cancer treatment

1. Hyperthermia
By
Dr Parneet Singh
Max Hospital ,Saket

2. • Elevation of temperature to a supra-physiologic
level in the range of 39°C to 45°C.
DEFINITION

3. • Edwin Smith, an Egyptian surgeon treated breast tumor with hyperthermia
some 5,000 yrs ago
• Since the 17th century there have been numerous reports of tumour
regressions in patients suffering with infectious fever
• In 1866 W. Busch, described that sarcoma of face disappeared with
prolonged infection with Erysipelas
• Westermark in 1898 deliberately use hyperthermia to treat cancer when he
used water-circulating cisterns to treat inoperable carcinomas of the uterus
with temperatures of 42–44°C.
History

4. Mechanism of
Hyperthermic Cytotoxity
• Direct Cytotoxicity
• Hyperthermia has additive & synergistic Radiosensitizing properties
• HT effects are brought about by alteration of proteins.
• Protein denaturation occurs, which leads to alterations in structures
like cytoskeleton membranes, and changes in enzyme complexes for
DNA synthesis and repair.

5. • The cytoskeleton of cells is particularly heat sensitive
• When it is collapsed by heat, there is disruption of cytoskeletal-
dependent signal transduction pathways as well as inhibition of cell
motility
• The heat sensitivity of the centriole leads to chromosomal
aberrations following thermal injury
• Many DNA repair proteins are heat sensitive and this may be one of
the mechanisms that leads to heat-induced radio- and
chemosensitization.

7. Physiology of HT
• As temperatures increase,
there is an increase in blood
flow. The temperature
threshold for this change is
41° to 41.5° C in skin
• Can lead to edema formation
stasis and hemorrhage
• Shift toward anaerobic
metabolism would decrease
oxygen consumption rates,
which could lead to
improvement in tumor
oxygenation

8. Effects of temperature
• Normal Tissue
(Normal Vasculature +
high ambient flow)
• Vessels dialate shunts
open
• Blood flow increases.
Heat carried away
• Tumour
(rel. poor vasculature +
unresponsive
microvasculature)
• Vessels incapable of
shunting blood
• Acts as heat reservoir killing
Increased temperature
Hence temperature in tumour > temp in normal tissues for Equal HT
delivery.

9. Effects of HT on Cell Survival Curves
• Hyperthermia kills cells in a log-
linear fashion depending on the
time at a defined temperature
• Initial shoulder region indicates
that damage has to accumulate to a
certain level before cells begin to
die.
• Shoulder region may not return to
the same level for a subsequent
heat fraction.
• At lower temperatures, a resistant
tail may appear at the end of the
heating period which is due to
induction of tolerance.
Cell survival curves in HT are similar
to those of X-rays!

10. • Defines temp dependence on rate of cell
killing
• The log slope of the HT survival curve
(l/Do) is plotted as a function of
reciprocal of the absolute
temperature(T).
• Biphasic curve
• Its slope gives the activation energy of
chemical process involved in cell kill
• Obvious change in slope K/a
Breakpoint
• The “Breakpoint’ in the Arrhenius plot
at 42.5-43°C is thought to be due to
development of thermotolerance during
exposure to temp <43C and the
inhibition of thermotolerance at temp
>43C
The Arrhenious Plot

11. • 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
• This analysis led to Hypothesis that Target for heat cell killing
is Cellular Protiens
• Heat of inactivation for cell killing & thermal damage is
similar to protien denaturation.
• Arrhenius plot derived from many in vitro & in vivo studies
are nearly identical.
• Basis for thermal dosimetry useful in clinical HT applications

12. 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 most tumor types : TER is >1 for tumor control
• TER for canine & human tumours were studied by Gillette et
al. & Overgaard et al.
• It was estimated to be approx. 1.15 for HT twice weekly
during a course of Fractionated RT
Typical TER
values
• 1.4 @ 41 C
• 2.7 @ 42.5C
• 4.3 @ 43C

13. Thermotolerence
• Transient non-heritable adaptation to thermal stress that
renders heated cells more resistant to additional heat stress.
• Since maximal thermotolerance (TT) occurs by 24 hours, daily
fractionation would completely waste any cumulative effect of
HT.
• All experimental normal tissues studied to date develop
thermotolerance and tumors are no exception.
• Heat induced Radiosensitization is relatively unaffected to
Thermotolerance.

14. • If heating at 44° c interrupted after 1 hr
and resumed 2 hrs later, DRC is much
shallower (cells resistant) than if heating
continued.
• Heat can induce TT in 2 ways
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.

15. Heat Shock Proteins(HSP)
• One of the primary functions of heat shock proteins is to refold
proteins that have been denatured or damaged
• Heat shock proteins do play a role in the repair or protection of
specialized DNA repair proteins and they are known to be the
mediators of thermotolerance
• A good correlation exists between the residual levels of HSP 70, 87,
and 110 and cell survival during the decay of thermotolerance

16. Thermal Dose
• 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)

17. Factors affecting response to HT
1. Temperature
2. Duration of heating
3. Rate of heating
4. Temporal fluctuations in temperature
5. Spatial distribution of temperature
6. Environmental factors (such as pH and nutrient levels)
7. Combination with radiotherapy, chemotherapy, immunotherapy,
etc.
8. Intrinsic sensitivity

18. Factors Modifying Thermal Isodose
Effect
• Thermotolerance shift the
Arrhenius plot to right and
downward, reflecting greater
thermal resistance to heat killing.
• Acute acidification shifted plot to
left and the R-value below
breakpoint approaches 0.5
because thermotolerance
induction is at least partially
inhibited.
• Step down heating occurs when
temperatures rises above
breakpoint and then drop below
breakpoint for remainder of a
treatment

19. Step down heating pH modification
• Sensitization of cells to
exposures to temperatures
below 43°C after exposure to
temperatures to 43°C for a
brief period.
• Results from the inhibition of
thermotolerance development
• Acute reduction in extracellular
pH can greatly enhance
sensitivity to hyperthermia.
• Most widely studied method
has been induction of
hyperglycemia.
• Addition of agents that can
selectively drive down tumor
intracellular pH, such as glucose
combined with the respiratory
inhibitors.

20. Rationale for combining RT + HT
•Cell in late S phase of cell cycle & Hypoxic cells are radio
resistant but are most sensitive to hyperthermia.
•Hyperthermia can lead to Reoxygenation which improves
radiation response(Radiosensitization)
•Inhibits the repair of sub lethal & potentially lethal
damage.

21. 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
sensitizers.

22. Taking Advantage of Physiological
Response to Hyperthermia
• Liposomes that are 100 nm in diameter do not extravasate at
normothermia
• 42°C hyperthermia increases microvessel pore size to sizes
between 100 to 400 nm
• The increase in extravasation is due to cytoskeletal collapse in
the vessel wall (endothelial cell)

23. Delivering
Hyperthermia

24. Modalities of Hyperthermia
Whole body
HT
Deep/regional
HT
Superficial
HT
Interstitial
HT
Body Orifice
insertion HT

26. Methods of Heating
Electromagnetic
heating
Ultrasound
heating
Radiant light
Thermal
conduction

27. Electromagnetic Heating
• Energy field oscillating between Electric &
magnetic potential.

28. EM
Heating
• Superficial heating
Effective penetration of 2
to 5 cm.
• Operate in Microwave
band at 433, 915 and 2450
MHz.
• waveguides, microstrip
or patch antennas
• Deep heating
penetration - >5 cm
• Use lower EM
frequencies in the RF
band 5 to 200 MHz.
Three techniques
 Magnetic induction
 Capacitive coupling
 Phased array fields

29. Superficial Heating
Wave guide applicator

30. Current sheet Applicator

31. Microstrip Applicators
Stanford Blanket

32. Magnetic induction
• Uses a time varying magnetic field to induce eddy currents
in conductive tissue.
• Field distribution - Consistently predictable.
• Eddy current distribution is governed by paths of least
resistance and will be affected by tissue conductivity

33. Capacitive coupling
• Uses RF field - Range of 5 to 30 MHz
• External capacitive heating -Method of electromagnetic
wave heating, in which the tumor is caught and heated
between two opposite applicators.
• Ion currents are driven between 2 or more conductive
electrodes
• Heat tends to be concentrated at electrodes.
• Electrodes make contact with tissue through a saline
pad or bolus.
• Temperature controlled to prevent hot spots on the skin
surface and superficial fat.

34. RF Phased Array Tech
• Consist of an array of RF antennas arranged
in geometric pattern conducive to the body
region that is to be heated.
• Driven from a common RF source
(i.e., coherent/Synchronus) to have fixed
phase relationship among the antennas.
• RF fields add together in a way to form a
null or a focus.
• With focus - one can achieve better
penetration into tissue.
• Antennas are arranged circumferentially in
abdomen and pelvis to allow RF E- fields
parallel to fat muscle interface.

35. Ultrasound
Heating
Acoustic field transfer energy with viscous friction.
• Energy absorption of ultrasound is characterized by the
acoustic absorption coefficient, which increases with frequency.
• Penetration of US field decreases with frequency.
• But, anatomic geometry and tissue heterogeneity (air reflects,
bone preferentially absorbs) severely limit the utility of US.
• Useful in intact breast & non-bony soft tissue sites.

36. • Parallel sets of devices using US radiation.
• Include single transducers and Multiple transducer
devices for superficial tumors (2 to 5 cm) heating .
• Operate in 1 to 3 MHz range
• 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.

37. 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

38. 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.
• Patients with metastatic disease
• Intended for activation of drugs or enhancement of immunologic
response.

39. 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.

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

41. ELECTRODES
OF
VARIOUS
SIZES
DEIONIZED
WATER BOLUS
FOR
ABDOMINAL
&
PELVIC
TUMOURS

42. TEMPERATURE CONTROLLER

43. TEMPERATURE PROBES

44. PHANTOM

45. Thermometry
• Invasive
Thermal mapping or its equivalent
is now a quality assurance requirement
• Current clinical treatments are characterized by sampling
several points within the volume during heating.
• 15 to 30 spatial points are sampled using multiple sensor
probes or by mechanically translating temperature probes
through invasively placed catheters (thermal mapping).

46. Non Invasive Thermometry
(MR thermometry)
• The ability to both monitor
temperature throughout a
volume and obtain useful
morphometric and
functional information from
tumor and normal tissues.
• Principle-PRFS(Proton
Resonant frequency shift)
technique
• It is of value, when deciding
whether a particular tumor is
a good candidate for
hyperthermia

47. Toxicities
1. Thermal burns – generally Grade I
2. Pain
3. Systemic stress

48. Evidence for Hyperthermia

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

50. • 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(82.7
6%)
32/56(57.1
4)
26%(.003)
BLADDER 38/52(67.8
6)
25/49(51.0
2)
22%(.01)
RECTUM 15/72(20.8
3)
11/71(15.4
9)
5.4 %(NS)

51. • 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).
• WHO Performance status was a significant
prognostic factor for local control.
• Hyperthermia did not significantly add to radiation-
induced toxicity compared with RT alone.
Franckena et al; IJROBP 2008

52. • 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

53. Results

54. Chemoradiation with Hyperthermia in
treatment of head and neck cancer
• 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
Nagraj et al Int J Hyperthermia. 2010 Feb

55. 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

56. 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.

57. • Further phase I and II 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.
• No of patients low in these studies
• 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

58. • 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

59. So why Isn`t Everyone offering HT
Depends on whom you talk to
• Administrators Reimbursement rates are too low
personnel demands are too high
• Clinicians Cannot treat all sites
Cannot deliver exact dose
• Physicist Non-uniformity in doses
Difficult/variable thermometry
• Technologists' Difficult to set up & delivery in some
positions
Uncomfortable for some patients.