Hyperthermia

By

Dr Parneet Singh

Max Hospital ,Saket

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

DEFINITION

• 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

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.

• 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.

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 tumoroxygenation

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.

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!

• 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

• 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

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

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.

• 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.

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

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 430C = ∑ t R(43 – Tavg)

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

Factors Modifying Thermal IsodoseEffect

• 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 thermotoleranceinduction is at least partially inhibited.

• Step down heating occurs when temperatures rises above breakpoint and then drop below breakpoint for remainder of a treatment

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 tumorintracellular pH, such as glucose combined with the respiratory inhibitors.

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.

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.

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)

DeliveringHyperthermia

Modalities of Hyperthermia

Whole body HT

Deep/regional HT

Superficial

HT

Interstitial

HT

Body Orifice insertion HT

Methods of Heating

Electromagnetic heating

Ultrasound heating

Radiant lightThermal

conduction

Electromagnetic Heating

• Energy field oscillating between Electric & magnetic potential.

EM Heating

• Superficial heating

Effective penetration of 2 to 5 cm.

• Operate in Microwave band at 433, 915 and 2450 MHz.

• waveguides, microstripor 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

Superficial Heating

Wave guide applicator

Current sheet Applicator

Microstrip ApplicatorsStanford Blanket

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

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.

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.

UltrasoundHeating

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.

• 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.

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 geometryHeating near the Electrodes causes treatment limiting pain

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.

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.

IRATHERM -2000

• Use special water-filtered infrared radiators ,resulting in an infrared spectrum near to visible light.

• Penetration depth is slightly higher.

ELECTRODES

OF

VARIOUS SIZES

DEIONIZED WATER BOLUS

FOR ABDOMINAL

&

PELVIC

TUMOURS

TEMPERATURE CONTROLLER

TEMPERATURE PROBES

PHANTOM

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).

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

Toxicities

1. Thermal burns – generally Grade I

2. Pain

3. Systemic stress

Evidence for Hyperthermia

• 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

• 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./PVALUE

CERVIX 48/58(82.76%)

32/56(57.14)

26%(.003)

BLADDER 38/52(67.86)

25/49(51.02)

22%(.01)

RECTUM 15/72(20.83)

11/71(15.49)

5.4 %(NS)

• 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

• 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

Results

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

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

Conclusions

• Overall CR rate for RT alone was 41% and 59% for RT +HT.

• Greatest effect was observed in patients with reccurentlesions in previously irradiated areas where further irradiation was limited.

• 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

• 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

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.