Radiation Oncology

1. Hyperthermia
Presenter : Dr. Gowtham Manimaran
Moderator : Dr. Jyoti Pannu

2. Hyperthermia
• In oncology - Hyperthermia is a type of medical procedure which raises the temperature of
tumor-loaded tissue to 39.5– 43 ° C and is generally applied as an additive treatment to
established non-surgical cancer treatments, namely chemotherapy and radiation therapy
• When Hyperthermia (HT) is combined with radiotherapy (RT), it is called
Thermoradiotherapy (RTHT).
• When Hyperthermia is combined with both radiotherapy and chemotherapy(CT) , this
trimodal treatment is called Thermochemoradiotherapy (RTHTCT).
Hyperthermia-related clinical trials on cancer treatment within the
ClinicalTrials.gov registry. Int J Hyperthermia.2015;31(6):609-14

3. Mechanism of Hyperthermic Cytotoxity

4. 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
 Different cell lines differ in their
sensitivity to hyperthermia
 There is NO consistent difference between normal
and malignant cells heated in vitro.

5. ,
HT vs RT
• Heated cells mostly die by apoptosis so
expressed early
• Heat affects differentiated as well dividing cells

6. Thermal Isoeffect Dose: The Arrhenius Relationship
 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)
 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

7. WHY DOES BREAK POINT OCCUR?
Different mechanisms of cell killing above
and below BP
Development of thermotolerance within
cells

8. THERMOTOLERENCE
 Development of a transient and nonhereditary resistance to
subsequent heating by an initial HT
 Begins a few hours after the first treatment and may take up to a
week to decay.
• Since maximal thermotolerance (TT) occurs by 24 hours, daily
fractionation would completely waste any cumulative effect of
HT.
 Thermotolerancec can alter the slope of survival curve by a factor
of 4 to 10.
 Clinical challenge – HTs once or twice per week.

9. 1. At temp. of 39 to 42°c TT is induced during heating
period after an exposure of 2-3 hrs.
2. Above 43 °c it takes time to develop after heating
stops and then decays slowly.
• 1st heat dose kills a substantial # of cells but
daily treatment becomes less effective because
of thermotolerance.
• Heat shock proteins (HSP ) has proposed to be the
mediators of thermotolerance in humans.
• Thermotolerance will decay if cells are not exposed
to heat again.
• Time of decay vary from 2 days to 2 wks.

10. Thermal Enhancement Ratio (TER)
• TER = ratio of doses RT -HT/ +HT
to achieve isoeffect
• TER -↑ with increasing heat dose
↓ with increasing time b/w RT & HT
• In almost all tumor types : TER is >1 for tumor control
Typical TER
values
• 1.4 @ 41 C
• 2.7 @ 42.5C
• 4.3 @ 43C

11. Thermal dosimetry
• Sapareto & Dewey proposed concept of “Cumulative Equivalent Minutes” [CEM]
• Normalize thermal data from hyperthermia treatments using this relationship
CEM 43°C = t R(43-T)
 where CEM 43°C is the cumulative equivalent minutes at 43°C (the temperature
suggested for normalization),
 t is the time of treatment,
 T is this 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 430
C = ∑ t R(43 – Tavg)

12. INDIRECT EFFECTS
1.Changes in Tumour microenvironment
42 to 44° C
Damage to tumor vascular endothelium
Decreased pO2,pH and nutrient status
Increased heat sensitivity but decreased
radiosensitivity
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)

13. 2.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 Ex :for liposomal soluble doxorubicin.

14. 3.EFFECT ON OXYGENATION
• Mild hyperthermia (41° to 41.5° C) can
promote tumor reoxygenation
• whereas hyperthermia at a cytotoxic
temperature (43.5° C) decreases the
median oxygen concentration due to
vascular damage.
Song CW, Shakil A, Osborn JL, et al. Tumour oxygenation
is increased by hyperthermia at mild temperatures. Int J
Hyperthermia. 2009;25[2]:91–95.)

15. EFFECT OF pH AND NUTRITION
• Cells in an acid pH environment appear to be
more sensitive to killing by heat. This is
certainly true of cells treated with heat soon
after their environmental pH is altered by
adjusting the buffer.
• The intracellular pH (pHi) of cells in an acidic
environment is slightly higher than the
extracellular pH (pHe).
• Cells deficient in nutrients are heat sensitive.
• This can be demonstrated with cells in culture,
in which sensitivity to heat increases
progressively as cells have their energy supply
compromised, either by depriving them of
glucose or by the use of a drug that uncouples
oxidative phosphorylation.

16. IMMUNOLOGIC EFFECTS
 Enhanced immunogenicity and antigen
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
Peer AJ, Grimm MJ, Zynda ER, et al. Diverse immune mechanisms may contribute to the survival benefit seen in cancer
patients receiving hyperthermia. Immunol Res. 2010;46:137–154

17. Factors affecting response to HT
• Temperature
• Duration of heating , Rate of heating
• Temoral fluctuations and spatial distribution of temperature
• Environmental factors (pH and nutrition)
• Intrinsic sensitivity
• Combination with radiotherapy , chemotherapy ,immunotherapy
• Anatomical variations
• Varying tissue interfaces
• body size , tumour positioning,technical factors depending on the delivery device

18. DELIVERY MODALITIES
Thermal conduction
Nonionizing electromagnetic radiation
Ultrasound

19. 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
Stanford blankets
Current sheet Applicator

20. 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

22. 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
• Useful in intact breast & non-bony soft
tissue sites.

23. Interstitial Hyperthermia
• Microwave Antennas,
Radiofrequency electrodes,
Ultrasound transducers,
Heat sources (ferromagnetic
seeds, hot water tubes), and
Laser fibres.
• It is usually combined with
brachytherapy where one
can make double use of the
implant for both
hyperthermia and radiation.
Limitations – Requires regular geometry
Heating near the Electrodes causes treatment limiting pain

24. Whole body HT
• 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 metastases, a steady state of maximum
temperatures of 42°C can be maintained for 1 h with acceptable adverse
effects.
• Intended for activation of drugs or enhancement of immunologic response.

25. AQUATHERM
• Enclosure of the patient in a radiant heat
chamber with infrared or water-RF heat
input, or entirely wrapping the patient in
hot-water blankets
• Isolated Moisture-Saturated chamber
equipped with water streamed tubes
(50–60°C) on the inner sides.
• Long-wavelength infrared waves are
emitted.
• Substantial increase in skin blood
circulation is induced and energy
absorbed superficially is transported
into the systemic circulation.

26. IRATHERM -2000
• Use special water-filtered infrared
radiators ,resulting in an infrared
spectrum near to visible light.
• Penetration depth is slightly
higher.

27. ELECTRODES
(applicators)
OF
VARIOUS
SIZES
DEIONIZED
WATERBOLUS
FOR
ABDOMINAL
&
PELVIC
TUMOURS

28. TEMPERATURE CONTROLLER

29. TEMPERATURE PROBES

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

31. 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

32. Thermotolerance -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

33. • 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
sensitizers.
HT in Chemotherapy

34. Hyperthermic intraperitoneal chemotherapy (
HIPEC)
• Delivered in the operating room once the cytoreductive surgical
procedure is finalized,
• constitutes the most common form of administration of
perioperative intraperitoneal chemotherapy
• Hyperthermia exhibits a selective cell-killing effect in malignant cells
by itself, potentiates cytotoxic effect of certain chemotherapy agents
and enhances tissue penetration of the administered drug
• Increase in the number of HT induced lysosomes and lysosomal
enzyme activity result in increased destructive capacity in tumor

35. • A heat exchanger keeps fluid being infused at
43-45°C so that the intraperitoneal fluid is
maintained at 41-43°C
• Morbidity associated with this procedure
includes myelosuppression, ileus, and fistula
• Heterogeneous distribution inside closed
abdomen technique may increase the rate of
intrabdominal complications.

36. PHASE III CLINICAL
TRIALS

37. • Hyperthermia prescribed once
weekly during the period of
external radiotherapy, 1–4 h
after radiotherapy, to a total of
five treatments.
Jacoba van der Zee et al Lancet 2000

38. • CR rates were 39% after RT
alone and 55% after RT plus HT
(p<0·001).
• The duration of local control
was significantly longer with
RT plus HT than with RT alone
(p=0·04).
• For cervical cancer, for which the
CR rate with RT plus HT was 83%
compared with 57% after RT
alone (p=0·003).
RT +HT RT ALONE DIFF./P
VALUE
CERVIX 48/58(82.76%) 32/56(57.14) 26%(.003)
BLADDER 38/52(67.86) 25/49(51.0
2)
22%(.01)
RECTUM 15/72(20.83) 11/71(15.49) 5.4 %(NS)

39. • At the 12-year follow-up, local control remained better
in the RT + HT group (37% vs. 56%; p = 0.01).
• Survival was persistently better after 12 years: 20%
(RT) and 37% (RT + HT; p = 0.03).
• Hyperthermia did not significantly add to radiation-
induced toxicity compared with RT alone.
Franckena et al; IJROBP 2008

40. • Six randomised studies included.
1. Datta et al 1987; 53 pt
2. Sharma et al 1991; 50pt
3. Chen et al 1997; 120 pt
4. Harima 2001; 40 pt
5. Van der Zee 2000; 114 pt
6. Vasanthan et al 2005;110 pt .
• CONCLUSION
• Superior local tumour control rates and Overall survival can be
achieved in patients with LACC by adding Hyperthermia to
standard Radiotherapy with no added toxicity.
Lutgens et al Cochrane Database Syst
Rev.2010 Jan

41. Chemoradiation with Hyperthermia in treatment of
head and neck cancer
Nagraj et al Int J Hyperthermia. 2010 Feb
• Purpose: To evaluate feasibility and efficacy of hyperthermia with
chemoradiation in advanced head and neck cancers.
• 40 patients with advanced head and neck cancers.
• Radiation - 70 Gy /35 # was given with weekly chemotherapy.
• HT on a Thermatron at 8.2 MHz for 30 min at 41°–43°C(twice weekly)
• CR - 76.23% (29 pts) and PR - 23.68% (9 pts)
• Overall survival - 75.69% at 1 year and 63.08% at 2 years.
• No enhanced Mucosal or Thermal toxicities
• Conclusion: Demonstrates feasibility and efficacy of CRT with HT in
advanced head and neck cancer

42. • In total 451 clinical cases from six studies were
included in the meta-analysis. Five of six trials were
randomised. The overall CR with radiotherapy alone
was 39.6% (92/232) and varied between 31.3% and
46.9% across the six trials. With thermoradiotherapy,
the overall CR reported was 62.5% (137/219) (range
33.9–83.3%).
• All in favour of combined treatment with hyperthermia
and radiotherapy over radiotherapy alone.
• Acute and late grade III/IV toxicities were reported to
be similar in both the groups.

43. Advanced Primary & Reccurent breast Ca
• Five randomised trial started from 1988 to 1991
• 306 patients
• Advanced primary or Recurrent breast cancer.
• Primary endpoint was local complete
response .
• In the setting of Recurrent breast cancer when the patient has already
received radiation, addition of hyperthermia may be beneficial.
International Collaborative
Hyperthermia Group IJROBP ;1996

44. Conclusions
• Overall CR rate for RT alone was 41% and 59% for RT +HT.
• Greatest effect was observed in patients with reccurent
lesions in previously irradiated areas where further
irradiation was limited.

45. Breast cancer
Summary of cited meta-analyses and randomized trials for breast cancer
s., arm study; BT, brachytherapy; CT, chemotherapy; CR, complete response; EFS, event-free survival; HR, hazard ratio; HT, hyperthermia; m, mean;
s, not significant; LR, local recurrence; MA, meta-analysis; OS, overall survival; OR, odds ratio; PRFS, pelvic recurrent-free survival; P #, patient
umber; p, phase; PA, patients alive; w, week; r, randomized; RT, radiotherapy; s, significant; RTHT, thermoradiotherapy; RTCT, chemoradiotherapy;
BRT, external beam therapy; à, with a single dose of; x/w, times per week.

46. Hyperthermia-related clinical trials
• This paper summarises all recent clinical trials registered in the ClinicalTrials.gov
registry.
• The records of 175,538 clinical trials registered at ClinicalTrials.gov were
downloaded till 2015
• A total of 109 trials were identified in which hyperthermia was part of the treatment
regimen.
• Of these, 49 trials (45%) had HIPEC) as the primary intervention, and 14 other
trials (13%) were also testing some form of intraperitoneal hyperthermic
chemoperfusion.
• Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural
n = 4, limb n = 2, hepatic n = 1).
• Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body
hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%)
interstitial hyperthermia

49. Regional hyperthermia for high-risk soft tissue sarcoma treatment:
present status
• In the EORTC 62961-ESHO 95 randomized trial, 341 patients were randomized between July
1997 and November 2006
• To receive ifosfamide–doxorubicine-based neo-adjuvant chemotherapy alone 4 cycles or in
combination with Regional Hyperthermia .
• The achieved heterogeneous temperature distribution was in range of 39–43° C
• All patients received comparable local standard treatment including surgery and
radiotherapy
• Response rate was more than doubled (28.8 vs.12.7%) in the combined treatment arm
• By December 2014, patients randomized to the combined treatment had significantly
prolonged overall survival compared with those randomized to neoadjuvant
chemotherapy along with
• 5-year overall survival of 63 versus 51%, and 9-year overall survival of 54 versus 43%.
Curr Opin Oncol. 2016 Sep;28(5):447-52. doi: 10.1097/CCO.0000000000000316.

50. • Further trials are needed to help define the Optimal thermal dose and
sequencing of HT with RT
• Including investigation of long-duration, simultaneous RT plus HT; and to
evaluate HT with chemotherapy
• Conventional liposomes, or thermosensitive liposomes, with or without RT.
• A major stumbling block for clinical HT has been the inability to adequately
heat the designated target volume of tissue.
• Non-uniformity in doses and Difficult/variable thermometry
• Difficult set up
• No of patients low in these studies

51. • Limitations of initial heating equipment were not fully recognized
until after the failure of early randomized trials.
• Further trials are in progress using more extensive thermometry and
“third-generation” heating equipment with significantly improved
planning and real-time control of heating patterns.
• These trials should confirm these positive results and establish the
safety and efficacy of HT in a larger number of disease sites to
expand the clinical utility of HT in the management of cancer

52. ADVERSE EFFECTS
External application of heat may cause
surface burns
Whole body hyperthermia can cause
swelling, blood clots, and bleeding
Systemic shock

53. Thank You