T2)
below 43 C : time decreases by factor of 4 -6 ,
so, t2/t1 = (4 to 6 ) T1 – T2
CEM at 43 C calculated by these expressions

5. Mechanisms of Hyperthermic Cytotoxicity
1. Cellular & tissue response
Primary target : protein (cell membrane, cytoskeleton, nucleolus)
cell killing by protein denaturation : heat of inactivation 130-170 kcal/mol
ultimate cell death : by apoptosis or necrosis
2. Physiological response
with temp increase
Vascular: -Aerobic metabolism↑ (sensitive enzymes)
↑ tissue perfusion -Shift to anerobic metabolism (↓ATP &↑lactic acid)
↑ microvessel pore size -Apoptosis ↑
Increased macromolecular Reoxygenation
& nanoparticle delivery.
↑ RT sensitivity
↑ antitumor effect of cct & killing

6. Thermotolerance
 transient resistance to subsequent heating by initial heat treatment
 MECH:
Repair of protein damage via heat shock proteins (HSP) 70 -90 kd
2 ways of TT devlopment : At low temp 39 – 42 c --- during heating
Above 43 c ---- after heating stopped
 HOW TO AVOID TT?
minimum of 48 hours between hyperthermia fractions in order to decay TT
 LIMITATION:
- HT can’t be used every day with conventionally fractionated radiation
- many early trials utilized HT with RT #on schemes with large doses / fraction (e.g., 4 Gy per
fraction, 2 to 3 times per week) -- higher n tissue complications & less total dose
 FACTS:
- temp for radiosensitization : largely below that for cell killing
- heat radiosensitization : unaffected by thermotolerance,
- best way is take advantage of heat radiosensitization, rather than hyperthermic cytotoxicity,
and ignore the issue of TT

7. Modifiers of the Thermotolerance Response:
 Thermal exposure above 43°C : TT during the heating prevented.
 Step down heating:
- It is an initial short heat shock above 43 °C, followed by a drop in temperature
below this threshold, delays TT
- difficult to achieve clinically.
 Acute reduction in pH, delays TT

8. Factors affecting response to hyperthermia
 Temperature
 Duration of heating
 Rate of heating
 Temporal fluctuations in temperature
 Environmental factors (pH & nutrient levels)
 Combination with radiotherapy, chemotherapy, immunotherapy etc
 Previous history
 Intrinsic sensitivity

9. Effect of temperature:
NORMAL TISSUE TUMOR
(normal vasculature with (rel. poor vasculature &
rel. unresponsive neovasculature)
high ambient blood flow)
INCRESED TEMP
Vessels incapable of shunting
Vessels dilate blood
Shunts open
Acts as heat ↓O2 , ↓ph
Blood flow increases resorvoir enhanced cell
Heat carried away killing
Therefore, temp in tumor > than normal tissues with hyperthermia

10. Thermal sensitizers
1) acute acidification (decreasing ph)
a) induction of hyperglycemia
b) glucose combined with resp inhibitor MIBG (meta iodo benzyl guanidine),
c) pharmacologic agents that block the extrusion of hydrogen ions from cells,
2) decreasing tumor blood flow
a) hydralazine
b) nitroprusside
c) angiotensin II
d) nitric oxide synthase inhibitors (L-NAME)
risk of hypotension

11. TECHNIQUES
Clinical hyperthermia achieved by exposing tissues to –
- Conductive heat sources
- Non – ionizing radiation – Electromagnetic(EM) -----RF, MW
Ultrasonic(US)

12. SHORT WAVE DIATHERMY:
Therapeutic elevation of temperature in tissue by means of an oscillations of EM
energy of high frequency
Effect – local(increased tissue parfusion & increased metabolism)
- distant (reflux vasodilatation)
Duration: 10 – 15 min
Contraindicated in malignant tumors :
- large area heated
- no preferential tumor heating

13. ELECTROMAGNETIC HEATING
• Mech :
Electric field passes through material : resistant heating occurs
• focus of heating broad : with low frequency & high wavelength
• can be invasive or non invasive
FOR SUPERFICIAL HEATING FOR DEEP HEATING
1 Microwave waveguides 1 Magnetic induction
2 Microstrip/ patch antenna 2 Capacitative coupling
3 Magnetic induction & capacitative 3 Phased RF / microwave arrays
coupling

14. Microwave wave guide Capacitative coupling
Depth Power directed frequency Coupling Disadvantge
treated to tumor site (RF) medium
Microwave Superficial By placing 433 Deionized -Limited depth t/t
wave guide 2-5 cm waveguide over 915 MHz water bolus -Heating pattern not
tumor 2450 controllable
Magnetic Deep No; Magnetic field air -Eddy currents
induction > 5 cm used follow least
resistance path
Capacitative Deep By placing 5 – 30 MHz Saline bolus -supf fat heats
coupling > 5 cm applicators / -use in thin pts only
electrodes

15. Radiofrequency
phased array
Array of RF antennas arranged in geometric pattern around target region
Depth Power directed frequency Coupling Disadvantge
treated to tumor site medium
Radiofrequ Deep By altering phase & 100 – 200 MHz Water bolus - Technically
ency > 5 cm amplitude of power challenging
phased from different
array antennas

16. ULTRASOUND HEATING
• Mech :
energy transfer associated with viscous friction
FOR SUPERFICIAL HEATING FOR DEEP HEATING
Planar US transducers Focussed transducer arrays
Depth Power directed US Coupling Disadvantge
treated to tumor site frequency medium
Planar US Superficial By placing 1- 3 MHz Degassed - good coupling to
transducers 2 – 5 cm transducer over water body reqd
tumor - Air & bone inhibit
penetration
Focussed Deep yes 0.5 – 2 MHz Degassed - Limited size of
transducer > 5 cm water acoustic window
arrays - air & bone reflect
SONOTHERM power
1000

17. Interstitial Hyperthermia
- has same characteristics as interstitial radiation:
- highly localized & invasive
- WAYS:
a) simultaneous delivery
b) 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
PRINCIPLE:
Usually combined with brachytherapy : double use of the implant for
both HT & RT

18. Radiofrequency waves (low frequency)
- depth : to treat tumors 1-1.5 cm deep
- frequency : (0.2 to 30 MHz)
- technique : two or more implanted needle
electrode pairs(needle arrays)are
connected to a RF generator.
RF current (mobile ions) flows b/w oppositely polarized electrodes
- mech of heat transfer : Direct contact b/w metal electrodes & tissue required
(conductive current transfer)
- Limitation:
- requires close electrode spacing (1 to 1.5 cm) and regular geometry.
- Heating near electrodes causes treatment-limiting pain.

19. MicroWave interstitial heating (co axial antennas)
depth : to treat tumors 1-1.5 cm deep
frequency : uses high frequency MW fields (300 – 1000 MHz)
technique : radioactive wires (Ir -192) & MW coaxial antennae introduced in same
catheter (nylon/ plastic catheter)
Antennas placed 1-1.5 cm from each other
mech of heat transfer :
current induction is predominantly capacitive (due to molecular
polarization) instead of conductive (due to free ion drift).

20. Hot Source Techniques
-For tissues with low to moderate perfusion
TECHNIQUES:
1) electrical resistive heating elements
2) hydraulic systems that circulate heated water through tubes
3) ferromagnetic seeds that are heated externally via a time-varying magnetic
field (simplifies reheating of permanent implants)

21. THERMOMETRY
 Thermometry : procedure to measure intra-tumoral temperature
 For supf tumors (< .5 cm) : probes attached on skin surface or mapped through catheters
lying on skin
 For deep tumors: invasive thermometry is std.
Angiocath inserted in tumor at a point ,prependicular to the direction of electric flow
Temperature measured by putting a thermocouple probe in angiocath
 Record: lowest thermal dose (lowest temp * time)
maximum 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 magnetization, resonance frequency of water atoms.

22. Hyperthermia and Radiation
Rationale for Combining the two:
1. Radioresistant cells in S-phase are most sensitive in hyperthermia
2. Hypoxic cells not resistant to hyperthermia.
3. lead to reoxygenation, further improve radiation response (RADIOSENSITIZER)
4. inhibits the repair of both sublethal and potentially lethal damage

23. Factors to Consider When Combining Hyperthermia with
Radiotherapy
Effect of heat alone HT + RT
43-46 C – vascular destruction 44 C - incresed thermal cytotoxicity
in highly perfused tissue (increased cell killing)
X ray survival curve : steepening(↓ D0)
43 C – vascular destruction in 40 – 43 C -No thermal cell killing
poorly perfused tissue -Thermal radiosensitization:
-Improved nutrients & oxygen
41-42 C – cellular cytotoxicity supply of radioresistant hypoxic
enhanced at low ph & S phase cells
-inhibited repair of XRT
40 C – increased perfusion in X ray survival curve : shoulder removed
all tissue types
36-38 C - normothermia Normothermia

24. 1. Thermal Enhancement Ratio
- Interaction b/w radiation & hyperthermia can be quantified
- TER = ratio of doses RT / RT+HT to achieve isoeffect
- for therapeutic gain : TERtumor > TERnormal tissue
- TER ↑ with increasing heat dose
↓ with increasing time b/w RT & HT
- In most tumor types : TER is >1 for tumor control
- For normal tissues : TER is < than those for tumor
2. Excessively high temp (>45 C for 60 min) : normal tissue damage due to rapid tumor
regression -- chronic complications eg. Fibrosis, fistula
Evidence from randomized trials:
HT + RT ------ ↑ local control

25. Sequence of HT & RT
SIMULTANEOUS HT + RT SEQUENTIAL HT + RT
(RT  HT
Most evident: radiosensitizing Hyperthermic cytotoxic mech
effect predominates
Same effect on tumor & normal Radioresistant hypoxic cells killed
tissue by HT t/t (but requires high temp)
Unless tumor temp> n tissue
When RT precedes HT –
sensitization no longer detectable
2-3 hrs after RT
When HT precedes RT – cells
can be sensitized for upto several
hrs
No increase in TR Radiation dose decreased
TG achieved
Thermo tolerance develops HT t/t once/twice a week without
altering radiation schedule

26. Normal tissue response to :
Heat Radiation
Cell death Apoptosis In attempting
subsequent mitosis
Cells affected Differentiating + dividing Only dividing cells
Repair mechanism Absent present

27. Hyperthermia and Chemotherapy
Rationale for combining the two:
Many chemotherapeutic agents demonstrate synergism with hyperthermia
Mechanisms:
(a) increased cellular uptake of drug
(b) increased oxygen radical production
(c) increased DNA damage and inhibition of repair
(d) reversal of drug resistant mechanisms

28. Factors to Consider When Combining Hyperthermia
with Chemotherapy
MECHANISM DRUGS
SYNERGISM WITH cisplatin , melphalan, cyclophosphamide, anthracyclines, nitrogen
HT mustards, hypoxic cell sensitizers, bleomycin, mitomycin C
COMMON Polyene antibiotics, local anesthetics, alcohol
MEMBRANE TARGET
TEMPERATURE Topoisomerase inhibitors (temp up to 41.8°C increase activity of
DEPENDENCE topoisomerase II)
REVERSAL OF cisplatin , melphalan , nitrosoureas , and doxorubicin
DRUG RESISTANCE
IMPROVE TUMOR Tubulin binding agents, such as taxol
OXYGN WITH RT
NO INTERACTION etoposide , vinca alkaloids, methotrexate
SEQUENCING For most drugs (excluding 5FU and other antimetabolites), esp platinum
compounds optimal seq : administer them simultaneously or give drug
imm. before heating.
Continuous infusion of 5 FU & maintaining temp b/w 39 C & 41C –
supraadditive effect

29.  INCREASED DRUG DELIVERY:
- A liposome : small lipid vesicle (100 nm dia) ,contains water or saline in the center
- threshold for ↑ liposomal extravasation : 40°C,
- for 1 °rise upto 42 °C : rate of extravasation ↑ by factor of 2
>42 °C : vascular stasis and hge, reduces liposomal extravasation
 ↑ in liposomal extravasation at mod HT : exploited as a drug delivery vehicle
enhanced antitumor efficacy of a variety of drugs
In Doxorubicin-containing liposomes (very rapid 50% release of drug) at 40 °C)
 For drugs with mol wt <1000 : HT rel little effect
(diffusion : not temp dependent)
for molecules >1000 mol wt : HT augment extravasation of agents
monoclonal antibodies
polymeric peptides that can carry drugs
radioisotopes

30. Hyperthermia and Gene therapy
 Under normothermic conditions: heat shock promoter : highly inducible & rel
quiescent
 HT : by means of HSPromoters can control gene expression
 eg: cells when transfected with adenovirus vectors containing HSP 70 promoter &
genes for green fluresence, IL 12, TNF alpha
heating to 42 °C for 30 minutes
several hundred-fold induction of above gene expression

31. Vernon multicentric trial (BREAST)
- Included 5 phase III trials
- Patients with chest wall recurrences
RT HT RT HYPERTHERMIA End point
n + No. Thermal
RT of # dose goal
n
Breast 135 171 29-50 Gy 1-8 Goal: T > 42.5 C CR: 59% vs 41% p
n 306 @ 1.8 - 4 every 30 min Acturial survival :
Gy/# +- 40% at 2 yrs in
boost both
- Greatest benefit : Recurrent lesions in previously irradiated areas

32. RTOG trial (1980) (SUPERFICIAL TUMORS)
- In superficial measurable tumors
RT HT RT HYPERTHERMIA End point
n + No. Thermal
RT of # dose goal
n
n = 307 117 119 32 gy/8# 8 HT imm follows Overall CRR:
- H & N –50% @ 4 gy/# RT &Goal: 42.5 C 32% vs 30%
-Breast cancers for 45 - 60 min LCR for
i.e chest wall 2#/wk; “good” * lesions < 3 cm,
recurrences – HT = 45 min at * chest wall recurrenc
33% 42.5 C * 4# 52% vs 25%
- Others
- LIMITATION:
variable heating techniques
thermal dosimetry inadequacies

33. Datta single institute trial INDIA (HEAD & NECK)
RT HT RT HYPERTHERMIA End point
n + No. Thermal
RT of # dose goal
n
Head & 32 33 50 Gy / twice a Goal: 20 min CR: 55 % vs 31% p
neck 25# week at at 8 wks
n 65 @ 2 Gy/# 72 hr > 42.5 C with stage III
+ boost 10 interval & IV
-15 Gy to No survival
gross ds advantage seen
No benefit in Stage I / II patients: with > 90 % patients achieving CR with either
t/t

34. Valdagni single institute trial ITALY (HEAD & NECK)
 Evaluated Locally advanced squamous cell carcinomas with metastatic cervical LN
RT HT RT HYPERTHERMIA End point Effect of heating
n + No. Thermal quality
RT of # dose goal
n
Head & 23 21 64-70 gy 2 vs 6 Goal: Tmin = 43 C CR: 82% vs 37% p CR 86% vs 80% for
Neck @2– every 30 min at 3 mths 2 vs 6 HT doses;
(multiple 2.5 gy/#
nodes in No correlation
some) b/w dose received
n 44 & outcome
5 yr 21/ 16/18 ------------- 5 yr Acturial
follow 22 nodes probability of LC
up on no in neck :
above des 69 % vs 24% p
patients 5 yr OS:
53 % vs 0 % p

35. Emami multicentre trial (RTOG STUDY)
(INTERSTITIAL HYPERTHERMIA)
- included 173 patients
- With persistent/ recurrent tumors after prior RT / Surgery , amenable to IT HT
ITRT ITHT INTERSTIT HYPERTHERMIA End point Effect of heating
n + IAL RT No. Thermal quality
ITRT of # dose goal
n
87 86 Prior dose 1 or 2 Goal: Tmin 43 C CR: 57% vs 54% LIMITATION:
+ study for 60 min PR: 14% vs 24% Only 1 patient
dose < (NOT met criteria for
100 Gy SIGNIFICANT) adequate HT t/t
Head & 35 40 CR: 62 % vs 52 % LED to RTOG
Neck PR: 10% vs 37 % guidelines for HT
45% LC: 43 % vs 37 %
Pelvis 37 38 CR: 60 % vs 57%
40% PR: 10 % vs 8 %

36. Sugimachi single institute trial (ESOPHAGUS)
CRT HT RT HYPERTHERMIA End point
n + No. Thermal
CCT of # dose goal
+
RT
n
Esophagus 34 32 30 gy/15#/ Bleomycin & HT given Downstaging effect of
66 @ 2gy/# concurrently 1 hr prior to RT Neoadjuvant therapy
3 weekly Effective in 69% vs
44% p
6 Goal: 42.5 – 44 C Pcr :
every 30 min 26% VS 8% P
OS:
50 % vs 24%
at 3 yrs
Esophagus CCT CCT 6 Goal: 42.5 – 44 C Pcr :
40 alone + HT every 30 min 41 % VS 19 % P

37. Overgaard multicentric trial (MALIGNANT MELANOMA)
HT RT HYPERTHERMIA End point Effect of heating
RT + No. Thermal quality
n RT of # dose goal
n
Melanoma 65 63 24 – 27 Gy 3 43 C for 60 min CR: 62% vs 35% p LIMITATION:
128 /3# @ at 3 mths Only 14% patients
8 – 9 Gy/# LC : 46% vs 28% p achieved the goal
at 2 yrs of HT
RR : RT+HT vs RT
alone
CR = 4.01
2 yr LC = 1.73

38. Sneed single institute trial (GBM)
Univ of California San Fransisco study
BT ITHT BT HYPERTHERMIA End point Effect of heating
boost + No. Thermal quality
n BT of # dose goal
n
GBM 33 35 59.4 Gy 2 median range TTP median: 8 patients
After /33# @ CME 43C 14.1 49 wk vs 33 wk p received only 1 HT
RT 1.8 Gy/# t/t
68
60 Gy @ median range TTLTP : Grade 3 Toxicity:
0.4-0.6 CME 43C 57 wk vs 35 wk p 7 patients vs 1
Gy/hr T 50: 74.6
I -125 in 2 yr OS: But no good
100 hrs 31% vs 15% thermal dose
relationship found
Median survival:
85 wks vs 76 wks

39. Vander zee phase III trial DUTCH STUDY 1990
(PELVIS)
- Previously untreated LA pelvic tumors
RT HT RT HYPERTHERMIA End point Effect of heating
n + No. Thermal quality
RT of # dose goal
n
361 176 182 1/wk ,upto 5 CR: 55% vs 39% 41% patients
Target = 60 min after any at 3 mths received fewer
point in tumor is 43 C OS: 30% vs 24% than 5 HT t/ts due
at 3 yrs to refusal
Cervix 56 58 46-50 Gy @ 1.8-2 Gy/# + BT boost CR: 83% vs 57% p Max benefit seen
114 LC: 61 % vs 41 %P among pelvic
OS: 51 % vs 27%P tumors
Rectum 71 72 46-50 Gy @ 1.8-2.3 Gy/# + 10 -12 Gy CR: 21% vs 15%
143 boost LC: 38% vs 26% p
OS: 13% vs 22%
Bladder 49 52 66-70 Gy @ 2 Gy/# CR: 73% vs 51% p
101 LC: 42 % vs 33 %
OS: 28 % vs 22%
Limitation: control arm RT alone received suboptimal therapy (no cct)

40. Sharma et al Randomized clinical study
PGI STUDY 1986 (CERVIX)
RT HT RT HYPERTHERMIA End point
n + No. Thermal of #
RT dose goal
n
CA 25 25 45 Gy / thrice a Goal: temp LC: 70 % vs 50% p
CERVIX 20#/4 wks week raised to 42-43 C
(II & III) @ 2.25 Gy/# over 15 min & No survival advantage
+ maintained over seen
ICA with Cs next 30 min
137 followed by RT Toxicity:
application after 30 min Only minor , tolerable
(35 Gy to pt & manageable, not
A) interrupting t/t
No late toxicity
Technique : endotract intravaginal applicator, active electrode, a larger
extracorporeal indifferent electrode & a R.F generator operating at 27.12
MHz
Thermocouple fixed to inner surface of endotract applicator

41. Overgaard meta-analysis
 22 trials
 Compared risk of failure for pts treated with RT + HT vs RT alone
 Significantly ↓ed risk of failure in pts who received RT + HT and p value
of <0.00001
 Clear evidence of benefit for melanomas, H& N, chest wall, cervical,
rectal & bladder cancers but no benefit for prostate & intact breast
cancers

42. HYPERTHERMIA TOXICITY
- HT toxicity (studies) with or without radiation is minor only
- Doesn’t result in treatment interruption
 Thermal burns – generally grade I
 Pain
 Systemic stress

43. LIMITATIONS
1. TECHNICAL CHALLENGES IN APPLICATION
- difficult for deep seated tumors
- invasive thermometry
- no recommended target temperature ranges to optimize HT t/t
- control of applied power
2. CONCURRENT CHEMORADIATION PROTOCOLS SUCCESS
- in increasing LCR of locally advanced cancers eg head & neck, cervix, colon
3. UPCOMING TARGETED THERAPIES
eg EGFR inhibitors in combination with RT
4. COMPETING TECHNIQUES
conformal techniques – selective dose delivery to desired target tissues

44. WHY HT STILL IN CONTINUED DEVELOPMENT PHASE?
1. Trimodality therapy (CCT + RT + HT) needed to achieve goal of 100% LC
2. Drug delivery to tumors remain a major challenge :
HT by increasing vascular permeability & volume fraction increase site specific
bioavailability
ex : Thermodox (temp sensitive liposome containing Doxorubicin) released rapidly
at temp of 40 C to 42 C

45. CONCLUSION
 Hyperthermia is an useful adjuvant to radiotherapy & chemotherapy
 Associated with increased local control rates with only minor/nil acute side effects
& no late toxicity
 Major block : inability to heat designated TV of tissue & inadequate thermometry
 Further advancement in HT technology needed to adequately utilize the gain

46. Thanks…

47. Hyperthermia and Metastases
 Hyperthermia
- increased tumor perfusion
- changes in endothelial gap size
opportunity for enhanced tumor cell shedding. So local hyperthermia may enhance
the metastatic rate
 exception of one study with the B16 melanoma, there is no evidence that local-
regional hyperthermia causes an increase in metastases